Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes.

In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure.

As a result of its presence in water as a volatile disinfection byproduct, bromodichloromethane (BDCM), which is mutagenic, poses a potential health risk from exposure via oral, dermal and inhalation routes. We developed a refined human physiologically based pharmacokinetic (PBPK) model for BDCM (including new chemical-specific human parameters) to evaluate the impact of BDCM exposure during showering and bathing on important measures of internal dose compared with oral exposure. The refined model adequately predicted data from the published literature for oral, dermal and bathing/showering exposures. A liter equivalency approach (L-eq) was used to estimate BDCM concentration in a liter of water consumed by the oral route that would be required to produce the same internal dose of BDCM resulting from a 20-min bath or a 10-min shower in water containing 10 µg l(-1) BDCM. The oral liter equivalent concentrations for the bathing scenario were 605, 803 and 5 µg l(-1) BDCM for maximum venous blood concentration (Cmax), the area under the curve (AUCv) and the amount metabolized in the liver per hour (MBDCM), respectively. For a 10-min showering exposure, the oral L-eq concentrations were 282, 312 and 2.1 µg l(-1) for Cmax, AUC and MBDCM, respectively. These results demonstrate large contributions of dermal and inhalation exposure routes to the internal dose of parent chemical reaching the systemic circulation, which could be transformed to mutagenic metabolites in extrahepatic target tissues. Thus, consideration of the contribution of multiple routes of exposure when evaluating risks from water-borne BDCM is needed, and this refined human model will facilitate improved assessment of internal doses from real-world exposures. Published 2015. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Comparison of pharmacokinetics and milk elimination of flunixin in healthy cows and cows with mastitis.

OBJECTIVE: To determine whether pharmacokinetics and milk elimination of flunixin and 5-hydroxy flunixin differed between healthy and mastitic cows. DESIGN: Prospective controlled clinical trial. ANIMALS: 20 lactating Holstein cows. PROCEDURES: Cows with mastitis and matched control cows received flunixin IV, ceftiofur IM, and cephapirin or ceftiofur, intramammary. Blood samples were collected before (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours after flunixin administration. Composite milk samples were collected at 0, 2, 12, 24, 36, 48, 60, 72, 84, and 96 hours. Plasma and milk samples were analyzed by use of ultra-high-performance liquid chromatography with mass spectrometric detection. RESULTS: For flunixin in plasma samples, differences in area under the concentration-time curve and clearance were detected between groups. Differences in flunixin and 5-hydroxy flunixin concentrations in milk were detected at various time points. At 36 hours after flunixin administration (milk withdrawal time), 8 cows with mastitis had 5-hydroxy flunixin concentrations higher than the tolerance limit (ie, residues). Flunixin residues persisted in milk up to 60 hours after administration in 3 of 10 mastitic cows. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics and elimination of flunixin and 5-hydroxy flunixin in milk differed between mastitic and healthy cows, resulting in violative residues. This may partially explain the high number of flunixin residues reported in beef and dairy cattle. This study also raised questions as to whether healthy animals should be used when determining withdrawal times for meat and milk.

Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus).

Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg(-1)) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted that extravascular routes of administration prolonged flunixin concentrations in milk, which could result in violative milk residues in treated cattle.

Pharmacokinetics and tissue elimination of tulathromycin following subcutaneous administration in meat goats.

OBJECTIVE: To determine the tissue depletion profile of tulathromycin and determine an appropriate slaughter withdrawal interval in meat goats after multiple SC injections of the drug. ANIMALS: 16 healthy Boer goats. PROCEDURES: All goats were administered tulathromycin (2.5 mg/kg, SC) twice, with a 7-day interval between doses. Blood samples were collected throughout the study, and goats were euthanized at 2, 5, 10, and 20 days after the second tulathromycin dose. Lung, liver, kidney, fat, and muscle tissues were collected. Concentrations of tulathromycin in plasma and the hydrolytic tulathromycin fragment CP-60,300 in tissue samples were determined with ultrahigh-pressure liquid chromatography-tandem mass spectrometry. RESULTS: The plasma profile of tulathromycin was biphasic. Absorption was very rapid, with maximum drug concentrations (1.00 ± 0.42 µg/mL and 2.09 ± 1.77 µg/mL following the first and second doses, respectively) detected within approximately 1 hour after injection. Plasma terminal elimination half-life of tulathromycin was 61.4 ± 14.1 hours after the second dose. Half-lives in tissue ranged from 2.4 days for muscle to 9.0 days for lung tissue; kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of the tissue tolerance limit in cattle of 5 ppm (µg/g), the calculated withdrawal interval for tulathromycin would be 19 days following SC administration in goats. On the basis of the more stringent guidelines recommended by the FDA, the calculated meat withdrawal interval following tulathromycin administration in goats was 34 days.

