TY - JOUR AB - Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs. AU - Danielsen, P.H.* AU - Knudsen, K.B.* AU - Štrancar, J.* AU - Umek, P.* AU - Koklič, T.* AU - Garvas, M.* AU - Vanhala, E.* AU - Savukoski, S.* AU - Ding, Y. AU - Madsen, A.M.* AU - Jacobsen, N.R.* AU - Weydahl, I.K.* AU - Berthing, T.* AU - Poulsen, S.S.* AU - Schmid, O. AU - Wolff, H.* AU - Vogel, U.* C1 - 57626 C2 - 47943 CY - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa TI - Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice. JO - Toxicol. Appl. Pharmacol. VL - 386 PB - Academic Press Inc Elsevier Science PY - 2020 SN - 0041-008X ER - TY - JOUR AB - The biokinetics of inhaled nanoparticles (NP) is more complex than that of larger particles since NP may NP deposited on the nasal mucosa of the upper respiratory tract (URT) may translocate to the olfactory bulb of the brain and also via the trigeminus (URT neuronal route); and (b) NP deposited in the lower respiratory tract (LRT) may cross the ABB into blood and enter the brain across the blood-brain-barrier (BBB) or take a neuronal route from enervated tracheo-bronchial epithelia via the vagus nerve. Translocation from both - the URT and the LRT - are quantified during the first 24h after a 1-hour aerosol inhalation of 20nm-sized, (192)Ir radiolabeled iridium NP by healthy adult rats using differential exposures: (I) nose-only exposure of the entire respiratory tract or (II) intratracheal (IT) inhalation of intubated and ventilated rats, thereby bypassing the URT and extrathoracic nasal passages. After nose-only exposure brain accumulation (BrAcc) is significantly nine-fold higher than after IT inhalation since the former results from both pathways (a+b) while the latter exposure comes only from pathway (b). Interestingly, there are significantly more circulating NP in blood 24h after nose-only inhalation than after IT inhalation. Distinguishing translocation from URT versus LRT estimated from the differential inhalation exposures, the former is significantly higher (8-fold) than from the LRT. Although the BrAcc fraction is rather low compared to total NP deposition after this short-term exposure, this study proofs that inhaled insoluble NP can accumulate in the brain from both - URT and LRT which may trigger and/or modulate adverse health effects in the central nervous system (CNS) during chronic exposure. AU - Kreyling, W.G. C1 - 47883 C2 - 39695 CY - San Diego SP - 41-46 TI - Discovery of unique and ENM-specific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats. JO - Toxicol. Appl. Pharmacol. VL - 299 PB - Academic Press Inc Elsevier Science PY - 2016 SN - 0041-008X ER - TY - JOUR AB - Ketamine is an anesthetic and analgesic regularly used in veterinary patients. As ketamine is almost always administered in combination with other drugs, interactions between ketamine and other drugs bear the risk of either adverse effects or diminished efficacy. Since cytochrome P450 enzymes (CYPs) play a pivotal role in the phase I metabolism of the majority of all marketed drugs, drug-drug interactions often occur at the active site of these enzymes. CYPs have been thoroughly examined in humans and laboratory animals, but little is known about equine CYPs. The characterization of equine CYPs is essential for a better understanding of drug metabolism in horses. We report annotation, cloning and heterologous expression of the equine CYP2B6 in V79 Chinese hamster fibroblasts. After computational annotation of all CYP2B genes, the coding sequence (CDS) of equine CYP2B6 was amplified by RT-PCR from horse liver total RNA and revealed an amino acid sequence identity of 77% and a similarity of 93.7% to its human ortholog. A non-synonymous variant c.226G>A in exon 2 of the equine CYP2B6 was detected in 97 horses. The mutant A-allele showed an allele frequency of 82%. Two further variants in exon 3 were detected in one and two horses of this group, respectively. Transfected V79 cells were incubated with racemic ketamine and norketamine as probe substrates to determine metabolic activity. The recombinant equine CYP2B6 N-demethylated ketamine to norketamine and produced metabolites of norketamine, such as hydroxylated norketamines and 5,6-dehydronorketamine. V(max) for S-/and R-norketamine formation was 0.49 and 0.45nmol/h/mg cellular protein and K(m) was 3.41 and 2.66μM, respectively. The N-demethylation of S-/R-ketamine was inhibited concentration-dependently with clopidogrel showing an IC(50) of 5.63 and 6.26μM, respectively. The functional importance of the recorded genetic variants remains to be explored. Equine CYP2B6 was determined to be a CYP enzyme involved in ketamine and norketamine metabolism, thus confirming results from inhibition studies with horse liver microsomes. Clopidogrel seems to be a feasible inhibitor for equine CYP2B6. The specificity still needs to be established with other single equine CYPs. Heterologous expression of single equine CYP enzymes opens new possibilities to substantially improve the understanding of drug metabolism and drug interactions in horses. AU - Peters, L.M.* AU - Demmel, S.* AU - Pusch, G. AU - Buters, J.T.M. AU - Thormann, W.* AU - Zielinski, J.* AU - Leeb, T.* AU - Mevissen, M.* AU - Schmitz, A.* C1 - 11278 C2 - 30581 SP - 101-108 TI - Equine cytochrome P450 2B6 - genomic identification, expression and functional characterization with ketamine. JO - Toxicol. Appl. Pharmacol. VL - 266 IS - 1 PB - Elsevier PY - 2013 SN - 0041-008X ER - TY - JOUR AB - The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61 y) who ingested a single dose (645 +/- 20 mu g/kg body weight) of ring-deuterated DEHP (DEHP-D-4). Concentrations of DEHP-D-4, of free ring-deuterated MEHP (MEHP-D-4), and the sum of free and glucuronidated MEHP-D-4 were measured in blood for up to 24 h; amounts of the monoesters MEHP-D-4, ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46 h after ingestion. The bioavailability of DEHP-D-4 was surprisingly high with an area under the concentration-time curve until 24 h (AUC) amounting to 50% of that of free MEHP-D-4. The AUC of free MEHP-D-4 normalized to DEHP-D-4 dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D-4 even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6 h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D-4 in blood, the parameter regarded as relevant for risk assessment. AU - Kessler, W. AU - Numtip, W. AU - Völkel, W.