Maximum Tissue Concentration Research Articles

Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent.

Purpose: To evaluate the pharmacokinetic profiles of the ocular hypotensive agent QLS-101, a novel ATP-sensitive potassium channel opening prodrug, and its active moiety levcromakalim, following topical ophthalmic and intravenous dosing of normotensive rabbits and dogs. Methods: Dutch belted rabbits (n = 85) and beagle dogs (n = 32) were dosed with QLS-101 (0.16-3.2 mg/eye/dose) or formulation buffer for 28 days. Pharmacokinetic profiles of QLS-101 and levcromakalim were evaluated in ocular tissues and blood by LC-MS/MS. Tolerability was assessed by clinical and ophthalmic examinations. Maximum systemic tolerated dose was evaluated in beagle dogs (n = 2) following intravenous bolus administrations of QLS-101 (0.05 to 5 mg/kg). Results: Plasma analysis following topical dosing of QLS-101 (0.8-3.2 mg/eye/dose) for 28 days indicated an elimination half-life (T1/2) of 5.50-8.82 h and a corresponding time (Tmax) range of 2-12 h in rabbits, and a T1/2 of 3.32-6.18 h with a Tmax range of 1-2 h in dogs. Maximum tissue concentration (Cmax) values ranged from 54.8-540 (day 1) to 50.5-777 ng/mL (day 28) in rabbits, and 36.5-166 (day 1) to 47.0-147 ng/mL (day 28) in dogs. Levcromakalim plasma T1/2 and Tmax were similar to QLS-101, while Cmax was consistently lower. Topical ophthalmic delivery of QLS-101 was well tolerated in both species, with sporadic mild ocular hyperemia noted in the group treated with the highest concentration (3.2 mg/eye/dose). Following topical ophthalmic dosing, QLS-101 and levcromakalim were found primarily in the cornea, sclera, and conjunctiva. Maximum tolerated dose was determined to be 3 mg/kg. Conclusions: QLS-101 was converted to its active moiety levcromakalim and showed characteristic absorption, distribution, and safety profiles of a well-tolerated prodrug.

Pharmacokinetics, absorption, distribution, metabolism and excretion of the MEK inhibitor zapnometinib in rats.

Zapnometinib is a MEK inhibitor currently under clinical development for the treatment of COVID-19 and influenza. Zapnometinib has both antiviral and immunomodulatory effects. Information concerning the absorption, distribution, metabolism, and excretion of the compound following single oral doses of 30mg/kg [14C]-zapnometinib to rats was required to support pharmacology and toxicology studies in animals and clinical studies in man. As part of the development and safety assessment of this substance, zapnometinib was radioactively labeled and used for the investigation of time-dependent plasma concentrations, the rates and routes of excretion, the extent and time-course of compound distribution in body tissues, the metabolite profiles in plasma, urine and feces and the chemical nature of its metabolites. The present study reveals a rapid but low absorption of zapnometinib from the gastrointestinal tract, with more than 90% of the compound being excreted within 48h, mainly via feces. Whole body autoradiography confirms that zapnometinib was rapidly and widely distributed, with greatest concentrations in the circulatory and visceral tissues. Maximum plasma and tissue concentrations occurred between two and 8h post dose. Penetration into the brain was low, and elimination from most tissues almost complete after 168h. Metabolic profiles showed that the main clearance routes were metabolism via oxidative reactions and glucuronidation. These results further strengthen the knowledge of zapnometinib with respect to the clinical development of the drug.