In vitro biodistribution of silver nanoparticles in isolated perfused porcine skin flaps.

Nanomaterials increasingly are playing a role in society for uses ranging from biomedicine to microelectronics; however, pharmacokinetic studies, which will be necessary for human health risk assessments, are limited. Currently the most widely used nanoparticle in consumer products is silver (Ag). The objective of the present study was to quantify the local biodistribution of two types of Ag nanoparticles, Ag-citrate and Ag-silica, in the isolated perfused porcine skin flap (IPPSF). IPPSFs were perfused for 4 h with 0.84 µg ml(-1) Ag-citrate or 0.48 µg ml(-1) Ag-silica followed by a 4-h perfusion with media only during a washout phase. Arterial and venous concentrations of Ag were measured in the media by inductively coupled plasma optical emission spectrometry (ICP-OES). Venous concentrations of Ag for both types of nanoparticles were best fit with a two compartment model. The normalized volumes of distribution estimated from the noncompartmental analysis of the venous concentrations indicated distribution of Ag greater than the vascular space; however, because total Ag was measured, the extravascular distribution could be attributed to diffusion of Ag ions. The estimated clearance for both types of Ag nanoparticles was 1 ml min(-1) , which was equal to the flap perfusion rate, indicating no detectable elimination of Ag from the system. Four hours after infusion of the Ag nanoparticles, the recovery of Ag in the venous effluent was 90 ± 5.0% and 87 ± 22% of the infused Ag for Ag-citrate and Ag-silica, respectively.

Acute vascular effects of nanoparticle infusion in isolated perfused skin.

The majority of studies on the effect of nanomaterials on biological function involves either isolated in vitro cell systems or are concerned with in vivo effects after inhalational or dermal exposure. The current work reports on an intriguing observation of the vascular effects seen in an ex vivo perfused tissue preparation, the isolated perfused porcine skin flap (IPPSF), in studies conducted to assess nanomaterial biodistribution. Compared with a relatively large dataset involving organic chemical infusions (n = 53), infusion of six different nanoparticles of diverse sizes and composition (silica or dextran coated Fe(2)O(3), silica or citrate coated silver, PEG or carboxylated quantum dots [QD]) resulted in statistically significant post-infusion flap weight gain and an increase in arterial perfusion pressure (especially with QD-PEG). In contrast, infusion with nC(60) nanoparticles did not produce these effects. These observations suggest certain nanoparticle infusions may be associated with acute vascular physiologic effects that merit further attention. FROM THE CLINICAL EDITOR: In this study utilizing a perfused porcine skin flap, specific nanoparticle infusions were demonstrated to be associated with significant acute vascular physiological effects.

The Toxicology Education Summit: building the future of toxicology through education.

Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the "Total Toxicologist"; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives.

Pharmacokinetics of tulathromycin following subcutaneous administration in meat goats.

Tulathromycin is a triamilide antibiotic that maintains therapeutic concentrations for an extended period of time. The drug is approved for the treatment of respiratory disease in cattle and swine and is occasionally used in goats. To investigate the pharmacokinetics of tulathromycin in meat goats, 10 healthy Boer goats were administered a single 2.5 mg/kg subcutaneous dose of tulathromycin. Plasma concentrations were measured by ultra-high pressure liquid chromatography tandem mass spectrometry (UPLC-MS/MS) detection. Plasma maximal drug concentration (Cmax) was 633 ± 300 ng/ml (0.40 ± 0.26 h post-subcutaneous injection). The half-life of tulathromycin in goats was 110 ± 19.9 h. Tulathromycin was rapidly absorbed and distributed widely after subcutaneous injection 33 ± 6 L/kg. The mean AUC of the group was 12,500 ± 2020 h ng/mL for plasma. In this study, it was determined that the pharmacokinetics of tulathromycin after a single 2.5 mg/kg SC injection in goats were very similar to what has been previously reported in cattle.

Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation.