* AU - Seckin, E.* AU - Csanády, G.A. AU - Pütz, C. AU - Klein, D. AU - Fromme, H.* AU - Filser, J.G. C1 - 10875 C2 - 30439 SP - 284-291 TI - Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP. JO - Toxicol. Appl. Pharmacol. VL - 264 IS - 2 PB - Elsevier Science PY - 2012 SN - 0041-008X ER - TY - JOUR AB - Poly(ethylene imine) (PEI) has widely been used as non-viral gene carrier due to its capability to form stable complexes by electrostatic interactions with nucleic acids. To reduce cytotoxicity of PEI, several studies have addressed modified PEIs such as block or graft copolymers containing cationic and hydrophilic non-ionic components. Copolymers of PEI and hydrophilic poly(ethylene glycol) (PEG) with various molecular weights and graft densities were shown to exhibit decreased cytotoxicity and potential for DNA and siRNA delivery. In this study, we evaluated the cytotoxicity and cell-compatibility of different PEGylated PEI polymers in two murine lung cell lines. We found that the degree of PEGylation correlated with both cytotoxicity and oxidative stress, but not with proinflammatory effects. AB type copolymers with long PEG blocks caused high membrane damage and significantly decreased the metabolic activity of lung cells. In addition, they significantly increased the release of two lipid mediators such as 8-isoprostanes (8-IP) and prostaglandin E(2) (PGE(2)) in a dose-dependent manner. In contrast, the cytokine profiles which indicated high levels of acute-phase cytokines such as TNF-alpha, IL-6, and G-CSF did not follow any clear structure-function relationship. In conclusion, we found that modification of PEI 25 kDa with high degree of PEGylation and low PEG chain length reduced cytotoxic and oxidative stress response in lung cells, while the proinflammatory potential remained unaffected. A degree of substitution in the range of 10 to 30 and PEG-chain lengths up to 2000 Da seem to be beneficial and merit further investigations. AU - Beyerle, A. AU - Merkel, O.* AU - Stöger, T. AU - Kissel, T.* C1 - 5180 C2 - 27611 SP - 146-154 TI - PEGylation affects cytotoxicity and cell-compatibility of poly(ethylene imine) for lung application: Structure-function relationships. JO - Toxicol. Appl. Pharmacol. VL - 242 IS - 2 PB - Elsevier PY - 2010 SN - 0041-008X ER - TY - JOUR AB - The impact of nanoparticles (NPs) in medicine and biology has increased rapidly in recent years. Gold NPs have advantageous properties such as chemical stability, high electron density and affinity to biomolecules, making them very promising candidates as drug carriers and diagnostic tools. However, diverse studies on the toxicity of gold NPs have reported contradictory results. To address this issue, a triple cell co-culture model simulating the alveolar lung epithelium was used and exposed at the air-liquid interface. The cell cultures were exposed to characterized aerosols with 15 nm gold particles (61 ng Au/cm2 and 561 ng Au/cm2 deposition) and incubated for 4 h and 24 h. Experiments were repeated six times. The mRNA induction of pro-inflammatory (TNFalpha, IL-8, iNOS) and oxidative stress markers (HO-1, SOD2) was measured, as well as protein induction of pro- and anti-inflammatory cytokines (IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, TNFalpha, INFgamma). A pre-stimulation with lipopolysaccharide (LPS) was performed to further study the effects of particles under inflammatory conditions. Particle deposition and particle uptake by cells were analyzed by transmission electron microscopy and design-based stereology. A homogeneous deposition was revealed, and particles were found to enter all cell types. No mRNA induction due to particles was observed for all markers. The cell culture system was sensitive to LPS but gold particles did not cause any synergistic or suppressive effects. With this experimental setup, reflecting the physiological conditions more precisely, no adverse effects from gold NPs were observed. However, chronic studies under in vivo conditions are needed to entirely exclude adverse effects. AU - Brandenberger, C.* AU - Rothen-Rutishauser, B.* AU - Mühlfeld, C.* AU - Schmid, O. AU - Ferron, G.A. AU - Maier, K.L. AU - Gehr, P.* AU - Lenz, A.-G. C1 - 1292 C2 - 27075 SP - 56-65 TI - Effects and uptake of gold nanoparticles deposited at the air-liquid interface of a human epithelial airway model. JO - Toxicol. Appl. Pharmacol. VL - 242 IS - 1 PB - Academic Press PY - 2010 SN - 0041-008X ER - TY - JOUR AB - Single-walled carbon nanotubes have gained enormous popularity due to a variety of potential applications which will ultimately lead to increased human and environmental exposure to these nanoparticles. This study was carried out in order to evaluate the inflammatory response of immortalised and primary human lung epithelial cells (A549 and NHBE) to single-walled carbon nanotube samples (SWCNT). Special focus was placed on the mediating role of lung surfactant on particle toxicity. The toxicity of SWCNT dispersed in cell culture medium was compared to that of nanotubes dispersed in dipalmitoylphosphatidylcholine (DPPC, the main component of lung lining fluid). Exposure was carried out for 6 to 48 h with the latter time-point showing the most significant responses. Moreover, exposure was performed in the presence of the pro-inflammatory stimulus tumour necrosis factor-alpha (TNF-alpha) in order to mimic exposure of stimulated cells, as would occur during infection. Endpoints evaluated included cell viability, proliferation and the analysis of inflammatory mediators such as interleukin (IL)-8, IL-6, TNF-alpha and macrophage chemoattractant protein-1 (MCP-1). Crocidolite asbestos was included as a well characterised, toxic fibre control. The results of this study showed that HiPco SWCNT samples suppress inflammatory responses of A549 and NHBE cells. This was also true for TNF-alpha stimulated cells. The use of DPPC improved the degree of SWCNT dispersion in A549 medium and in turn, leads to increased particle toxicity, however, it was not shown to modify NHBE cell responses. AU - Herzog, E.