Lower Elimination Rate Research Articles

A Novel Disease Affecting the Predatory Mite Phytoseiulus persimilis (Acari, Phytoseiidae): 2. Disease Transmission by Adult Females

Adult female Phytoseiulus persimilis Athias-Henriot (Acari, Phytoseiidae) of one of our laboratory populations (=NR-population), show the following set of symptoms: predators shrink several days after mating, cease egg production and die several days after shrinking, show a lower degree of attraction to herbivore-induced plant volatiles and a shorter choice time in olfactometer tests, have the tendency to leave a prey patch with ample food, may carry excretory crystals in the legs, may cease prey consumption, and have a lower excretion rate. We hypothesized earlier that this characteristic syndrome, called non-responding (=NR-) syndrome, is caused by a pathogen infecting P. persimilis. To further support this hypothesis we here study several transmission modes of the factor causing the NR-syndrome. In all tests we measured size, short-term fecundity, mortality, predator position, response to plant odors and crystal location, thus including 6 of the 9 symptoms known yet. No evidence was found for vertical transmission from parent to offspring. Eggs from symptomatic females of the NR-population mated by males of the NR-population gave rise to normal-sized, well performing predators, when they had been surface sterilized or transferred to a new leaf. However, such eggs gave rise to shrunken females (17%) when left on the leaf where they had been laid. In the latter case transmission via products deposited on the leaf by the mothers was possible. We therefore tested several modes of horizontal transmission by exposing females of a commercial population that never showed the NR-syndrome (=R1-population) to products related to the symptomatic NR-population. No evidence was found for transmission via food or via squashed adult females. However, symptoms were induced in adult females of the R1-population after a 3-day exposure to a live adult female of the NR-population (incubation period=3-7 days, fraction shrunken females=53%) and after a 1-day exposure to feces and debris collected from such females (incubation period=2-4 days, fraction shrunken females=65%). Contact with live females and feces of the R1-population did not induce the syndrome. These results clearly indicate that the NR-syndrome is a contagious phenomenon and that the factor inducing the syndrome is transmitted horizontally among and between generations via feces and debris deposited by symptomatic females. The results are discussed in the context of mite pathology and biological control.

Organotin accumulation in an estuarine food chain: Comparing field measurements with model estimations

The bioaccumulation model OMEGA (optimal modelling for ecotoxicological applications) is used to explore accumulation of organotins in the Western Scheldt food chain, consisting of herbi-detritivores, primary and secondary carnivorous fish and a piscivorous bird. Organotins studied are tributyltin (TBT) and triphenyltin (TPT) and the respective di- and mono-organotin metabolites. Empirical elimination rate constants are compared to model predictions for organic substances and metals. It is found that field bioaccumulation ratios are higher than predicted based on elimination kinetics relevant for organic compounds. The results indicate that uptake of organotins mainly occurs via hydrophobic mechanisms, whereas elimination may occur via metal-like kinetics. This results in very low elimination rates, which are comparable to model predictions for metals.

Unusual causes of hypokalaemia and paralysis

We demonstrate how the application of physiological principles may help to identify unusual causes of a very low plasma potassium (K+) concentration (P(K)) and paralysis. In the two patients described, the short time course of the illness suggested that there was an acute shift of K+ into cells. The combination of a low rate of excretion of K+, the absence of a metabolic acid-base disorder, and the fact that the clinical findings occurred very soon after a large intake of carbohydrate supported this impression. Surprisingly, the P(K) remained low for many hours after these stimuli to shift K+ into cells had abated. The missing link in this story was eventually provided by the attending medical team with the help of their mentor, Professor McCance.

