Toxicokinetics and toxic effects of a Chinese PFOS alternative F-53B in adult zebrafish.

6:2 chlorinated polyfluorinated ether sulfonate (F-53B), a Chinese PFOS alternative, has recently been identified in river water, sewage sludge, wildlife and humans, causing great concerns about its potential toxic effects. Here, we report the first investigation of the toxicokinetics and oxidative stress of F-53B in adult zebrafish. Adult male and female zebrafish were exposed to 10 and 100 µg/L of F-53B for 7 days followed by a 5-d depuration period to examine bioaccumulation, distribution, and depuration of F-53B in fish. The results showed that F-53B was readily accumulated in fish tissues with log BCF values of 2.36-3.65, but was eliminated slowly (t1/2 = 152.4-358.5 h). F-53B accumulation was greater in males than in females and the concentration in tissues decreased in the following order: gonad ≈ liver ≫ gill ≫ brain in females and liver ≈ gill ≫ gonad ≫ brain in males, showing sex- and tissue- specific accumulation of F-53B in fish. After chronic exposure to F-53B for 28 days, a significant dose-dependent increase in histopathological changes in the liver were mainly manifested by vacuolation. Furthermore, F-53B also significantly reduced the enzyme activity (or content) of most of the measured oxidative stress-related markers (e.g., SOD, CAT and MDA) except for an increase in GSH-Px activity, indicating that oxidative stress was induced in zebrafish after treatment with F-53B. The results of this study provide important information on the toxicokinetics and toxic effects of F-53B, which will contribute to the ecological risk assessments of F-53B released into surface waters.

Uptake and elimination of emerging polyfluoroalkyl substance F-53B in zebrafish larvae: Response of oxidative stress biomarkers.

6:2 chlorinated polyfluorinated ether sulfonate (F-53B) has been widely applied as a mist suppressant to replace perfluorooctane sulfonate (PFOS) in the metal plating industry in China for decades. Recently, F-53B has been frequently identified in the aquatic environment and wild-caught fish. However, studies on the uptake and elimination kinetics, and the toxicological effects of F-53B were very scarce. In this study, zebrafish larvae (72 h post fertilization, hpf) were exposed to F-53B (10, 100 µg/L) for 48 h, followed by a 24 h of depuration to examine both the dynamics of accumulation and elimination of F-53B and responses of antoxidant defense system in fish. The results showed that F-53B rapidly accumulated in zebrafish larvae in a concentration and time-dependent manner with BCF values of 3612-3615, but was eliminated slowly (half-life ranged from 241.5 to 258.6 h). F-53B exposure induced oxidative stress in zebrafish larvae, as reflected by the reduction in the GSH and MDA contents, CAT, SOD, CuZn-SOD, and GSH-ST activities, and the increase in GSH-Px activity as well as CAT and SOD protein levels. However, these oxidative stress markers were restored to control levels except for a decrease in protein level of SOD after depuration. Collectively, the results of this work indicate that F-53B behaves like PFOS and is bioaccumulative and persistent in zebrafish larvae, and further induced oxidative stress responses.

Tissue Distribution and Whole Body Burden of the Chlorinated Polyfluoroalkyl Ether Sulfonic Acid F-53B in Crucian Carp (Carassius carassius): Evidence for a Highly Bioaccumulative Contaminant of Emerging Concern.

Following the global actions to phase out perfluoroctanesulfonic acid (PFOS) a large number of alternative per- and polyfluoroalkyl substances, with poorly defined hazard properties, are being used in increasing quantities. Here, we report on the first detection of the chlorinated polyfluoroalkyl ether sulfonic acid F-53B in biological samples and determine the tissue distribution and whole body bioaccumulation factors (BAFwhole body) in crucian carp (Carassius carassius). Analysis of fish samples from Xiaoqing River (XR) and Tangxun Lake (TL) demonstrated a similar level of F-53B contamination with median concentrations in blood of 41.9 and 20.9 ng/g, respectively. Tissue/blood ratios showed that distribution of F-53B primarily occurs to the kidney (TL: 0.48, XR: 0.54), gonad (TL: 0.36, XR: 0.54), liver (TL: 0.38, XR: 0.53), and heart (TL: 0.47, XR: 0.47). Median Log BAFwhole body values for F-53B (XR: 4.124, TL: 4.322) exceeded regulatory bioaccumulation criterion and were significantly higher than those of PFOS in the same data sets (XR: 3.430, TL: 3.279). On the basis of its apparent omnipresence and strong bioaccumulation propensity, it is hypothesized that F-53B could explain a significant fraction of previously unidentified organofluorine in biological samples from China, and regulatory actions for this compound are encouraged.