* AU - Byrne, H.J.* AU - Casey, A.* AU - Davoren, M.* AU - Lenz, A.-G. AU - Maier, K.L. AU - Duschl, A.* AU - Oostingh, G.J.* C1 - 1163 C2 - 26066 SP - 378-390 TI - SWCNT suppress inflammatory mediator responses in human lung epithelium in vitro. JO - Toxicol. Appl. Pharmacol. VL - 234 IS - 3 PB - Academic Press Inc Elsevier Science PY - 2009 SN - 0041-008X ER - TY - JOUR AB - Nanoparticles (NPs) are being used within diverse applications such as medicines, clothing, cosmetics and food. In order to promote the safe development of such nanotechnologies it is essential to assess the potential adverse health consequences associated with human exposure. The liver is recognised as a target site for NP toxicity, due to NP accumulation within this organ subsequent to injection, inhalation or instillation. The uptake of fluorescent polystyrene carboxylated particles (20 nm or 200 nm diameter) by hepatocytes was determined using confocal microscopy; with cells imaged "live" during particle exposure or after exposure within fixed cells. Comparisons between the uptake of polystyrene particles by primary rat hepatocytes, and human hepatocyte cell lines (C3A and HepG2) were made. Uptake of particles by hepatocytes was size, time, and serum dependent. Specifically, the uptake of 200 nm particles was limited, but 20 nm NPs were internalised by all cell types from 10 min onwards. At 10 min, 20 nm NP fluorescence co-localised with the tubulin cytoskeleton staining; after 30 min NP fluorescence compartmentalised into structures located within and/or between cells. The fate of internalised NPs was considered and they were not contained within early endosomes or lysosomes, but within mitochondria of cell lines. NPs accumulated within bile canaliculi to a limited extent, which suggests that NPs can be eliminated within bile. This is in keeping with the finding that gold NPs were eliminated in bile following intravenous injection into rats. The findings were, in the main, comparable between primary rat hepatocytes and the different human hepatocyte cell lines. AU - Johnston, H.J.* AU - Semmler-Behnke, M. AU - Brown, D.M.* AU - Kreyling, W.G. AU - Tran, L.* AU - Stone, V.* C1 - 1323 C2 - 26772 SP - 66-78 TI - Evaluating the uptake and intracellular fate of polystyrene nanoparticles by primary and hepatocyte cell lines in vitro. JO - Toxicol. Appl. Pharmacol. VL - 242 IS - 1 PY - 2009 SN - 0041-008X ER - TY - JOUR AB - Reported herein are semi-empirical calculations of the molecular geometry of TCDD, TCPT, TCPT-sulfoxide (TCPT-O), TCPT-sulfone (TCPT-O(2)), N-methyl-TCPT (Me-TCPT), N-methyl-TCPT-sulfoxide (Me-TCPT-O), and N-methyl-TCPT-sulfone (Me-TCPT-O(2)), the characterization of their AhR binding affinity in rat hepatic cytosol, and their ability to induce EROD activity in a rat hepatoma cell line in vitro. Semi-empirical calculations yielded detailed information about the stereochemistry and the preferred conformation of each of these compounds. These results in combination with observations reported in this paper were used to determine structure-activity relationships. In vitro displacement of (3)H-TCDD was measured by increasing concentrations of the respective ligands. This assay revealed a strong binding affinity of TCPT to the AhR with a K(i) value of 1.08 nM. TCDD had a K(i) value of 0.54 nM. The affinity of TCPT derivatives for the AhR decreased with increasing degree of oxidation. Moreover, N-methylation further lowered the affinity, so that the N-methyl sulfone derivative of TCPT displayed the highest K(i) at approximately 1200 nM (=460.4 ng/ml). A corresponding trend was observed regarding the potency of TCPT and derivatives to induce EROD activity in vitro. However, the potencies were considerably lower than that of TCDD. Enzyme induction was measured in a rat hepatoma cell line H4IIEC/T3 by quantification of ethoxyresorufin-O-deethylase (EROD) activity. Induction was measured at 12, 24, 48 and 72 h to determine time dependence. Sulfoxidated and N-methylated phenothiazines displayed a lower potency than their respective parent compounds. TCPT and all derivatives induced enzyme activity at an efficacy similar to TCDD at all time points measured. The reported findings clearly separate the induction of EROD activity by TCPT and derivatives from their binding affinities to the AhR. In contrast, a direct correlation between the two is generally assumed in drug development, leading to - in our view - unwarranted termination of drug candidates. Therefore, a lack of such a correlation for TCPT and derivatives in fact supports their further development as possible drug leads. AU - Fried, K.W.* AU - Bazzi, R.* AU - Levy Lopez, W. AU - Corsten, C. AU - Schramm, K.-W. AU - Bell, D.R.* AU - Rozman, K.K. C1 - 2397 C2 - 24837 SP - 147-155 TI - Relationship between aryl hydrocarbon receptor-affinity and the induction of EROD activity by 2,3,7,8-tetrachlorinated phenothiazine and derivatives. JO - Toxicol. Appl. Pharmacol. VL - 224 IS - 2 PB - Elsevier PY - 2007 SN - 0041-008X ER - TY - JOUR AU - Peters, A. C1 - 1851 C2 - 23115 SP - 477-482 TI - Particulate matter and heart disease: Evidence from epidemiological studies. JO - Toxicol. Appl. Pharmacol. VL - 207 PY - 2005 SN - 0041-008X ER - TY - JOUR AU - Gilmour, P.S.* AU - Ziesenis, A. AU - Morrison, E.R.* AU - Vickers, M.A.* AU - Drost, E.M.* AU - Ford, I.* AU - Karg, E.W. AU - Mossa, C. AU - Schröppel, A. AU - Ferron, G.A. AU - Heyder, J. C1 - 2183 C2 - 22077 SP - 35-44 TI - Pulmonary and systematic effects of short-term inhalation exposure to ultrafine carbon black particles. JO - Toxicol. Appl. Pharmacol. VL - 195 PY - 2004 SN - 0041-008X ER - TY - JOUR AU - Kessler, W. AU - Numtip, W. AU - Grote, K.