End-stage renal disease in Brazil: Epidemiology, prevention, and treatment

Brazil is one of the largest and most populous nations in the world, ranking among the 5 largest economies in the Americas and among the 15 largest economies in the world. However, Brazil is still plagued by social problems such as the persistence of poverty and immense deficiencies in its health system. Currently, there are approximately 390 patients on chronic renal replacement therapy (RRT) per million population, about one third the US prevalence, which suggests that end-stage renal disease is either underdiagnosed or undertreated. The epidemiology of renal disease in the small remaining native Brazilian population is largely unknown. However, it is likely that the prevalence of renal disease is low among at least 2 tribes: the Yanomamis in northern Brazil and the Xingu Indians in central Brazil. Sodium intake is very low, physical activity is intense, and the prevalence of hypertension and cardiovascular disease is negligible among these people, which stresses the potential pathogenic importance of so-called civilized habits. There is currently no conclusive evidence that African descendants or any other Brazilian ethnic minorities are especially vulnerable to renal disease. Access to RRT in Brazil is universal. However, because both the end-stage renal disease population and operational RRT costs are steadily increasing, the system may face severe limitations in the near future. Much effort is needed to limit the prevalence of renal disease, to detain or retard the progression of chronic nephropathies, and to ensure that high-quality RRT will remain available to all those who need it.

The toxicokinetics of cadmium in carp under normoxic and hypoxic conditions

Temporal depletion of oxygen, i.e. hypoxic events, frequently occurs in natural waters. It has been suggested that accumulation of micro-pollutants increases in aquatic animals as a result of an increased ventilation rate during such occasions. The observed increased toxicity under hypoxia of micro-pollutants may support this hypothesis, but for heavy metals the available uptake studies are contradictory. The present study tests whether accumulation of cadmium in common carp, Cyprinus carpio (L.) is increased under hypoxia and if the toxicokinetics are altered. A cadmium toxicity study was performed in which the cadmium uptake rates were determined using the radiotracer 109Cd under hypoxia and normoxia. The cadmium toxicokinetics were studied with radiotracer experiments at 100% air saturation, 50%, and 25% saturation from 6.5 nmol/L Cd at 25 °C. We could confirm the higher sensitivity of carp to cadmium under hypoxia. Hypoxic conditions did not influence the uptake rates or the accumulation dynamics. Therefore, the increased sensitivity of carp for Cd under hypoxia cannot be explained by a higher Cd body burden, initiated by a higher uptake rate or lower elimination rate under hypoxia. Additional, possible indirect effects, such as internal anoxia due to gill damage, could play a role in Cd toxicity under hypoxia.

Occurrence and fate of pharmaceutically active compounds in the environment, a case study: Höje River in Sweden

Pharmaceutically active compounds (PhACs) in the environment lately have been acknowledged to constitute a health risk for humans and terrestrial and aquatic ecosystems. Human and veterinary applications are the main sources of PhACs in the environment and the major pathways are excretion and discharge to the environment through sewage treatment plants (STPs). In this study, the occurrence and fate of selected human PhACs belonging to different therapeutic classes (non-steroidal anti-inflammatory drugs, lipid regulators, anti-epileptics, antibiotics and β-blockers) were investigated in a small river in the very south of Sweden. The objectives of the study were to evaluate the impact of a high and rather constant load in sewage influent on downstream concentrations and whether substances that are metabolized to a high degree in humans also show a low persistency in a natural aquatic environment. Water samples were collected from the influent and effluent of the STP, in a series of dammed reservoirs leading to discharge into the Höje River in Sweden, and at several locations in the river downstream of the outfall. After enrichment by solid-phase extraction, the compounds were analyzed using GC–MS (methylated derivatives) or LC–MS/MS. In addition to the targeted pharmaceuticals, GC–MS analysis of the samples revealed the presence of other sewage-related pollutants (triclosan, caffeine, flame-retardants, antioxidants) and these results where included for comparison. Removal efficiencies were calculated in the STP and found to display a wide range with numerous species surviving treatment at greater than half their influent concentrations, including diclofenac, the anti-epileptic carbamazepine, a β-blocker (propanolol), and antibiotics trimetoprim and sulfamethoxazole. Low removals were also observed for Tris(2-chloroisopropyl)phosphate (flame retardant), BHT-aldehyde (oxidation product of BHT) and synthetic musk (HHCB). The concentrations of chloride (Cl −) and boron (B) were used as natural inert tracers to estimate the relative extent of dilution of PhACs measured in the effluent of the STP on concentrations measured further downstream. Based on spatial trends of concentrations (recalculated to reflect a hypothetical scenario with no dilution), ibuprofen, ketoprofen, naproxen and dicofenac were shown to be subject to significant abiotic or biotic transformations or physical sequestration in the river. The β-blockers atenolol, metoprolol and propanolol, the antibiotics trimetoprim and sulfametoxazole, and carbamazepine demonstrated a high degree of persistence. Fluctuations in the concentration of carbamazepine and gemfibrozil were observed along the series of reservoirs and within the river and are hypothesized to be due to release of parent compound from glucuronides. Several of the investigated substances (metaprolol, propanolol and carbamazepin) that exhibit low excretion rates as parent compounds demonstrate a surprising persistence in the aquatic environment. It is concluded that pharmaceutical substances with a high metabolic rate in humans (low excretion rate) do not necessarily induce a short lifetime in aquatic environments. Results from this study emphasize the need for a broader view on the concept of persistence that accounts for loading rates, in addition to removal mechanisms (e.g., transformation, volatility and physical sequestration by solids), under a variety of spatial and temporal scales.