Perfluoroalkyl sulfonates and carboxylic acids in liver, muscle and adipose tissues of black-footed albatross (Phoebastria nigripes) from Midway Island, North Pacific Ocean.

The Great Pacific Garbage Patch (GPGP) is a gyre of marine plastic debris in the North Pacific Ocean, and nearby is Midway Atoll which is a focal point for ecological damage. This study investigated 13 C4-C16 perfluorinated carboxylic acids (PFCAs), four (C4, C6, C8 and C10) perfluorinated sulfonates and perfluoro-4-ethylcyclohexane sulfonate [collectively perfluoroalkyl acids (PFAAs)] in black-footed albatross tissues (collected in 2011) from Midway Atoll. Of the 18 PFCAs and PFSAs monitored, most were detectable in the liver, muscle and adipose tissues. The concentrations of PFCAs and PFSAs were higher than those in most seabirds from the arctic environment, but lower than those in most of fish-eating water birds collected in the U.S. mainland. The concentrations of the PFAAs in the albatross livers were 7-fold higher than those in Laysan albatross liver samples from the same location reported in 1994. The concentration ranges of PFOS were 22.91-70.48, 3.01-6.59 and 0.53-8.35 ng g(-1) wet weight (ww), respectively, in the liver, muscle and adipose. In the liver samples PFOS was dominant, followed by longer chain PFUdA (8.04-18.70 ng g(-1) ww), PFTrDA, and then PFNA, PFDA and PFDoA. Short chain PFBA, PFPeA, PFBS and PFODA were below limit of quantification. C8-C13 PFCAs showed much higher composition compared to those found in other wildlife where PFOS typically predominated. The concentrations of PFUdA in all 8 individual albatross muscle samples were even higher than those of PFOS. This phenomenon may be attributable to GPGP as a pollution source as well as PFAA physicochemical properties.

Aquatic hazard, bioaccumulation and screening risk assessment for 6:2 fluorotelomer sulfonate.

This study assessed the aquatic toxicity and bioaccumulation potential of 6:2 fluorotelomer sulfonate (6:2 FTSA). Acute and chronic aquatic hazard endpoints indicate 6:2 FTSA is not classified for aquatic hazard according to GHS or European CLP legislation. The aqueous bioconcentration factors for 6:2 FTSA were <40 and the dietary assimilation efficiency, growth corrected half-life and dietary biomagnification factor (BMF) were 0.435, 23.1d and 0.295, respectively. These data indicate that 6:2 FTSA is not bioaccumulative in aquatic organisms. Comparison of PNECs with the reported surface water concentrations (non-spill situations) suggests low risk to aquatic organisms from 6:2 FTSA. Future studies are needed to elucidate the biotic and abiotic fate of commercial AFFF surfactants in the environment.

In vitro analysis of the effect of alkyl-chain length of anionic surfactants on the skin by using a reconstructed human epidermal model.

We investigated the effect of the alkyl-chain length of anionic surfactants on the skin using an in vitro model. The evaluated anionic surfactants were sodium alkyl sulfate (AS) and sodium fatty acid methyl ester sulfonate (MES), which had different alkyl-chain lengths (C8-C14). Skin tissue damage and permeability were examined using a reconstructed human epidermal model, LabCyte EPI-MODEL24. Skin tissue damage was examined by measuring cytotoxicity with an MTT assay. Liquid chromatography/tandem mass spectrometry (LC/MS-MS) and liquid chromatography/mass spectrometry (LC/MS) were used to detect surfactants that permeated into the assay medium through an epidermal model. To assess the permeation mechanism and cell damage caused by the surfactants through the epidermis, we evaluated the structural changes of Bovine Serum Albumin (BSA), used as a simple model protein, and the fluidity of 1,2-dipalmitoyl-sn-glycero-3-phosphpcholine (DPPC) liposome, which serves as one of the most abundant phospholipid models of living cell membranes in the epidermis. The effects of the surfactants on the proteins were measured using Circular Dichroism (CD) spectroscopy, while the effects on membrane fluidity were investigated by electron spin resonance (ESR) spectroscopy. ET50 (the 50% median effective time) increased as follows: C10 < C12 < C8 < C14 in AS and C8, C10 < C12 < C14 in MES. The order of permeation through the LabCyte EPI-MODEL24 was C10 > C12 > C14, for both AS and MES. For both AS and MES, the order parameter, which is the criteria for the microscopic viscosity of lipid bilayers, increased as follows: C10 < C12 < C14, which means the membrane fluidity is C10 > C12 > C14. It was determined that the difference in skin tissue damage in the LabCyte EPI-MODEL24 with C10 to C14 AS and MES was caused by the difference in permeation and cell membrane fluidity through the lipid bilayer path in the epidermis.