* AU - Csanády, G.A. AU - Chahoud, I.* AU - Filser, J.G. C1 - 1356 C2 - 22211 SP - 142-153 TI - Blood burden of di(2-ethylhexyl) phthalate and its primary metabolite mono(2-ethylhexyl) phthalate in pregnant and nonpregnant rats and marmosets. JO - Toxicol. Appl. Pharmacol. VL - 195 PY - 2004 SN - 0041-008X ER - TY - JOUR AU - Rozman, K.K. C1 - 4634 C2 - 22234 SP - S.126 TI - Letter to the Editor. JO - Toxicol. Appl. Pharmacol. VL - 195 PY - 2004 SN - 0041-008X ER - TY - JOUR AU - Osterman-Golkar, S.* AU - Czene, K.* AU - Lee, M.S. AU - Faller, T.H. AU - Csanády, G.A. AU - Kessler, W. AU - Perez, H.L.* AU - Filser, J.G. AU - Segerbäck, D.* C1 - 22322 C2 - 21146 SP - 245-254 TI - Dosimetry by means of DNA and hemoglobin adducts in propylene oxide-exposed rats. JO - Toxicol. Appl. Pharmacol. VL - 191 PY - 2003 SN - 0041-008X ER - TY - JOUR AB - Immature Sprague-Dawley rats received daily doses of indole-3-carbinol (I3C, 0-1.5 g/kg/day), 3,3'-diindolymethane (DIM, 0-400 mg/kg/day), tamoxifen (TAM, 0-0.5 mg/kg/day), or vehicle to determine if their antiestrogenic effects occur by the same mechanism and whether I3C's action is mediated by DIM. Follicular development was induced on day 24 of age by equine chorionic gonadotropin (eCG, 5 IU) 1 day after the initial dose. In a hormone replacement study, human chorionic gonadotropin (hCG, 10 IU sc, 48 h post-eCG) was used to mimic a normal preovulatoy luteinizing hormone (LH) surge following treatment with either I3C or TAM. Blood and ovaries were collected throughout follicular development and the number of ova shed was measured on the morning following expected ovulation (72 h post-eCG). I3C but not TAM reduced body weight gain at higher doses after 4 days of dosing. Ovarian weight gain and ovulation were inhibited by both I3C and TAM in a dose-dependent fashion. During the preovulatory period, both I3C and TAM blocked normal LH and follicle-stimulating hormone (FSH) surges and suppressed serum progesterone (P(4)) profoundly without changing circulating levels of estrogen (E(2)). At the time of expected ovulation, serum E(2) was increased in rats receiving I3C or tamoxifen, whereas serum P(4) was dose-dependently decreased. DIM exerted no significant effects on any of the endpoints studied, even at the highest dose, indicating that the antiestrogenic effects of I3C are not mediated by this metabolite of I3C. hCG successfully restored ovarian weight gain and ovulation in TAM-treated rats. However, hCG only partially reversed the blockage of ovulation by I3C, although ovarian weight gain was restored to normal. In summary, both I3C and TAM block ovulation by altering preovulatory concentrations of LH and FSH, but I3C appears to exert its effect(s) by (a) different mechanism(s) of action. I3C seems to act at both the ovarian and hypothalamic levels by mechanisms similar to those seen in TCDD-treated rats, whereas TAM appears to act only on the hypothalamic-pituitary axis as an anti-estrogen. AU - Gao, X.* AU - Petroff, B.K.* AU - Oluola, O.* AU - Georg, G.* AU - Terranova, P.F.* AU - Rozman, K.K. C1 - 23882 C2 - 31382 SP - 179-188 TI - Endocrine disruption by indole-3-carbinol and tamoxifen: Blockage of ovulation. JO - Toxicol. Appl. Pharmacol. VL - 183 IS - 3 PB - Elsevier PY - 2002 SN - 0041-008X ER - TY - JOUR AB - Essential cytoskeletal functions of macrophages are migration, phagocytosis of foreign materials, and intracellular transport and digestion The influence of fine and ultrafine test particles (UFP), such as TiO2, elemental carbon, commercial carbon black, diesel exhaust particulate matter, and urban dust (UrbD), on cytoskeleton-related functions of macrophages, such as phagocytosis, phagosome transport mechanisms, and mechanical cytoskeletal integrity, were studied by flow cytometry and by cytomagnetometry. Additionally, necrosis and apoptosis caused by the test particles was detected. The diameter of the test particles ranged from 12 to 220 nm and the Brunauer-Emmet-Teller specific surface area ranged from 6 to 600 m(2)/g. Primary alveolar macrophages from beagle dogs (BD-AM), obtained by bronchoalveolar lavage, were used as well as macrophages originating from the cell line J774A.1. For cytomagnetometry studies, spherical 1.8-mum ferromagnetic particles served as probes for cytoskeletal functions and were incubated together with the macrophages 24 h prior to UFP exposure. Macrophages were exposed in vitro with 10-320 mug UFP/ml/10(6) cells up to 24 h. In all experiments, J774A.1 macrophages were more sensitive than BD-AM to UFP exposure. Cytoskeletal dysfunctions evaluated by cytomagnetometry were an impaired phagosome transport and an increased cytoskeletal stiffness and occurred at concentrations of 100 mug UFP/ml/106 cells and above, in both BD-AM and J774A.1. Only fine TiO2 did not show any effect. Urban dust (standard reference material 1649a) and diesel exhaust particles (DEP, standard reference material 1650) caused comparable cytoskeletal dysfunctions to elemental carbon with high specific surface area. Cytoskeletal dysfunctions induced by DEP or UrbD could be reduced after washing the particles by dichloromethane. UFP caused an impaired phagocytosis of 1-mum diameter fluorescent latex beads, inhibited cell proliferation, and decreased cell viability. All recorded cytotoxic parameters showed only weak correlations with the specific surface area or the total number of UFP, which can result from the different types of particles and different surface compositions. UFP cause cytoskeletal toxicity in vitro in macrophages, which can cause cellular dysfunctions, such as impaired proliferation, impaired phagocytic activity, and retarded intracellular transport processes as well as increased cell stiffness and can result in impaired defense ability in the lung. AU - Möller, W. AU - Hofer, T.P. AU - Ziesenis, A. AU - Karg, E.W. AU - Heyder, J. C1 - 9845 C2 - 20352 SP - 197-207 TI - Ultrafine Particles Cause Cytoskeletal Dysfunctions in