Recurrent uric acid stones

A 46-year-old female had a history of recurrent uric acid stone formation, but the reason why uric acid precipitated in her urine was not obvious, because the rate of urate excretion was not high, urine volume was not low, and the pH in her 24-h urine was not low enough. In his discussion of the case, Professor McCance provided new insights into the pathophysiology of uric acid stone formation. He illustrated that measuring the pH in a 24-h urine might obscure the fact that the urine pH was low enough to cause uric acid to precipitate during most of the day. Because he found a low rate of excretion of NH(4)(+) relative to that of sulphate anions, as well as a high rate of citrate excretion, he speculated that the low urine pH would be due to a more alkaline pH in proximal convoluted tubule cells. He went on to suspect that there was a problem in our understanding of the function of renal medullary NH(3) shunt pathway, and he suggested that its major function might be to ensure a urine pH close to 6.0 throughout the day, to minimize the likelihood of forming uric acid kidney stones.

NOM increase in drinking water reservoirs - relevance for drinking water production

In the last 10–15 years in some German drinking water reservoirs an increase in the NOM (natural organic matter) content has occurred. The impact of such a change on the drinking water quality was almost unknown. A research project was carried out at several drinking water reservoirs and water works concerning the change in the NOM quality and the nutrient situation. The results indicate that the NOM increase in the reservoir is predominately caused by an increasing input of high and intermediate molecular weight humic substances from the catchment area into the reservoir. The fractions of the polysaccharides and the high molecular weight humic substances are significantly reduced in the treatment process. In contrast, the elimination rate for the substances with an intermediate and low molecular weight was low. Due to the low elimination rate particularly of the intermediate humic fraction, the NOM content of the treated water increased with the change in the raw water. Furthermore, the BDOC of the treated water increased with the NOM content. For the AOC of the treated water no relationship was found with the NOM content. However, the change of this parameter was affected by the snowmelt and the circulation in the reservoir.

Treatment with Pegylated Interferon α (PegIntron) for High-Risk Essential Thrombocythemia: Results of a Phase II Study.

In high risk Essential Thrombocythemia (ET) there is a indication for cytoreductive therapy. However, especially in younger patients long-term use of alkylating agents or hydroxyurea is a matter of concern. Modification of the pharmacokinetic profile of interferon α, a non-leukemogenic agent, through addition of a polyethylenglicol (pegylation) has resulted in slower absorption and lower elimination rate, thus enabling a weekly application with potentially increased compliance compared to conventional interferon α.In this phase II study we evaluate the safety, tolerability and efficacy of pegylated Interferon α (PegIntron, Essex Pharma) in high risk essential thrombocythemia. PegIntron is administered subcutaneously at a starting dose of 50 μg weekly. In patients not achieving a platelet count < 500 G/l after 8–12 weeks, the dosages can be increased by 25 μg/week up to 150 μg/week. Between 12/01 and 09/03 a total of 36 high risk ET patients (either platelet > 1500 G/l, or age> 60 years, or previous ET related complications) were enrolled by a total of 16 centers (16 male and 20 female patients, median platelet count at diagnosis 900 G/l, median age at diagnosis 54 years [range: 24–72 years]). Treatment was indicated because of at least one of the following reasons: Age > 60 years (38%), platelet count > 1500 G/l (36%) or previous ET related complications (50%). 10 patients (28%) were previously treated (hydroxyurea: 8 patients, anagrelide: 2 patients).In this analysis there are 35 of 36 patients evaluable, 1 patient was lost to follow-up. Of these 35 patients, 24 (69%) are still on therapy with PegIntron after a median observation time of 18 months. The individual dosages of PegIntron are shown in table 1. A platelet count < 500 G/l was achieved in 57% of the patients after 3 months and in 75% and 89% after 6 and 12 months, respectively.In 9 patients (26%) therapy was stopped because of drug related side effects (alopecia: 2 patients, arthralgia: 2 patients, flu-like symptoms: 2 patients, psoriasis: 1 patient, depression: 1 patient, diarrhea: 1 patient). In one patient an alternative cytoreductive therapy was initiated because of an insufficient platelet control. One patient suffered from a cerebral stroke and subsequently was taken off PegIntron application. After a median observation time of 18 months, we observed one potentially ET related complication (stroke) during PegIntron therapy so far.These preliminary data indicate the efficacy of PegIntron in the treatment of high risk ET at relatively low doses and reasonable toxicity and safety compared to conventional interferon α. [Display omitted]