Environmental risk assessment and bioaccumulation of pharmaceuticals in a large urbanized estuary

We screened for the presence of 66 different pharmaceutical residues in surface waters and in multiple invertebrate and fish species of the Tejo estuary to produce an environmental risk assessment of individual pharmaceuticals and their mixtures, as well as evaluate the bioaccumulation of pharmaceuticals in one of Europe's largest estuarine systems. Sixteen pharmaceutical residues, from seven therapeutic classes, were detected in estuarine waters, with environmental mixture concentrations ranging from 42 to 1762 ng/L. Environmental risk assessment via the determination of risk quotients, demonstrated high ecological risk for the antibiotic amoxicillin and angiotensin II receptor blockers irbesartan and losartan. Moderate risk was estimated for antidepressants, antiepileptics, anxiolytics and beta-blockers, but the risk quotient of the accumulated mixture of compounds was over 380-fold higher than the no risk threshold, driven by antibiotics and angiotensin II receptor blockers. In biota, higher risk therapeutic groups were found in higher concentrations, with nine pharmaceutical residues detected, including six antibiotics and two neuroactive compounds, and maximum tissue concentrations up to 250 μg/kg. Bioaccumulation was species- and compound-specific, with only two compounds found simultaneously in water and biota, likely a result of the complex dynamics and fate of pharmaceuticals in estuarine waters. Nonetheless, higher detection frequencies were observed in species living directly on or just above the substrate (i.e. benthic and demersal species), underpinning the importance of habitat use, as well the potential role of sediment and diet based routes for pharmaceutical uptake. Ultimately, results support urgent action on managing the impact of pharmaceuticals in coastal environments, striving for improved monitoring schemes tailored to the dynamic nature and ecological diversity of estuaries and coastal ecosystems.

Enantioselective Behavior of the Fungicide Tebuconazole in Soil

Enantioselectivity (defined as the enantiomer fraction, EF) in sorption, dissipation and bioaccumulation was assessed for the model compound tebuconazole. Tebuconazole sorption in soils was affected by organic carbon (OC) and clay contents and cation exchange capacity, and appeared to be non-enantioselective for both tested soils, soil components and soil amendments. The bioaccumulation test consisted of two phases: the uptake phase and the elimination phase including the assessment of enantiospecific uptake and elimination rates. Unlike dissipation in soils, bioaccumulation of tebuconazole from these soils was enantioselective for both tested earthworm species (Eisenia andrei and Lumbricus terrestris). Peak-shaped bioaccumulation profiles were observed for all tested earthworm–soil variants with the maximum tissue concentrations reached within 7–10 days of exposure. Bioaccumulation factors ranged from 0.03 to 0.87. EF values of earthworm extracts varied from 0.28 to 0.52 with EF values <0.50 dominating. Enantioselectivity in bioaccumulation resulted from different excretion rates of the enantiomers. The interspecies similarity suggests that enantioselectivity in accumulation is a common phenomenon, and therefore, the risk assessment of tebuconazole should preferentially be evaluated at the enantiomer level. If this is not the case, a chiral correction factor of 2 (based on the enantiomer-specific BAF that differed by up to a factor of 2) may be recommended to account for enantioselectivity in tebuconazole bioaccumulation.

Influence of enrofloxacin traces in drinking water to doxycycline tissue pharmacokinetics in healthy and infected by Mycoplasma gallisepticum broiler chickens

Most of antibiotics, administrated in the treatment of poultry diseases are dissolved in drinking water, and it can lead to water supply systems contamination, especially when the regular cleaning is not using. This situation can lead to unconscious administration of low doses of antibiotics to untreated animals. The aim of this study was to clarify the impact of the exposure of enrofloxacin traces (500 μg l−1) to doxycycline pharmacokinetics in healthy and experimentally Mycoplasma gallisepticum infected broiler chickens., Two experimental groups, received of enrofloxacin in water and all groups, received 20 mg kg−1 bw of doxycycline. The compounds concentrations in muscles and livers were determined by LC-MS/MS. The maximum drug tissue concentration (Cmax) of doxycycline was highest in liver obtained from infected chickens which, received enrofloxacin traces (ENR + DC/MG). It was about 40% higher than in healthy chickens from group I which received only doxycycline. It was found that the concentration–time curve AUC(0-t) values in group ENR + DC/MG were almost 75% higher than in the group (DC) and 35% higher than in group (ENR + DC) which also received enrofloxacin traces.The constant exposure of broiler chickens on enrofloxacin traces as well as infection, may significantly influenced on doxycycline tissue pharmacokinetic profile.