There are a number of cancer and toxicity studies that have been carried out to assess hazard from methyl tertiary-butyl ether (MTBE) exposure via inhalation and oral administration. MTBE has been detected in surface as well as ground water supplies which emphasized the need to assess the risk from exposure via drinking water contamination. This model can now be used to evaluate route-to-route extrapolation issues concerning MTBE exposures but also as a means of comparing potential dose metrics that may provide insight to differences in biological responses observed in rats following different routes of MTBE exposure. Recently an updated rat physiologically based pharmacokinetic (PBPK) model was published that relied on a description of MTBE and its metabolite tertiary-butyl alcohol (TBA) binding to alpha 2u-globulin, a male rat-specific protein. This model was used to predict concentrations of MTBE and TBA in the kidney, a target tissue in the male rat. The objective of this study was to use this model to evaluate the dosimetry of MTBE and TBA in rats following different exposure scenarios, used to evaluate the toxicity and carcinogenicity of MTBE, and compare various dose metrics under these different conditions. Model simulations suggested that although inhalation and drinking water exposures show a similar pattern of MTBE and TBA exposure in the blood and kidney (i.e. concentration-time profiles), the total blood and kidney levels following exposure of MTBE to 7.5mg/ml MTBE in the drinking water for 90 days is in the same range as administration of an oral dose of 1000 mg/kg MTBE. Evaluation of the dose metrics also supports that a high oral bolus dose (i.e. 1000 mg/kg MTBE) results in a greater percentage of the dose exhaled as MTBE with a lower percent metabolized to TBA as compared to dose of MTBE that is delivered over a longer period of time as in the case of drinking water.

Evaluation of perfused porcine skin as a model system to quantitate tissue distribution of fullerene nanoparticles.

Nanomaterials are increasingly playing a role in society for uses ranging from biomedicine to microelectronics, however pharmacokinetic studies, which will be necessary for human health risk assessments, are limited. Tissue distribution, one component of pharmacokinetics, can be assessed by quantifying arterial extraction of materials in an isolated perfused porcine skin flap (IPPSF). The objective of this study was to assess the IPPSF as a model system to quantitate the distribution of fullerene nanoparticles (nC(60)) from the vascular space into tissues. IPPSFs were perfused for 4h with 0.885 microg/mL nC(60) in media with immunoglobulin G present (IgG(+)) or absent (IgG(-)) followed by a 4h perfusion with media only during a washout phase. Arterial and venous concentrations of nC(60) were measured in the media by HPLC-UV/vis chromatography. Steady state differences in the arterial and venous nC(60) concentrations were compared to determine extraction from the vascular space of the IPPSF, and the venous nC(60) concentration versus time profiles were used to calculate compartmental pharmacokinetic parameters. The steady state differences in the arterial and venous concentrations in the IPPSF were small with extraction percentages (mean+/-sd) of 8.2+/-5.7% and 4.2+/-6.7% for IgG(+) and IgG(-) media, respectively, and were not significantly different between the types of media. The venous concentrations of nC(60) in both types of media were best fit with a 2 compartment model with terminal half lives (harmonic mean) of 17.5 and 28.0 min for IgG(+) and IgG(-) media, respectively. The apparent volumes of distribution at steady state were 0.12+/-0.047 and 0.10+/-0.034 L/kg, for IgG(+) and IgG(-) media, respectively. By 4 h following infusion of nC(60), the recovery of nC(60) in the venous effluent was 94+/-5.5% and 97+/-6.8% of the infused nC(60) for IgG(+) and IgG(-) media, respectively. Based on the apparent volume of distribution, the low extraction during the perfusion, and the high percentage recovery following the washout phase, there was limited distribution of nC(60) from the vascular space into the extracellular space and negligible intracellular uptake of nC(60) in this system.

Pharmacokinetics of radiolabeled tungsten ((188)W) in male Sprague-Dawley rats following acute sodium tungstate inhalation.