Lutetium Speciation and Toxicity in a Microbial Bioassay: Testing the Free-Ion Model for Lanthanides

The validity of the free-ion model (FIM) for the element lutetium (Lu), a member of the lanthanides, was assessed in experiments with the bacterium Vibrio fischeri. The FIM is mainly based on divalent metals and synthetic ligands and has not yet been validated for the trivalent lanthanides. The bioluminescence response of V. fischeri was studied at different Lu concentrations in the presence and absence of natural and synthetic organic ligands [citrate, malate, oxalate, acetate, ethylenediaminetetraacetate (EDTA), and nitrilotriacetate (NTA)]. All ligands were tested separately to ensure that their concentrations would not cause adverse effects themselves. Free Lu3+ concentrations were calculated with a speciation program, after extension of its database with the relevant Lu equilibria. The results confirmed the FIM for Lu: that is, in contrast to total dissolved Lu concentrations, free Lu3+ concentrations had an apparent relationship with the response of V. fischeri. However, a contribution of minor inorganic Lu complexes cannot be ruled out. In the presence of malate and oxalate, the EC50 for Lu3+ decreased faster in time than for the other ligands, indicating lower elimination rates. With an EC50 of 1.57 microM, Lu3+ is more toxic than La3+, Cd2+, or Zn2+ and approximately equally as toxic as Cu2+. Although the pH increased slightly during the experiments, it was shown that the influence of pH on Lu speciation was limited.

Bioavailability and assimilation of sediment-associated benzo[a]pyrene by Ilyodrilus templetoni (Oligochaeta).

Benzo[a]pyrene (BaP)-amended sediment was desorbed by a sequential batch method using an isopropanol solution wash. The observed isotherm showed no evidence of desorption resistance, as indicated by increased partitioning to the solid phase at low concentrations. This was consistent with the prediction of minimal desorption resistance for highly hydrophobic compounds using a biphasic model. Bioavailability of BaP in desorbed sediments was assessed by toxicokinetic measures of uptake, bioaccumulation, and elimination in the deposit-feeding, freshwater tubificid oligochaete Ilyodrilus templetoni. Worms were exposed to sediments with BaP concentrations of approximately 26 and 11 microg/g dry weight sediment after desorption for one and three batches, respectively. The I. templetoni tissue concentration attained an apparent steady state after approximately one month and resulted in a biota-sediment accumulation factor of approximately 1.3 for both sediments. This is consistent with the paradigm that pore-water concentration predicts the uptake of organic contaminants into lipids despite the literature data showing that the major uptake route for BaP is likely from the ingestion of sediment particles. Ilyodrilus templetoni exhibited a high assimilation efficiency (80%) during a single-gut passage, a low elimination rate (k(c) = 0.0032 h(-1)), and negligible biotransformation of sediment-associated BaP.