Bactericidal effects of various concentrations of enrofloxacin, florfenicol, tilmicosin phosphate, and tulathromycin on clinical isolates of Mannheimia haemolytica.

To determine bactericidal effects of enrofloxacin, florfenicol, tilmicosin, and tulathromycin on clinical isolates of Mannheimia haemolytica at various bacterial densities and drug concentrations. 4 unique isolates of M haemolytica recovered from clinically infected cattle. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined for each drug and isolate. Mannheimia haemolytica suspensions (10(6) to 10(9) CFUs/mL) were exposed to the determined MIC and MPC and preestablished maximum serum and tissue concentrations of each drug. Log10 reduction in viable cells (percentage of cells killed) was measured at various points. Bacterial killing at the MIC was slow and incomplete. After 2 hours of isolate exposure to the MPC and maximum serum and tissue concentrations of the tested drugs, 91% to almost 100% cell killing was achieved with enrofloxacin, compared with 8% growth to 93% cell killing with florfenicol, 199% growth to 63% cell killing with tilmicosin, and 128% growth to 43% cell killing with tulathromycin over the range of inoculum tested. For all drugs, killing of viable organisms was evident at all bacterial densities tested; however, killing was more substantial at the MPC and maximum serum and tissue drug concentrations than at the MIC and increased with duration of drug exposure. Rank order of drugs by killing potency was enrofloxacin, florfenicol, tilmicosin, and tulathromycin. Findings suggested that antimicrobial doses that equaled or exceeded the MPC provided rapid killing of M haemolytica by the tested drugs, decreasing opportunities for antimicrobial-resistant subpopulations of bacteria to develop during drug exposure.

Tissue distribution, bioconcentration, metabolism, and effects of erythromycin in crucian carp (Carassius auratus)

In this study, the tissue distribution, bioconcentration, metabolism and biological effects of the macrolide antibiotic erythromycin (ERY) were investigated in fish using crucian carp (Carassius auratus) as a model. Crucian carp were exposed to various concentrations of ERY (4, 20, and 100μg/L) for 28days. The UPLC/MS/MS analysis of both water and tissue provided the bioconcentration of ERY and its metabolites in the fish body. The results from tissue samples showed that a maximum tissue concentration occurred in the muscle and that the bioconcentration factor (BCF) of 72.2 was lower than the theoretical BCF of 90.4 calculated from the octanol-water coefficient of ERY. A significant portion of the absorbed ERY was metabolized via demethylation and dehydration and observed in the form of descladinose in fish. In addition, the relevant biomarkers, including acetylcholinesterase in the brain, as well as 7-ethoxyresorufin O-deethylase and superoxide dismutase in the liver, changed significantly during 28days of exposure (P<0.05). These results clearly indicated that ERY accumulated in fish and that similar metabolites as those observed in mammals were produced, resulting in the biochemical disturbance of biological systems.