Macrophages. JO - Toxicol. Appl. Pharmacol. VL - 182 PB - Academic Press PY - 2002 SN - 0041-008X ER - TY - JOUR AB - Kinetics of the metabolic inactivation of 1,2-epoxypropane (propylene oxide; PO) catalyzed by glutathione S-transferase (GST) and by epoxide hydrolase (EH) were investigated at 37 degrees C in cytosol and microsomes of liver and lung of B6C3F1 mice, F344 rats, and humans and of respiratory and olfactory nasal mucosa of F344 rats. In all of these tissues, GST and EH activities were detected. GST activity for PO was found in cytosolic fractions exclusively. EH activity for PO could be determined only in microsomes, with the exception of human livers where some cytosolic activity also occurred, representing 1-3% of the corresponding GST activity. For GST, the ratio of the maximum metabolic rate (V(max)) to the apparent Michaelis constant (K(m)) could be quantified for all tissues. In liver and lung, these ratios ranged from 12 (human liver) to 106 microl/min/mg protein (mouse lung). Corresponding values for EH ranged from 4.4 (mouse liver) to 46 (human lung). The lowest V(max) value for EH was found in mouse lung (7.1 nmol/min/mg protein); the highest was found in human liver (80 nmol/min/mg protein). K(m) values for EH-mediated PO hydrolysis in liver and lung ranged from 0.83 (human lung) to 3.7 mmol/L (mouse liver). With respect to liver and lung, the highest V(max)/K(m) ratios were obtained for GST in mouse and for EH in human tissues. GST activities were higher in lung than in liver of mouse and human and were alike in both rat tissues. Species-specific EH activities in lung were similar to those in liver. In rat nasal mucosa, GST and EH activities were much higher than in rat liver. AU - Faller, T.H. AU - Csanády, G.A. AU - Kreuzer, P.E. AU - Baur, C.M.* AU - Filser, J.G. C1 - 23898 C2 - 31395 SP - 62-74 TI - Kinetics of propylene oxide metabolism in microsomes and cytosol of different organs from mouse, rat, and humans. JO - Toxicol. Appl. Pharmacol. VL - 172 IS - 1 PB - Elsevier PY - 2001 SN - 0041-008X ER - TY - JOUR AB - Sprague-Dawley rats (23-day-old) were dosed with TCDD (32 mug/kg) in corn oil or vehicle alone. Equine chorionic gonadotropin (eCG) was injected (5 IU, sc) 24 h later to induce follicular development. Another 24 h later, half of TCDD- or corn oil-treated rats were injected (sc) with 17 beta -estradiol-cypionate (ECP, at 0.004 to 0.5 mg/kg), Blood and ovaries were collected on expected proestrous (preovulatory period) at 51, 54, and 58 h after eCG injection as well as in the morning after ovulation (72 h after eCG), Serum concentrations of 17 beta -estradiol (E), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined by radioimmunoassay, The number of ova shed was measured at 72 h after injection of eCG by irrigating ova from oviducts, During the preovulatory period (similar to 58 h after eCG injection), a circulating level of 70-100 pg E/ml coincided with LH and FSH surges and later normal ovulation of 10 to 12 ova/rat was observed in controls. However, the same concentration of E was not associated with LH and FSH surges in rats treated with TCDD (32 mug/kg), resulting in reduced ovarian weight gain and reduction of ovulation by 70 to 80% (2-3 ova/rat), Blockage of the gonadotropin surge, reduced ovarian weight gain, and ovulation were all reversed completely by the lowest effective dose of ECP (0.1 mg/kg), At 72 h after eCG, serum P secretion was reduced and serum E levels were significantly increased compared to those of corn oil-treated controls. ECP alone had no effect on serum P levels at any time point, but in rats treated with TCDD and ECP, both the reduction of P (at 58 and 72 h) and the increase in E secretion (72 h) were completely reversed. Further studies confirmed that restoration by ECP of gonadotropin surges and associated ovulation could not be attained until circulating levels of E rose sufficiently high to trigger the LH and FSH surges. The new action threshold of E for inducing gonadotropin surges in rats treated with TCDD (32 mug/kg) was determined to be eight- to 10-fold higher than that in controls. Thus, it is apparent that TCDD decreased the responsiveness of the hypothalamus to E as a feedback inducer of preovulatory gonadotropin secretion. AU - Gao, X.* AU - Mizuyachi, K.* AU - Terranova, P.F.* AU - Rozman, K.K. C1 - 21870 C2 - 20086 SP - 181-190 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin decreases responsiveness of the hypothalamus to estradiol as a feedback inducer of preovulatory gonadotropin secretion in the immature gonadotropin- primed rat. JO - Toxicol. Appl. Pharmacol. VL - 170 IS - 3 PB - Academic Press Elsevier PY - 2001 SN - 0041-008X ER - TY - JOUR AU - Csanády, G.A. AU - Denk, B. AU - Pütz, C. AU - Kreuzer, P. AU - Kessler, W. AU - Baur, C.* AU - Gargas, M.L.* AU - Filser, J.G. C1 - 21557 C2 - 19682 SP - 1-26 TI - A Physiological Toxicokinetic Model for Exogenous and Endogenous Ethylene and Ethylene Oxide in Rat, Mouse and Human : Formation of 2-Hydroxyethyl Adducts with Hemoglobin and DNA. JO - Toxicol. Appl. Pharmacol. VL - 165 PY - 2000 SN - 0041-008X ER - TY - JOUR AU - Filser, J.G. AU - Schmidbauer, R. AU - Rampf, F. AU - Baur, C.M.* AU - Pütz, C. AU - Csanády, G.A. C1 - 21556 C2 - 19681 SP - 40-51 TI - Toxicokinetics of Inhaled Propylene in Mouse, Rat and Human. JO - Toxicol. Appl. Pharmacol. VL - 169 PY - 2000 SN - 0041-008X ER - TY - JOUR AU - Gao, X.* AU - Terranova, P.F.* AU - Rozman, K.K. C1 - 21868 C2 - 20088 SP - 115-124 TI - Effects of Polychlorinated Dibenzofurans, Biphenyls and their Mixture with Dibenzo-p-dioxins on Ovaluation in the Gonadotropin-Primed Immature Rat : Support for the Toxic Equivalency Concept. JO - Toxicol. Appl. Pharmacol. VL - 163 PY - 2000 SN - 0041-008X ER - TY - JOUR AU - Gao, X.* AU - Son, D.-S.* AU - Terranova, P.F.