Aerosol cloud formation may occur when certain tungsten munitions strike hard targets, placing military personnel at increased risk of exposure. Although the pharmacokinetics of various forms of tungsten have been studied in animals following intravenous and oral administration, tungsten disposition following inhalation remains incompletely characterized. The objective of this study was to evaluate the pharmacokinetics of inhaled tungstate (WO(4)) in rats. Male, 16-wk-old, CD rats (n = 7 rats/time point) underwent a single, 90-min, nose-only exposure to an aerosol (mass median aerodynamic diameter [MMAD] 1.50 mum ) containing 256 mg W/m(3) as radiolabeled sodium tungstate (Na(2)(188)WO(4)). (188)W tissue concentrations were determined at 0, 1, 3, 7, and 21 days postexposure by gamma spectrometry. The thyroid and urine had the highest (188)W levels postexposure, and urinary excretion was the primary route of (188)W elimination. The pharmacokinetics of tungsten in most tissues was best described with a two-compartment pharmacokinetic model with initial phase half-lives of approximately 4 to 6 h and a longer terminal phase with half-lives of approximately 6 to 67 days. The kidney, adrenal, spleen, femur, lymph nodes, and brain continued to accumulate small amounts of tungsten as reflected by tissue:blood activity ratios that increased throughout the 21-day period. At day 21 all tissues except the thyroid, urine, lung, femur, and spleen had only trace levels of (188)W. Data from this study can be used for development and refinement of pharmacokinetic models for tungsten inhalation exposure in environmental and occupational settings.

Acute sodium tungstate inhalation is associated with minimal olfactory transport of tungsten (188W) to the rat brain.

Olfactory transport of represents an important mechanism for direct delivery of certain metals to the central nervous system (CNS). The objective of this study was to determine whether inhaled tungsten (W) undergoes olfactory uptake and transport to the rat brain. Male, 16-week-old, Sprague-Dawley rats underwent a single, 90-min, nose-only exposure to a Na(2)(188)WO(4) aerosol (256 mg W/m(3)). Rats had the right nostril plugged to prevent nasal deposition of (188)W on the occluded side. The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 3, 7, and 21 days post-exposure. Gamma spectrometry (n=7 rats/time point) was used to compare the levels of (188)W found on the left and right sides of the nose and brain and blood to determine the contribution of olfactory uptake to brain (188)W levels. Respiratory and olfactory epithelial samples from the side with the occluded nostril had significantly lower end-of-exposure (188)W levels confirming the occlusion procedure. Olfactory bulb, olfactory tract/tubercle, striatum, cerebellum, rest of brain (188)W levels paralleled blood (188)W concentrations at approximately 2-3% of measured blood levels. Brain (188)W concentrations were highest immediately following exposure, and returned to near background concentrations within 3 days. A statistically significant difference in olfactory bulb (188)W concentration was seen at 3 days post-exposure. At this time, (188)W concentrations in the olfactory bulb from the side ipsilateral to the unoccluded nostril were approximately 4-fold higher than those seen in the contralateral olfactory bulb. Our data suggest that the concentration of (188)W in the olfactory bulb remained low throughout the experiment, i.e., approximately 1-3% of the amount of tungsten seen in the olfactory epithelium suggesting that olfactory transport plays a minimal role in delivering tungsten to the rat brain.

Physiologically based pharmacokinetic model of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to alpha2u-globulin.

Current physiologically based pharmacokinetic (PBPK) models for the fuel additive methyl tertiary butyl ether (MTBE) and its metabolite tertiary butyl alcohol (TBA) have not included a mechanism for chemical binding to the male rat-specific protein alpha2u-globulin, which has been postulated to be responsible for renal effects in male rats observed in toxicity and carcinogenicity studies with MTBE. The objective of this work was to expand the previously published models for MTBE to include binding to alpha2u-globulin in the kidney of male rats. In the model, metabolism of MTBE was assumed to occur only in the liver via two saturable pathways. TBA metabolism was assumed to occur only in the liver via one saturable, low-affinity pathway and to be inducible following repeated exposures. The binding of MTBE and TBA to alpha2u-globulin was modeled as saturable and competitive and was assumed to only affect the rate of hydrolysis of alpha2u-globulin in the kidney. The developed model characterized the differences in kidney concentrations of MTBE and TBA in male versus female rats from inhalation exposures to MTBE, as well as the observed changes in blood and tissue concentrations from repeated exposure to TBA. The model-predicted binding affinity of MTBE to alpha2u-globulin was greater than TBA, and the hydrolysis rate of chemically bound alpha2u-globulin was approximately 30% of the unbound protein. This PBPK model supports the role of MTBE and TBA binding to the male rat-specific protein alpha2u-globulin as essential for predicting concentrations of these chemicals in the kidney following exposure.

Comparison of quantum dot biodistribution with a blood-flow-limited physiologically based pharmacokinetic model.