Two-Photon Fluorescence Microscopy of Corneal Riboflavin Absorption

To correct for attenuation in two-photon fluorescence (TPF) measurements of riboflavin absorption in porcine corneas. Two-photon fluorescence imaging of riboflavin was performed using excitation at a wavelength of 890 nm, with fluorescence signal detected between 525 and 650 nm. TPF signal attenuation was demonstrated by imaging from either side of a uniformly soaked corneoscleral button. To overcome this attenuation, a reservoir of dextran-free 0.1% wt/vol riboflavin 5'-monophosphate in saline and hydroxypropyl methylcellulose (HPMC) was placed on top of porcine corneas (globe intact-epithelium removed). TPF imaging was performed through this reservoir with image stacks acquired at 10-μm steps through the cornea repeated at regular intervals for up to 60 minutes. A novel correction method was applied to achieve corneal riboflavin concentration measurements in whole eyes (n = 4). Significant attenuation of the TPF signal was observed in all eyes, with the signal decreasing approximately linearly with depth in uniformly soaked tissue. Cross-sectional TPF images taken of excised corneal strips confirmed the tissue was uniformly soaked so that the decrease in signal was not due to spatial variations in riboflavin concentration. After correcting for signal attenuation, we observed increased riboflavin concentrations with longer soak duration, with the mean (standard deviation) maximum tissue concentration recorded at 0.094% (± 0.001) wt/vol [1.36 mg/mL]. Uniform riboflavin absorption was achieved after a minimum 50 minutes. Following a standard corneal cross-linking soak of 30 minutes, a mean stromal concentration of 0.086% (± 0.001) wt/vol [1.25 mg/mL] was achieved at a depth of 300 μm. The accuracy of TPF measurements of corneal riboflavin absorption can be increased by applying a correction for depth-related signal attenuation.

Diagnosis of Periprosthetic Joint Infection

Diagnosis of Periprosthetic Joint Infection

Effect of r1 and r2 relaxivity of gadolinium‐based contrast agents on the T1‐weighted MR signal at increasing magnetic field strengths

Most contrast agents for magnetic resonance imaging (MRI) are gadolinium-based T₁ shortening agents. At increasing magnetic field strengths their r1 relaxivity tends to decrease while the r₂ relaxivity increases. In parallel, at high fields the tissue T1 times increase and may mitigate the loss in contrast enhancement in T₁-weighted images owing to improved background suppression. In the present work we explored the MR signal for T₁-weighted spoiled gradient echo MRI sequences by simulations at three magnetic field strengths: 3, 7 and 9.4 T. The maximal available contrast enhancement (maxCE) was evaluated in absolute terms with the purpose of assessing how much of the full, underlying magnetization can be exploited, for a wide range of compound properties (r₁, 2-45 mM⁻¹ s⁻¹ ; r₂ /r₁, 1.2-30). Despite the theoretically predicted loss in r1 relaxivity at high fields, the same maxCE can be obtained as at low fields if the r₂ /r₁ ratio remains unchanged, albeit at the cost of a longer sequence repetition time and 1.5-2 times higher administered doses. For a fixed maximum tissue concentration, there is an optimum field-dependent value for the r1 relaxivity that yields the greatest maxCE. If the upper bound for the gadolinium concentration is 2 mM, the greatest maxCE is found for compounds with a r₂/r₁ ratio of 1.2 and an r₁ relaxivity of 20.5 mM⁻¹ s⁻¹ at 3 T, 18 mM⁻¹ s⁻¹ at 7 T and 16.5 mM⁻¹ s⁻¹ at 9.4 T. For compounds that do not change their r1 relaxivity or r₂ /r₁ ratios, the necessary dose can be reduced by 10-15% owing to the improved background suppression at higher fields.

Systemic Exposure, Tissue Distribution, and Disease Evolution of a High Solubility Ciprofloxacin–Aluminum Complex in a Murine Model of Septicemia Induced bySalmonella entericaSerotype Enteritidis

A new pharmaceutical derivative obtained by stoichiometric complexation of ciprofloxacin (CIP) with aluminum (CIP-complex) has been investigated and reported in this study. Such product has high solubility in the gastrointestinal pH range and was successful in the development of optimized formulations while maintaining its antimicrobial potency. The systemic exposure, tissue distribution, and the disease evolution after given CIP-complex were assessed. The systemic exposure and distribution in intestines, lungs, and kidneys after a single intragastric administration of CIP-complex and CIP given alone, used as reference, were performed in Balb-C mice at a dose of 5 mg CIP/kg. For the assessment of the disease evolution assay, mice were infected with a virulent strain of Salmonella enterica serotype Enteritidis and treated intragastrically once or twice daily during 5 consecutive days with solutions of CIP-complex or the reference. Clinical follow up and survival was measured during 15 days post inoculation and health state was scored during this period from 0 to 5. CIP-complex showed a 32% increase in C(max), an earlier T(max), and a smaller AUC(0-12) than the reference. Maximum tissue concentrations (0.5-1 h) were significantly higher in CIP-complex (447% in intestine, 93% in kidney, and 44% in lungs). In the infection model used in this study, survival in CIP-complex versus CIP groups was 40% versus 20% (twice-daily administration) and 30% versus 0% (once-daily administration). Health state of the survivors of CIP-complex group (5/5) was higher than CIP group (3/5). The greater effectiveness of CIP-complex is attributed to the higher levels of CIP in the intestine. Our results supported the fact that CIP-complex is a promising candidate to develop dose-efficient formulations of CIP for oral administration.

Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis

Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection. The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment. While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species. About 10–20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA). While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA. However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis. The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8°C for 3months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4μg/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h.The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure.

Brain distribution and elimination of recombinant human TIMP-1 after cerebral ischemia and reperfusion in rats

Objective: To investigate recombinant human TIMP-1 (125I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm.Method: A suture model of the middle cerebral artery occlusion was used. 125I-labeled rhTIMP-1 at 60 μg/kg (11·23 μCi/μg) was administered to rats intravenously at the beginning of reperfusion. Blood and brain tissue were collected. The radioactivity was detected with a gamma counter and analyzed by autoradiography.Results: The blood half-life T1/2 of 125I-rhTIMP-1 was 42·2 hours. Thirty minutes after 125I-rhTIMP-1 administration, an increased accumulation of 125I-rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration Cmax was 26·1 ng/g at 1·5 hours in the striatum and 13·9 ng/g at 5 hours in the cortex when the uptake percentage of brain tissue to blood was 6·1±0·4 and 6·7±2·1%, respectively. The cortex and striatum elimination half-lives T1/2 were 45·3 and 39·2 hours, respectively. Electrophoretic analysis of ischemic samples for 125I-rhTIMP-1 showed a clear 28 kDa band 1·5 hours after 125I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3·0 hours of the administration. Some 125I-rhTIMP-1 maintained its molecular integrity for 8·5 hours in ischemic striatum after reperfusion.Discussion: 125I-labeled rhTIMP-1 was distributed quickly into ischemic brain tissue and had a slow elimination in both blood and brain tissue. These results, along with other studies suggesting therapeutic benefits, will aid in the development of TIMP-1 for protecting ischemic stroke.

Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape

Nitroxides are a class of stable free radicals that have several biomedical applications including radioprotection and noninvasive assessment of tissue redox status. For both of these applications, it is necessary to understand the in vivo biodistribution and reduction of nitroxides. In this study, magnetic resonance imaging was used to compare tissue accumulation (concentration) and reduction of two commonly studied nitroxides: the piperidine nitroxide Tempol and the pyrrolidine nitroxide 3-CP. It was found that 3-CP was reduced 3 to 11 times slower (depending on the tissue) than Tempol in vivo and that maximum tissue concentration varies substantially between tissues (0.6–7.2mM). For a given tissue, the maximum concentration usually did not vary between the two nitroxides. Furthermore, using electron paramagnetic resonance spectroscopy, we showed that the nitroxide reduction rate depends only weakly on cellular pO2 in the oxygen range expected in vivo. These observations, taken with the marked variation in nitroxide reduction rates observed between tissues, suggest that tissue pO2 is not a major determinant of the nitroxide reduction rate in vivo. For the purpose of redox imaging, 3-CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo.