Structural effects in photopolymerized sodium AMPS hydrogels crosslinked with poly(ethylene glycol) diacrylate for use as burn dressings.

Synthetic hydrogel polymers were prepared by free radical photopolymerization in aqueous solution of the sodium salt of 2-acrylamido-2-methylpropane sulfonic acid (Na-AMPS). Poly(ethylene glycol) diacrylate (PEGDA) and 4,4'-azo-bis(4-cyanopentanoic acid) were used as the crosslinker and UV-photoinitiator, respectively. The effects of varying the Na-AMPS monomer concentration within the range of 30-50% w/v and the crosslinker concentration within the range of 0.1-1.0% mol (relative to monomer) were studied in terms of their influence on water absorption properties. The hydrogel sheets exhibited extremely high swelling capacities in aqueous media which were dependent on monomer concentration, crosslink density, and the ionic strength and composition of the immersion medium. The effects of varying the number-average molecular weight of the PEGDA crosslinker from [Formula: see text] = 250 to 700 were also investigated. Interestingly, it was found that increasing the molecular weight and therefore the crosslink length at constant crosslink density decreased both the rate of water absorption and the equilibrium water content. Cytotoxicity testing by the direct contact method with mouse fibroblast L929 cells indicated that the synthesized hydrogels were nontoxic. On the basis of these results, it is considered that photopolymerized Na-AMPS hydrogels crosslinked with PEGDA show considerable potential for biomedical use as dressings for partial thickness burns. This paper describes some structural effects which are relevant to their design as biomaterials for this particular application.

Hyaluronidase: its effects on HI-6 dichloride and dimethanesulphonate pharmacokinetic profile in pigs.

Pigs were administered intramuscularly molar equivalents of HI-6 salts (HI-6 dichloride 10.71 mg/kg and HI-6 DMS 13.59 mg/kg) either with or without hyaluronidase (60 U/kg). Hyaluronidase is supposed to increase tissue permeability and diminishes discomfort caused by the intramuscular injection. Doses of HI-6 salts corresponded with standard HI-6 dichloride dose in one autoinjector (500 mg) and were recalculated for 1 kg of body weight. According to the results, both HI-6 salts applied in combination with hyaluronidase had increased tissue absorption and improved pharmacokinetic profile. The Cmax was significantly higher in case of HI-6 DMS plus hyaluronidase (29.6 ± 2.98 µg/ml) administration increase compared to HI-6 DMS (23.8 ± 3.04 µg/ml) and HI-6 dichloride (19.0 ± 0.93 µg/ml); both without hyaluronidase. Bioavailability calculated as AUCtotal (HI-6 DMS with hyaluronidase, 4,119 ± 647 min µg/ml) was also significantly higher compared to HI-6 DMS (2,259 ± 329 min µg/ml) and HI-6 dichloride (1,969 ± 254 min µg/ml); both without hyaluronidase. The results suggest that administration of HI-6 salt with higher solubility is the first step in the improvement of application strategy, but use some substances with spreading effect (hyaluronidase) may also leads to better absorption and better bioavailability. Improved bioavailability could to go hand in hand with increased effectiveness of therapy without the need of multiple autoinjector applications.

Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus.