* AU - Rozman, K.K. C1 - 21869 C2 - 20087 SP - 107-116 TI - Toxic Equivalency Factors of Polychlorinated Dibenzo-p-dioxins in an Ovaluation Model : Validation of the Toxic Equivalency Concept for One Aspect of Endocrine Disruption. JO - Toxicol. Appl. Pharmacol. VL - 157 PY - 1999 SN - 0041-008X ER - TY - JOUR AU - Roth, W.L. AU - Weber, L.W.D. AU - Stahl, B.U. AU - Rozman, K.K. C1 - 19374 C2 - 12459 SP - 126-137 TI - A Pharmacodynamic Model of Triglyceride Transport and Deposition During Feed Deprivation or after Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Rat. JO - Toxicol. Appl. Pharmacol. VL - 120 PY - 1993 SN - 0041-008X ER - TY - JOUR AB - Four rhesus monkeys were administered various doses of hexachlorobenzene (HCB) po, to achieve widely varying adipose tissue levels. One month later, each animal was provided with a bile duct bypass allowing for interruption of the enterohepatic circulation (EHC). Effects of mineral oil-supplemented diet and/or interruption of the EHC on urinary, biliary, and fecal excretion of HCB and its metabolites were quantified. Urinary excretion of HCB was not affected by mineral oil but was reduced 20 to 60% by interruption of the EHC. Similarly, biliary excretion of HCB was also reduced 25 to 60% by interruption of the EHC and was not altered by mineral oil. Fecal excretion was increased about fivefold by mineral oil, whereas interruption of the EHC had no effect on the amount of HCB in feces. Results demonstrate that interruption of the EHC reduced urinary and biliary excretion of HCB metabolites, whereas mineral oil specifically stimulated intestinal excretion of the parent compound. AU - Rozman, K.K. AU - Rozman, J. AU - Greim, H.A. C1 - 20689 C2 - 13907 SP - 255-261 TI - Stimulation of Nonbiliary, Intestinal Excretion of Hexachlorobenzene in Rhesus Monkeys by Mineral Oil. JO - Toxicol. Appl. Pharmacol. VL - 70 PY - 1993 SN - 0041-008X ER - TY - JOUR AB - 5L cells, dedifferentiated descendents of the rat hepatoma line H4IIEC3, constitute one of the rare continuous lines which are sensitive to the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the present study we investigated the nature of TCDD toxicity in these cells. The following results were obtained: (1) Exposure to 0.1 nM TCDD for 48 hr inhibits the proliferation of 5L cells by more than 50%, as determined by the increase in the number of cells and the amount of DNA per culture. (2) TCDD doubles the amount of protein and the uptake of neutral red per cell during the 48-hr exposure period. (3) TCDD restores neither constitutive levels of tyrosine aminotransferase, a marker of liver-specific functions, nor its inducibility by dexamethasone. (4) The effects of TCDD are reversible when TCDD-containing growth media are replaced by TCDD-free medium. (5) 5L cells grown at 2% of fetal bovine serum are considerably more sensitive to TCDD than those grown at 10% serum. The results indicate that TCDD inhibits the proliferation of 5L cells without retarding the rate of growth or overtly changing the status of differentiation. The dioxin possibly causes unbalanced cell growth by interfering with the action of hormones or factors contained in the growth medium. AU - Göttlicher, M. AU - Wiebel, F.J. C1 - 33975 C2 - 40223 SP - 496-503 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin causes unbalanced growth in 5L rat hepatoma cells. JO - Toxicol. Appl. Pharmacol. VL - 111 IS - 3 PY - 1991 SN - 0041-008X ER - TY - JOUR AU - Rozman, K.K. C1 - 19293 C2 - 12371 SP - 568-569 TI - Letters to the Editor: This letter concerns the article by Howie et al. in Toxicol.Appl.Pharmacol. 105, 254-263 (1990). JO - Toxicol. Appl. Pharmacol. VL - 108 PY - 1991 SN - 0041-008X ER - TY - JOUR AU - Stahl, B.U. AU - Rozman, K.K. C1 - 18233 C2 - 11446 SP - 158-162 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCCD)-Induced Appetite Suppression in the Sprague- Dawley Rat is not a Direct Effect on Feed Intake Regulation in the Brain. JO - Toxicol. Appl. Pharmacol. VL - 106 PY - 1990 SN - 0041-008X ER - TY - JOUR AB - The most striking sign of acute toxicity of TCDD in animals is a progressive reduction of feed intake, accompanied by loss of body weight eventually resulting in death. The mechanism(s) of this voluntary feed refusal is (are) not known but it is generally accepted that both centrally and peripherally (via feedback) acting anorectic agents exert their effect(s) in the hypothalamus. In this study direct administration into the lateral cerebral ventricle of rats resulted in much higher concentrations of TCDD in the hypothalamus and also in other regions of the brain than after a lethal intravenous (iv) injection. While rats injected iv displayed the expected cachectic syndrome, intracerebroventricularly (icv)-dosed animals ate and gained weight normally. These findings preclude the possibility of a direct effect of TCDD on appetite-regulating areas of the brain. Moreover, these results require the assumption that the appetite suppressive effect of TCDD is due to a (feedback) mechanism originating in the periphery. AU - Stahl, B.U.* AU - Rozman, K.K. C1 - 42342 C2 - 0 SP - 158-162 TI - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced appetite suppression in the sprague-dawley rat is not a direct effect on feed intake regulation in the brain. JO - Toxicol. Appl. Pharmacol. VL - 106 IS - 1 PY - 1990 SN - 0041-008X ER - TY - JOUR AB - The uptake of Hg vapor (Hg0) by suspensions of human and BALB-c mouse erythrocytes was studied in a closed exposure system. The formation of catalase-compound-I and thereby the oxidation of Hg0 was initiated by microinfusion of hydrogen peroxide. The degradation of H2O2 by the glutathione (GSH)/GSH peroxidase system was reduced by t-butyl-hydroperoxide (t-BOOH) or by 1-chloro-2,4-dinitrobenzene (CDNB). In human red blood cells, CDNB and t-BOOH increased the rate of Hg vapor oxidation at the low and intermediate H2O2 supplementation rates. In mouse erythrocytes, Hg uptake was increased by CDNB over the entire H2O2 infusion range. In human cells, t-BOOH (0.1 mM) produced a remarkably high Hg uptake even without added H2O2. This Hg uptake in absence of exogenous H2O2 was inhibited by aminotriazole as was the activity of catalase. Hence, the Hg uptake was likely