Health Risk Assessment of Chemical Mixtures Exposure to Residents in the Lake Taihu Region, China

ABSTRACT This study assessed the mixture health risk for the residents of China's Lake Taihu region posed by a Persistent Organic Pollutants (POPs) mixture of dichloro-diphenyl-trichloroethane (DDT) and hexachlorocyclohexane (HCH). Multiple-pathway exposure models were used for exposure assessment in order to estimate the DDT and HCH exposure dose. The DDT and HCH PBPK models were developed and used for consequence assessment in order to analyze the pollutant distribution and accumulation process in human tissues. The tissue dose hazard index (HI) was used to estimate the mixture health risk. The results showed that the total exposure doses for male residents and female residents were 4.01 × 10− 4∼ 7.67 × 10− 3 mg/kg/day and 3.73 × 10− 4∼ 6.75 × 10− 3 mg/kg/day for DDT, respectively, and 3.78 × 10− 4∼ 5.14 × 10− 3 mg/kg/day and 3.53 × 10− 4∼ 4.66 × 10− 3 mg/kg/day for HCH, respectively. The maximum tissue concentrations in fat for male and female residents reached 110.51 mg/l and 97.21 mg/l for DDT, respectively, and 189.66 mg/l and 171.72 mg/l for HCH, respectively. The tissue dose hazard indexes for male and female residents were 0.1472 ∼ 2.4990 and 0.1377 ∼ 2.2230, respectively, and the probabilities of the risk exceeding the acceptable risk (HI = 1) for male and female were 24.60% and 16.51%, respectively.

Distribution and Excretion of Bilberry Anthocyanins in Mice

The physiology and tissue distribution of bilberry anthocyanins were studied in mice. After oral administration of bilberry extract (100 mg/kg body weight), both unmodified and methylated anthocyanins appeared in the plasma. The plasma concentration of total anthocyanins reached a maximum of 1.18 +/- 0.3 microM after 15 min and then sharply decreased. Their urinary excretion was highest between 0 and 6 h after administration and had ceased by 24 h. The total quantities of bilberry anthocyanins excreted into urine represented 1.88% (range, 0.62% to 2.45%) of consumed anthocyanins. Thirteen anthocyanins were identified in bilberry extracts. Of these, malvidin-3-glucoside and -3-galactoside were the principal anthocyanins in the plasma 60 min after administration. When mice were maintained for 2 weeks on a diet containing 0.5% of bilberry extracts, the plasma concentration of anthocyanins reached a maximum of 0.26 muM. Anthocyanins were detected only in the liver, kidney, testes, and lung, with maximum tissue concentrations of 605, 207, 149, and 116 pmol/g, respectively. In these organs, malvidin-3-glucoside and -3-galactoside were the predominant anthocyanins. Anthocyanins were not detectable in the spleen, thymus, heart, muscle, brain, white fat, or eyes. We conclude that bilberry anthocyanins were absorbed into the body and distributed in specific organs, particularly the liver, kidney, and testis. The most common anthocyanins in tissues were malvidin glycosides.

Differences in simulated liver concentrations of toxic coumarin metabolites in rats and different human populations evaluated through physiologically based biokinetic (PBBK) modeling

Coumarin is bioactivated via 3,4-epoxidation resulting in formation of the hepatotoxic o-hydroxyphenylacetaldehyde (oHPA) and detoxified by cytochrome P450 2A6 (CYP2A6) hydroxylation leading to 7-hydroxycoumarin. The present study defines physiologically based biokinetic (PBBK) models to predict liver levels of the toxic oHPA metabolite of coumarin in rats and in human subjects with normal or deficient CYP2A6 catalyzed coumarin 7-hydroxylation. The results reveal that the predicted maximum tissue concentration (C(max)) of oHPA in the liver of wild type human subjects and of subjects deficient in CYP2A6 catalyzed 7-hydroxylation are, respectively, three and one order of magnitude lower than the values predicted for rat liver. Another difference between CYP2A6 deficient and wild type human subjects is a 500-fold difference in the area under the curve 0-24h (AUC(0-24h)) for the time-dependent oHPA liver concentration pointing at a relative higher percentage of the original dose converted in time through this pathway when CYP2A6 is deficient. For wild type human subjects and the subjects with completely deficient coumarin 7-hydroxylation the AUC(0-24h) values for oHPA in the liver are, respectively, three and one order of magnitude lower than that for rat liver. Even when 7-hydroxylation is deficient, the chances on formation of the hepatotoxic oHPA metabolite will be significantly lower in the liver of humans than those expected in the liver of rats when exposed to a similar dose on a body-weight basis. This conclusion should be taken into account when extrapolating data from experimental studies in sensitive animals, i.e., rats, to the general human population.