The effects of tesaglitazar on renal function (assessed as urinary clearance of 125I-sodium iothalamate or estimated by the modification of diet in renal disease formula) were studied in a 24-week open-label trial in type 2 diabetes mellitus patients randomized to daily doses of either tesaglitazar 2 mg or pioglitazone 45 mg. The aim of the analysis was to develop a population pharmacokinetic-pharmacodynamic model that could simultaneously describe the interrelationship between tesaglitazar exposure and reduction in renal function over time in patients with type 2 diabetes mellitus. The pharmacokinetic-pharmacodynamic model could adequately describe the interplay between tesaglitazar and glomerular filtration rate. A one-compartment model in which the apparent clearance was influenced by glomerular filtration rate characterized the pharmacokinetics of tesaglitazar. An indirect-response model was used for the slow time course of change in glomerular filtration rate, which decreased from 100 to 78 mL/min/1.73m(2) after 12 weeks of treatment. All tesaglitazar-treated patients had a reduction in glomerular filtration rate, and available demographic variables could not explain differences in response. Patients treated with an angiotensin converting enzyme inhibitor were more sensitive to tesaglitazar and had larger glomerular filtration rate decrease compared to nontreated patients. Approximately 8 weeks after discontinuing treatment, mean glomerular filtration rate had returned towards baseline. The model and data give valuable insights into the dynamic changes in glomerular filtration rate over time.

Evaluation and prediction of pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model.

Perfluoroalkyl acid carboxylates and sulfonates (PFAAs) have many consumer and industrial applications. The persistence and widespread distribution of these compounds in humans have brought them under intense scrutiny. Limited pharmacokinetic data is available in humans; however, human data exists for two communities with drinking water contaminated by PFAAs. Also, there is toxicological and pharmacokinetic data for monkeys, which can be quite useful for cross-species extrapolation to humans. The goal of this research was to develop a physiologically-based pharmacokinetic (PBPK) model for PFOA and PFOS for monkeys and then scale this model to humans in order to describe available human drinking water data. The monkey model simulations were consistent with available PK data for monkeys. The monkey model was then extrapolated to the human and then used to successfully simulate the data collected from residents of two communities exposed to PFOA in drinking water. Human PFOS data is minimal; however, using the half-life estimated from occupational exposure, our model exhibits reasonable agreement with the available human serum PFOS data. It is envisioned that our PBPK model will be useful in supporting human health risk assessments for PFOA and PFOS by aiding in understanding of human pharmacokinetics.

Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function--evidence of interconversion.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tesaglitazar, is predominantly metabolized (to an acyl glucuronide of the parent compound) and 20% of given dose is found unchanged in the urine. Acyl glucuronides are know to be unstable and can become hydrolysed back to parent compound, a phenomena called interconversion. WHAT THIS STUDY ADDS: A likely mechanism (interconversion) for the cause of the increased exposure of tesaglitazar in subjects with impaired renal function. A possible modelling framework to evaluate interconversion without dosing of the metabolite based on the simultaneous analysis of plasma and urine data from a group of subjects with varying renal function. A mechanistic understanding of the pharmacokinetic properties of tesaglitazar and its metabolite. AIMS To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function. METHODS: Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation. RESULTS: The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h(-1)) and metabolic (1.9 l h(-1)) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V(max) = 0.19 micromol l(-1) and K(m) = 0.04 micromol l(-1)) and nonrenal clearances (1.2 l h(-1)), biliary secretion (12 h(-1)) to the gut, where interconversion and reabsorption (0.8 h(-1)) of tesaglitazar occurred. CONCLUSION: A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.

Food does not affect the pharmacokinetics of tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist.

Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (C(max)). Mean C(max) was approximately 18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] mumol/L), and median time to C(max) was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of t(max) was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.

Tesaglitazar: a promising approach in type 2 diabetes.