to have been induced by endogenous hydrogen peroxide. These findings support the view that the intact GSH/GSH peroxidase system can diminish the efficiency of compound-I-induced Hg vapor oxidation in erythrocytes. AU - Halbach, S. AU - Ballatori, N. AU - Clarkson, T. C1 - 17260 C2 - 10175 SP - 517-524 TI - Mercury Vapor Uptake and Hydrogen Peroxide Detoxification in Red Blood Cells. JO - Toxicol. Appl. Pharmacol. VL - 96 IS - 3 PY - 1988 SN - 0041-008X ER - TY - JOUR AB - Five methods of metallothionein (MT) estimation in biological materials (Hg-saturation assay, Cd-saturation assay, thiolate group determination, Sephadex G-75 gel chromatography with subsequent Cd determination by Zeeman-AAS, and a radioimmunoassay (RIA)) were compared for their ability to recover standard MT (rabbit Cd-MTI) from liver or kidney S9. Uniform molar calibration of all assays was achieved using the known amino acid composition of standard MT and the nitrogen content of the standard MT stock solution as measured after complete Kjeldahl digestion. Known molar amounts of standard MT were added exogenously to rat liveror kidney-S9 samples and recoveries measured using the methods indicated. In an overall rating, RIA and Cd-saturation assay performed best with recoveries of 97 ± 12.0 and 105 ± 9.7%, respectively. On the other hand, the remaining methods either underestimated (thiolate group determination, G-75 Cd-AAS) or overestimated (Hg-saturation assay) the theoretical expectation by up to 44%. AU - Dieter, H.H.* AU - Müller, L.V.* AU - Abel, J.* AU - Summer, K.H. C1 - 41559 C2 - 36089 SP - 380-388 TI - Determination of Cd-thionein in biological materials: Comparative standard recovery by five current methods using protein nitrogen for standard calibration. JO - Toxicol. Appl. Pharmacol. VL - 85 IS - 3 PY - 1986 SN - 0041-008X ER - TY - JOUR AB - The disposition of hexachlorobenzene (HCB) was studied in partially jejunectomized (middle section) or colectomized (excision of cecum and proximal colon) rats after iv or ip dosage (1.5 to 2.0 mg/kg). Excision of about 50% of the jejunum had no effect on body weight, feed intake, volume of urine, weight of feces, or urinary and fecal excretion of HCB as demonstrated by a comparion of sham-operated and jejunectomized animals. Similarly, colectomy did not affect weight, feed intake, volume of urine, or urinary excretion of HCB. However, the wet weight of feces was significantly higher and the amount of HCB in feces significantly lower in colectomized than in sham-operated rats. Hexadecane increased fecal excretion of HCB about two- to threefold without affecting its urinary excretion. The effect of jejunectomy and colectomy was similar in hexadecane-treated animals to that seen in untreated rats. Concentration of HCB in adipose tissue was significantly higher in colectomized rats than in sham-operated controls. Data represent in vivo evidence that in major site of nonbiliary, intestinal excretion of HCB is the large intestine. AU - Rozman, J. AU - Scheufler, E. AU - Rozman, K.K. C1 - 20718 C2 - 13937 SP - 421-427 TI - Effect of Partial Jejunectomy and Colectomy on the Disposition of Hexachlorobenzene in Rats Treated or Not Treated with Hexadecane. JO - Toxicol. Appl. Pharmacol. VL - 78 PY - 1985 SN - 0041-008X ER - TY - JOUR AU - Rozman, K.K. AU - Rozman, J. AU - Greim, H. C1 - 20721 C2 - 13940 SP - 372-376 TI - Effect of Thyroidectomy and Thyroxine on 2,3,7,8,-Tetrachlorodibenzo-p-dioxin (TCDD) Induced Toxicity. JO - Toxicol. Appl. Pharmacol. VL - 72 PY - 1984 SN - 0041-008X ER - TY - JOUR AB - The hepatocarcinogenic effect of Clophen A 30 and Clophen A 60 was tested in male weanling rats by long-term feeding over a period of 832 days. The mortality rate was investigated in 100-day intervals. In the first 800 days liver carcinoma accounted for 21% of necropsies in the Clophen A 60 group but only 2% of the necropsies in the Clophen A 30 group and none in the control animals. The tumors were first observed after 700 days. After 800 days hepatocellular carcinoma was the most common lesion observed in the Clophen A 60 animals (61%) whereas it was only observed in 3% of animals in the Clophen A 30 group and 2% in the controls. Preneoplastic lesions, such as foci of hepatocellular alterations and neoplastic nodules, were first observed after Day 500. The incidence of foci predominated in all time intervals, but an increase in neoplastic nodules and hepatocellular carcinomas was observed with increased time. There was a marked trend from foci to neoplastic nodule to hepatocellular carcinoma with time. The total mortality rate and the incidence of thymoma, inflammatory lesions of the urogenital tract, in the experiment were significantly reduced by Clophen administration. Whether this protective effect could be induced by polychlorinated biphenyls (PCBs) is discussed. AU - Schaeffer, E.H. AU - Greim, H.A. AU - Goessner, W. C1 - 42307 C2 - 38340 SP - 278-288 TI - Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats. JO - Toxicol. Appl. Pharmacol. VL - 75 IS - 2 PY - 1984 SN - 0041-008X ER - TY - JOUR AB - Sixty rats were divided into two groups; one group received normal Rat Chow and the other the same feed supplemented with 5% hexadecane. Twenty-four hours later, the rats were injected iv with 1.0 mg/kg [14C]hexachlorobenzene (HCB). For 1 month after dosing, the activity of 14C was determined in various tissues and in serum at predetermined intervals. A biexponential decline of radioactivity was observed in serum and tissues of both groups; the decline of 14C in tissues roughly paralleled the decline of radioactivity in serum; exceptions were fat, skin, and the content of the large intestine, which showed an initial uptake phase. Hexadecane increased the disposition rate constant β in serum, leading to a significantly reduced body burden after 4 weeks of treatment. The more rapid loss of tissue radioactivity was accompanied by increased levels of 14C in intestinal contents of the large intestine. Biliary excretion was unaffected. Data are compatible with describing the kinetics of HCB by a two-compartment open model, where elimination occurs from a part of the peripheral compartment. AU - Scheufler, E. AU - Rozman, K.K.