Food safety aspects of toxic element accumulation in fish from wastewater‐fed ponds in Hanoi, Vietnam

To evaluate the food safety of fish from production systems in Hanoi feed with domestic and industrial wastewater with respect to the potentially toxic elements such as arsenic (As), cadmium (Cd) and lead (Pb). Common carp (Cyprinus carpio), silver carp (Hypophthalmichthys molitrix) and tilapia (Oreochromis niloticus) were sampled from wastewater-fed ponds, and total concentrations of As, Cd and Pb were determined in skin, liver and muscle. Arsenic, Cd and Pd concentrations were generally low and for many samples below the detection limit. The highest concentrations of Cd and Pb were found in the liver of tilapia, and the highest As concentration in the skin of tilapia. Maximum concentrations in muscle tissue were 0.120, 0.079 and 0.082 mg/kg fresh weight (f.w.) for As, Cd and Pb, respectively. Consumption of fish with maximum muscle tissue concentration will result in a human intake corresponding to 6.2%, 8.7% and 2.5% of the tolerable intake of these elements set by Codex Alimentarious Commission. The consumption of common carp, silver carp and tilapia produced in wastewater-fed ponds of Hanoi seems not to constitute a food safety problem with respect to As, Cd and Pb.

Mortality and toxin bioaccumulation in Bufo marinus following exposure to Cylindrospermopsis raciborskii cell extracts and live cultures

Cylindrospermopsis raciborskii is a cyanobacterium responsible for the production of the toxin, cylindrospermopsin (CYN). Tadpoles of the cane toad Bufo marinus were exposed to freeze-thawed whole cell extracts or live cultures of C. raciborskii containing maximum CYN concentrations of 400 μg L −1 or 232 μg L −1, respectively. Exposure to live culture treatment solutions resulted in up to 66% mortality of B. marinus, whereas tadpoles exposed to whole cell extracts containing similar toxin concentrations survived. Decreases in relative growth rates and time spent for swimming were recorded from tadpoles during both types of exposure regimes. Bioconcentration of CYN was not evident following exposure to whole cell extracts containing extracellular toxin. In contrast exposure to live cultures, which contained cell-bound toxin, resulted in maximum average tissue concentrations of 895 μg free-CYN kg −1 fresh weight. This is the first investigation of C. raciborskii exposure effects and toxin bioaccumulation in the developmental stages of an amphibian.

Assessment of a sewage sludge treatment on cadmium, copper and zinc bioavailability in barley, ryegrass and earthworms

The toxicity and bioavailability of metals were assessed to verify the efficiency of a new chemical leaching process (METIX-AC) to minimize the risk of metals found in municipal sewage sludge. For this purpose, sludge samples were spiked with cadmium, copper and/or zinc before being treated using METIX-AC. The sludge decontamination resulted in a removal of spiked metals (79–89%), in a decrease of the more labile fractions, and in a corresponding increase of the residual fraction. The toxicity observed after exposure of two plant species, barley ( Hordeum vulgare) and ryegrass ( Lolium perenne), and a terrestrial invertebrate, Eisenia andrei, to sludge-soil mixtures, disappeared after treatment, although the adverse effects were minor before treatment. The sludge treatment also significantly decreased the bioaccumulation of cadmium, copper, and zinc in the exposed species. For cadmium, maximum tissue concentrations of 0.45 ± 0.08 mg/kg in barley, 0.79 ± 0.27 mg/kg in ryegrass, and 21.82 ± 1.85 mg/kg in earthworm exposed to sludge before treatment decreased after treatment to values similar to those observed with negative controls.