While glycemic control remains the cornerstone of clinical management for patients with type 2 diabetes, the importance of a more comprehensive approach that addresses the multiple metabolic abnormalities seen in this population is now widely recognized. Abnormal lipid metabolism resulting in dyslipidemia contributes greatly to the markedly increased risks of cardiovascular disease observed in diabetic patients and in prediabetic patients with signs of insulin resistance. The peroxisome proliferator-activated receptors (PPARs) play a key role in the regulation of energy homeostasis and the coordination of inflammatory responses. As such, they are interesting targets for addressing both the glucose and lipid abnormalities associated with insulin resistance. The thiazolidinediones (TZDs), which activate PPARgamma, appear to improve glycemic control primarily by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. They have also demonstrated modest beneficial effects on some lipid parameters. The fibrate drugs, which activate PPARalpha, produce robust improvements in dyslipidemia, decrease atherosclerotic lesions and may have an effect on cardiovascular events, but do not affect glycemia. Theoretically, a compound targeting both the alpha and gamma PPARs simultaneously might combine the benefits of TZDs and fibrates. Tesaglitazar is a dual-acting PPARalpha/gamma agonist currently being investigated in phase III clinical trials as an alternative treatment for insulin resistance and the characteristic dyslypidemia of type 2 diabetes. This article reviews the available data on the clinical efficacy and safety of tesaglitazar in patients with type 2 diabetes and in individuals without diabetes but with insulin resistance.

Perflouroalkyl contaminants in liver tissue from East Greenland polar bears (Ursus maritimus).

Perfluoroalkyl substances were determined in polar bears (Ursus maritimus) collected in East Greenland (69 degrees 00'N to 74 degrees 00"N) to compare with other populations and to examine effects of age and gender on concentrations of these contaminants. Hepatic tissue (n = 29) was analyzed for perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate, heptadecafluorooctane sulfonamide (PFOSA), and perfluoroalkyl carboxylates (PFCAs) with C9-C15 perfluorinated carbon chains by liquid chromatography tandem mass spectrometry. Concentrations of PFOS found in samples from East Greenland (mean = 2,470+/-1,320 ng/g wet weight) were similar to Hudson Bay, Canada, and both populations had significantly greater concentrations than those reported for Alaska, suggesting a spatial trend. Male bears showed a significant increase in concentration up to age six for PFCAs with C10-C14 carbon chains (r2 > or = 0.50, p < or = 0.05). Significant correlations were found between adjacent chain length PFCAs, (e.g., PFNA to PFDA: p < 0.05; r2 = 0.90). This may indicate a common source for these chemicals, although the specifics of source and mode of transport are unknown. No significant correlations were found between concentrations of PFCAs in liver tissue and previously reported polychlorinated biphenyl (PCB) congeners analyzed in fat samples from the same bears.

Pharmacokinetics and metabolism of tesaglitazar, a novel dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, after a single oral and intravenous dose in humans.

The pharmacokinetics of tesaglitazar (GALIDA), a novel dual-acting peroxisome proliferator-activated receptor alpha and gamma agonist, were studied in eight healthy male subjects. The subjects initially received either a single oral or intravenous (i.v.) dose of 1 mg of [(14)C]tesaglitazar. After a washout period, they received 1 mg of nonlabeled tesaglitazar via the alternative administration route. Serial blood samples and complete urine and feces were collected until 336 h postdose. Tesaglitazar absorption was rapid, with maximum plasma concentration (C(max)) at approximately 1 h postdose, and the absolute bioavailability was approximately 100%, suggesting no, or negligible, first-pass metabolism. Mean plasma clearance was 0.16 l/h and the volume of distribution at steady state was 9.1 liters. After either route of administration, the plasma concentration-time profiles of radioactivity and tesaglitazar were virtually identical, indicating low systemic metabolite concentrations and formation rate limitation of metabolite elimination. The elimination half-life of radioactivity and tesaglitazar was approximately 45 h. Radioactivity recovery was complete in all subjects, with mean values of 99.9% (i.v.) and 99.6% (oral). Tesaglitazar was mainly metabolized before excretion, and most radioactivity (91%) was recovered in urine. Approximately 20% of the dose was recovered unchanged after either administration route, resulting in a renal clearance of 0.030 l/h. Most of the radioactivity in urine was identified as acyl glucuronide of tesaglitazar. Plasma protein binding of tesaglitazar was high ( approximately 99.9%), and the mean blood-plasma partitioning ratio was 0.66, suggesting low affinity for red blood cells. There was no indication of partial inversion of the (S)-enantiomer to the corresponding (R)-form. Tesaglitazar was well tolerated.

Identification of long-chain perfluorinated acids in biota from the Canadian Arctic.