A physiologically based pharmacokinetic model with partition coefficients estimated from quantum dot (QD) 705 biodistribution was compared with the biodistribution of other QDs in mice and rats to determine the model's predictive ability across QD types, species, and exposure routes. The model predicted the experimentally observed persistence of QDs in tissues but not early time profiles or different QD biodistribution. Therefore, more complex models will be needed to better predict QD biodistribution in vivo.

Disposition of bromodichloromethane in humans following oral and dermal exposure.

Exposure to bromodichloromethane (BDCM), one of the most prevalent disinfection byproducts in drinking water, can occur via ingestion of water and by dermal absorption and inhalation during activities such as bathing and showering. The objectives of this research were to assess BDCM pharmacokinetics in human volunteers exposed percutaneously and orally to (13)C-BDCM and to evaluate factors that could affect disposition of BDCM. Among study subjects, CYP2E1 activity varied fourfold; 20% had the glutathione S-transferase theta 1-1 homozygous null genotype; and body fat ranged from 7 to 22%. Subjects were exposed to (13)C-BDCM in water (target concentration of 36 mug/l) via ingestion and by forearm submersion. Blood was collected for up to 24 h and analyzed for (13)C-BDCM by solid-phase microextraction and high-resolution GC-MS. Urine was collected before and after exposure for mutagenicity determinations in Salmonella. After ingestion (mean dose = 146 ng/kg), blood (13)C-BDCM concentrations peaked and declined rapidly, returning to levels near or below the limit of detection (LOD) within 4 h. The T(max) for the oral exposure ranged from 5 to 30 min, and the C(max) ranged from 0.4 to 4.1 ng/l. After the 1 h dermal exposure (estimated mean dose = 155 ng/kg), blood concentrations of (13)C-BDCM ranged from 39 to 170 ng/l and decreased to levels near or below the LOD by 24 h. Peak postdose urine mutagenicity levels that were at least twice that of the predose mean level occurred in 6 of 10 percutaneously exposed subjects and 3 of 8 orally exposed subjects. These results demonstrate a highly significant contribution of dermal absorption to circulating levels of BDCM and confirm the much lower oral contribution, indicating that water uses involving dermal contact can lead to much greater systemic BDCM doses than water ingestion. These data will facilitate development and validation of physiologically based pharmacokinetic models for BDCM in humans.

Evaluating transport of manganese from olfactory mucosa to striatum by pharmacokinetic modeling.

Increased brain manganese (Mn) following inhalation can result from direct transport via olfactory neurons and blood delivery. Human health risk assessments for Mn should consider the relative importance of these pathways. The objective of this study was to develop a pharmacokinetic model describing the olfactory transport and blood delivery of Mn in rats following acute MnCl(2) or MnHPO(4) inhalation. Model compartments included the olfactory mucosa (OM), olfactory bulb, olfactory tract and tubercle, and striatum. Intercompartmental transport of Mn was described as ipsilateral, anterograde movement to deeper brain regions. Each compartment contained free and bound Mn and included blood influx and efflux. First-order rate constants were used to describe transport. Model parameters were estimated by comparing the model with published experimental data in rats exposed by inhalation to (54)MnCl(2) or (54)MnHPO(4) with both nostrils patent or one nostril occluded. The model-derived elimination rate constant from the OM was higher for the chloride salt (0.022 per hour) compared with the phosphate salt (0.011 per hour), consistent with their relative solubilities. Rate constants for Mn transport among the other compartments were similar for both Mn forms. Our results indicate that direct olfactory transport provided the majority of Mn tracer in the olfactory regions during the 21 days following exposure to (54)MnHPO(4) and 8 days following exposure to (54)MnCl(2). Only a small fraction of Mn tracer from the tract and tubercle was predicted to be delivered to the striatum, 3 and 0.1% following (54)MnHPO(4) or (54)MnCl(2) exposure, respectively.

Respiration in Sprague-Dawley rats during pregnancy.