* C1 - 40916 C2 - 38467 SP - 190-197 TI - Effect of hexadecane on the pharmacokinetics of hexachlorobenzene. JO - Toxicol. Appl. Pharmacol. VL - 75 IS - 2 PY - 1984 SN - 0041-008X ER - TY - JOUR AB - The ability of quail and trout to perform a number of representative phase I and phase II biotransformations was examined. To facilitate interspecies comparisons, metabolism of the same substrates was examined simultaneously under uniform conditions for rat, mouse, rabbit, guinea pig, cat, and dog. Both nonmammalian species can metabolize four representative substrates of phase I mixed-function oxidases and one substrate of epoxide hydrolase, though activity tended to be lower than that of the mammals. Important differences in the conjugative pathways were also noted. Among these differences were the quail's relative deficiency in glutathione conjugation and the trout's low ability to conjugate sulfate compounds. Trout liver UDP-glucuronosyltransferase activity was remarkably high toward testosterone and bilirubin, while quail liver formed glucuronides of naphthol, p-nitrophenol, and digitoxigenin-monodigitoxoside. Also noteworthy was the high N-acetyltransferase activity of both quail and trout toward isoniazid, β-naphthylamine, and 2-aminofluorene. Differences in substrate specificity for a given enzymatic pathway may be an indication that multiple forms of drug metabolizing systems also occur in these nonmammalian species. Observation of several hundred- or even thousand-fold differences between species in their enzyme activities for certain substrates under uniform conditions reemphasizes the need for caution in extrapolation of xenobiotic metabolism from one species to another. AU - Gregus, Z. AU - Watkins, J.B. AU - Thompson, T.N. AU - Harvey, M.J. AU - Rozman, K.K. AU - Klaassen, C. C1 - 41966 C2 - 38371 SP - 430-441 TI - Hepatic phase I and phase II biotransformations in quail and trout: Comparison to other species commonly used in toxicity testing. JO - Toxicol. Appl. Pharmacol. VL - 67 IS - 3 PY - 1983 SN - 0041-008X ER - TY - JOUR AB - Four rhesus monkeys were administered various doses of hexachlorobenzene (HCB) po, to achieve widely varying adipose tissue levels. One month later, each animal was provided with a bile duct bypass allowing for interruption of the enterohepatic circulation (EHC). Effects of mineral oil-supplemented diet and/or interruption of the EHC on urinary, biliary, and fecal excretion of HCB and its metabolites were quantified. Urinary excretion of HCB was not affected by mineral oil but was reduced 20 to 60% by interruption of the EHC. Similarly, biliary excretion of HCB was also reduced 25 to 60% by interruption of the EHC and was not altered by mineral oil. Fecal excretion was increased about fivefold by mineral oil, whereas interruption of the EHC had no effect on the amount of HCB in feces. Results demonstrate that interruption of the EHC reduced urinary and biliary excretion of HCB metabolites, whereas mineral oil specifically stimulated intestinal excretion of the parent compound. AU - Rozman, K.K. AU - Rozman, T.A. AU - Greim, H.A. C1 - 41283 C2 - 0 SP - 255-261 TI - Stimulation of nonbiliary, intestinal excretion of hexachlorobenzene in rhesus monkeys by mineral oil. JO - Toxicol. Appl. Pharmacol. VL - 70 IS - 2 PY - 1983 SN - 0041-008X ER - TY - JOUR AU - Rozman, K.K. AU - Mueller, W.F. AU - Coulston, F. AU - Korte, F. C1 - 41941 C2 - 40353 SP - A93 TI - The involvement of the lymphatic system in the absorption, transport, and excretion of hexachlorobenzene in rats and rhesus monkeys. JO - Toxicol. Appl. Pharmacol. VL - 48 IS - 1 II PY - 1979 SN - 0041-008X ER - TY - JOUR AB - The urinary excretion of mercapturic acids has been considered as an indicator for human exposure to environmental chemicals. To evaluate this concept, the excretion of urinary mercapturic acids was determined in chimpanzees and rats after the oral administration of single doses of naphthalene and diethylmaleate. The excretion rate of endogenous thioethers in the urine of untreated chimpanzees and rats was 18.0 ± 1.1 and 94.4 ± 2.8 μmol/kg/24 hr respectively. The value for man was nearly the same as found in chimpanzees. After the administration of naphthalene (30, 75, and 200 mg/kg) a dose-dependent increase of the excretion rate of urinary mercapturic acids up to 408 μmol/kg/24 hr was observed in the rat. In the chimpanzees the same treatment failed to increase the urinary thioether concentrations. The administration of diethylmaleate (30, 75, and 200 mg/kg) led to a dose-dependent increase in the excretion of urinary mercapturic acids in both species. In rats this increase was about twice that of chimpanzees. The results suggest that the chimpanzee is a relevant model for man to study the urinary excretion of mercapturic acids deriving from electrophilic compounds, whereas the rat is not. Experiments with [14C]-naphthalene indicate that the species differences observed are due to differences in the glutathione conjugation. © 1979. AU - Summer, K.H. AU - Rozman, K.K. AU - Coulston, F. AU - Greim, H.A. C1 - 42183 C2 - 0 SP - 207-212 TI - Urinary excretion of mercapturic acids in chimpanzees and rats. JO - Toxicol. Appl. Pharmacol. VL - 50 IS - 2 PY - 1979 SN - 0041-008X ER - TY - JOUR AU - Summer, K.H. AU - Rozman, K.K. AU - Coulston, F. AU - Greim, H.A. C1 - 42726 C2 - 40442 SP - A160 TI - Species differences in the excretion of mercapturic acids between rats and chimpanzees dosed with naphthalene and diethylmaleate. JO - Toxicol. Appl. Pharmacol. VL - 48 IS - 1 II PY - 1979 SN - 0041-008X ER - TY - JOUR AU - Koegel, W. AU - Iatropoulos, M.J. AU - Mueller, W.F. C1 - 40953 C2 - 40382 SP - No. 147 TI - Metabolism, body distribution, and histopathology of pentachloronitrobenzene in rhesus monkeys. JO - Toxicol. Appl. Pharmacol. VL - 45 IS - 1 PY - 1978 SN - 0041-008X ER -