Recently it was discovered that humans and animals from various urban and remote global locations contained a novel class of persistent fluorinated contaminants, the most pervasive of which was perfluorooctane sulfonate (PFOS). Lower concentrations of perfluorooctanoate, perfluorohexane sulfonate, and heptadecafluorooctane sulfonamide have also been detected in various samples. Although longer perfluoroalkyl carboxylates (PFCAs) are used in industry and have been detected in fish following a spill of aqueous film forming foam, no studies have been conducted to examine the widespread occurrence of long-chain PFCAs (e.g., CF3(CF2)xCOO-, where x > 6). To provide a preliminary assessment of fluorinated contaminants, including PFCAs, in the Canadian Arctic, polar bears, ringed seals, arctic fox, mink, common loons, northern fulmars, black guillemots, and fish were collected at various locations in the circumpolar region. PFOS was the major contaminant detected in most samples and in polar bear liver was the most prominent organohalogen (mean PFOS = 3.1 microg/g wet weight) compared to individual polychlorinated biphenyl congeners, chlordane, or hexachlorocyclohexane-related chemicals in fat. Using two independent mass spectral techniques, it was confirmed that all samples also contained ng/g concentrations of a homologous series of PFCAs, ranging in length from 9 to 15 carbons. Sum concentrations of PFCAs (sum(PFCAs)) were lower than total PFOS equivalents (sum(PFOS)) in all samples except for mink. In mink, perfluorononanoate (PFNA) concentrations exceeded PFOS concentrations, indicating that PFNA and other PFCAs should be considered in future risk assessments. Mammals feeding at higher trophic levels had greater concentrations of PFOS and PFCAs than mammals feeding at lower trophic positions. In general, odd-length PFCAs exceeded the concentration of even-length PFCAs, and concentrations decreased with increasing chain length in mammals. PFOS and PFCA concentrations were much lower for animals living in the Canadian Arctic than for the same species living in mid-latitude regions of the United States. Future studies should continue to monitor all fluorinated contaminants and examine the absolute and relative toxicities for this novel suite of PFCAs.

Hepatobiliary excretion of dipyrrinone sulfonates in Mrp2-deficient (TR(-)) rats.

The biliary excretion of the sodium salts of 8-(2-ethanesulfonic acid)-3-ethyl-2,7,9-trimethyl-1,10-dihydro-11H-dipyrrin-1-one (xanthosulfonic acid) and a fluorescent analogue (8-desethyl-N,N'-carbonyl-kryptopyrromethenone-8-sulfonic acid) was compared in Mrp2-deficient (TR(-)) and normal rats. Both organic anions were excreted rapidly in bile in Mrp2-deficient rats, but the biliary excretion of the fluorescent sulfonate was impaired relative to normal controls. The rat clearly has efficient Mrp2-independent mechanisms for biliary efflux of these anions that are not used by bilirubin or its mono- and diglucuronides.

Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.

The clinical pharmacology of alkylating agents in high-dose chemotherapy.

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.

Ethane sulfonate metabolite of alachlor: assessment of oncogenic potential based on metabolic and mechanistic considerations.

Chronic administration of alachlor has been shown to produce neoplastic responses in the nasal turbinate mucosa, glandular stomach mucosa, and thyroid follicular epithelium of rats. Subsequent studies have shown that specific metabolic activation of alachlor is required for nasal tumor formation, and that non-genotoxic, threshold-sensitive processes produce all three tumors. The herbicide alachlor is degraded in the soil by microbial action to the tertiary ethane sulfonate metabolite (ESA). The acute and subchronic toxicity of ESA is very low, and the metabolite did not produce developmental toxicity or genotoxicity. The studies described here were conducted to determine whether ESA shares a common mechanism of oncogenicity with alachlor in rats. Specifically, we studied ESA's pharmacokinetics and ability to produce changes that are causally associated with the oncogenicity of alachlor. These studies demonstrated that ESA was poorly absorbed and underwent minor metabolism, which contrasted with the significant absorption and substantial metabolism observed with alachlor. ESA was also excreted more quickly than alachlor and showed no evidence of accumulation in the nasal turbinates, a site of oncogenicity for alachlor in the rat. In addition, ESA did not elicit the characteristic preneoplastic changes observed in the development of alachlor-induced nasal, stomach, and thyroid tumors. The results of these studies support the conclusion that ESA does not share a common oncogenic mechanism with alachlor and would not be expected to produce the same oncogenic responses observed following chronic alachlor exposure in rats.