Minute ventilation and tidal volume increase in humans during pregnancy. Little data exists, however, on the respiration in pregnant rats, despite their widespread use as an animal model. Since respiration will affect the pharmacokinetics of volatile compounds and ultimately the dose to the fetus, we conducted a study to evaluate respiration in rats during pregnancy. Whole-body plethysmography was used to measure the breathing frequency and tidal volume approximately every other day from gestation day (GD) 1 to 21 in 16 timed pregnant and 16 nonpregnant, female, Sprague-Dawley rats. Minute ventilation was calculated as a product of the breathing frequency and tidal volume, and the body weight of each rat was used to determine the scaled ventilation. Multivariate analysis of variance methods for a repeated-measures design were used to analyze the respiratory data. Breathing frequency was not affected by pregnancy; however, tidal volume was somewhat greater in pregnant versus nonpregnant rats. The increase in tidal volume resulted in significantly increased minute ventilation in pregnant rats compared to nonpregnant rats during the latter period of gestation. Due to the increased body weight of the pregnant rats, the scaled ventilation at the end of gestation was significantly lower in pregnant rats compared to nonpregnant rats. This study provides important reference values that can be used in pharmacokinetic models during pregnancy.

Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers.

Methyl tertiary butyl ether (MTBE), a gasoline additive used to increase octane and reduce carbon monoxide emissions and ozone precursors, has contaminated drinking water and can lead to exposure by oral, inhalation, and dermal routes. To determine its dermal, oral, and inhalation kinetics, 14 volunteers were exposed to 51.3 microg/ml MTBE dermally in tap water for 1 h, drank 2.8 mg MTBE in 250 ml Gatorade(R), and inhaled 3.1 ppm. MTBE for 1 h. Blood and exhaled breath samples were then obtained. Blood MTBE peaked between 15 and 30 min following oral exposure, at the end of inhalation exposure, and ~5 min after dermal exposure. Elimination by each route was described well by a three-compartment model (Rsq >0.9). The Akaike Information Criterion for the three-compartment model was smaller than the two-compartment model, supporting it over the two-compartment model. One metabolite, tertiary butyl alcohol (TBA), measured in blood slowly increased and plateaued, but it did not return to the pre-exposure baseline at the 24-h follow-up. TBA is very water-soluble and has a blood:air partition ratio of 462, reducing elimination by exhalation. Oral exposure resulted in a significantly greater MTBE metabolism into TBA than by other routes based on a greater blood TBA:MTBE AUC ratio, implying significant first-pass metabolism. The slower TBA elimination may make it a better biomarker of MTBE exposure, though one must consider the exposure route when estimating MTBE exposure from TBA because of first-pass metabolism. Most subjects had a baseline blood TBA of 1-3 ppb. Because TBA is found in consumer products and can be used as a fuel additive, it is not a definitive marker of MTBE exposure. These data provide the risk assessment process of pharmacokinetic information relevant to the media through which most exposures occur-air and drinking water.

Lack of antiandrogenic effects in adult male rats following acute exposure to 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE).

Although the insecticide dichlorodiphenyltrichloroethane (DDT) was banned in the US in 1972, DDT and its major metabolite 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE) are still persistent in the environment. DDE at high doses is antiandrogenic in fetal and adult rats and, therefore, is of concern in humans exposed environmentally. The objective of this work was to determine the dose-response relationship between DDE and its antiandrogenic effect in adult, male rats and to quantitate the concentration of DDE in tissues following oral exposures. Adult, male, Long-Evans rats (11-13 weeks) were castrated, implanted with testosterone capsules, and dosed by oral gavage with 0, 5, 12.5, 25, 50, or 100 mg DDE per kg body weight (BW) per day in corn oil for 4 days. On day 5 the rats were euthanized and liver, adrenals, ventral prostate, and seminal vesicles were weighed as a measure of response to DDE exposure. Blood, adrenals, brain, fat, kidney, lung, liver, muscle, ventral prostate, seminal vesicles, and skin were analyzed for DDE concentrations. Testosterone and dihydrotestosterone were measured in serum. There was a decrease in prostate weight that was not dose dependent; only the prostate weights in rats treated with 12.5 mg DDE per kg BW per day were reduced significantly compared to controls. The liver displayed a dose-dependent increase in weight that was significantly greater than control at DDE doses of 25, 50, and 100 mg/kg BW per day. Blood concentrations of DDE ranged from 0.32 to 11.3 ppm, while tissue concentrations ranged from 0.72 to 2620 ppm with the highest concentration in fat. Although DDE concentrations in the androgen-responsive tissues were higher than concentrations previously shown in vitro to inhibit androgen-receptor transcriptional activity, these concentrations did not appear to be antiandrogenic in vivo. The doses administered to the rats in this study are at least 10(5)-fold greater than the daily, average of human dietary intake of DDE.