The Effect of Dietary Selenium Source and Vitamin E Levels on Performance of Male Broilers

Selenium and vitamin E are micronutrients essential for normal health and maintenance in poultry. They are necessary in preventing free radical damage to phospholipid membranes, enzymes and other important molecules. Two experiments were conducted in a semi-commercial environment to examine the effect of Se source and vitamin E level in diet on broiler performance and meat quality. Increasing vitamin E from 50 IU to 100 IU did not affect growth performance of broilers although the 24 h drip-loss was tended to be reduced (p=0.06). There was an interaction between vitamin E and the source of Se in glutathione peroxidase activity (GSH-Px) and Se concentration in excreta. Increasing vitamin E from 50 IU to 100 IU elevated GSH-Px and Se concentration in excreta by 42 IU/g Hb and 0.9 ppm for the organic Se group, respectively, but reduced GSH-Px and Se concentration in excreta by 16 IU/g Hb and 1.3 ppm for inorganic group, respectively. Vitamin E played no role in the feather coverage of the birds when scored on day 37. Organic Se is more effective in improving feather score and 24 h drip-loss, with a markedly higher deposition rate in breast muscle and a lower excretion rate in the excreta (p 0.05) the energy utilisation by birds. (Asian-Aust. J. Anim. Sci. 2004. Vol 17, No. 7 : 1000-1006)

Seasonal variations in the physiological condition of the benthic amphipods Monoporeia affinis and Pontoporeia femorata in the Gulf of Riga (Baltic Sea)

Seasonal variations in the physiological condition of two benthic deposit-feeding amphipods were studied in two environmentally differing areas in the Gulf of Riga (Baltic Sea) with the purpose of estimating their role in benthic mineralisation. At the shallower (26 m) nearshore station, Monoporeia affinis exhibited low ammonia excretion rate (VNH 4 + ) throughout the year. After intensive accumulation of lipids in spring, the lipid reserves of the individuals became rapidly depleted during autumn. Gravid females in winter-early spring showed exceedingly low lipid and triacylglycerol (TAG) levels compared to studies carried out in open-sea areas. Pontoporeia femorata studied at the deeper (43 m) offshore station exhibited a higher VNH 4 + at all times with no significant seasonal variation. Lipid and TAG accumulated continuously until November, reaching higher levels than recorded previously for this species. Experiments showed that the temperature coefficient Q10 determined for VNH 4 + is likely to depend on the recent feeding history of the amphipods. Mineralisation of nitrogen and carbon by the amphipod populations at the study sites was estimated to be 1.7-3.0 g C and 11.3-13.5 mmol NH 4 + m–2 yr–1. Conclusively, both biotic and abiotic factors affect the condition of the amphipods, while the species also have genuine differences in their metabolic characteristics.

Quantitative assay of hepatitis B surface antigen in serum or plasma using laurell electrophoresis.

Hepatitis B virus (HBV) leads to an overexpression of its surface antigen (HBsAg) in the infected hepatocytes. HBsAg is constitutively secreted as pleomorphic particles, predominantly spherical and partly filamentous. Their diameter appears in negatively stained electron micrographs as approx 20 nm. HBsAg typically reaches serum concentrations between 30 and 100 μg/mL during the incubation phase before acute hepatitis B; in immunotolerant hepatitis B e antigen (HBeAg)-positive HBV carriers and immunosuppressed carriers, HBsAg reaches serum concentrations up to 1000 μg/mL, corresponding to 2×1013 or 2×1014 particles/mL, respectively (). Ahigh HBsAg concentration reflects both a large number of HBsAg-expressing cells and a low elimination rate of HBsAg.

Pharmacokinetic profile of meropenem, administered at 500 milligrams every 8 hours, in plasma and cantharidin-induced skin blister fluid.

The pharmacokinetic disposition of meropenem, administered at 500 mg every 8 h, in plasma and cantharidin-induced blister fluid is described. Peak meropenem concentrations in blister fluid lagged behind peak meropenem concentrations in plasma, while a lower elimination rate from blister fluid was also noted. The mean penetration of meropenem into blister fluid was 67%. The pharmacokinetic profile of meropenem in blister fluid supports the utility of this dose in the management of skin and soft tissue infections.

Physiological energetics of the protobranch bivalve Yoldia hyperborea in a cold ocean environment

Yoldia hyperborea is a deposit-feeding circumpolar protobranch that also inhabits muddy sediments of the cold water boreal system of Conception Bay, Newfoundland, Canada. Little is known about this species, despite its wide distribution and frequent high density in the benthos. The present work deals with oxygen consumption and ammonia excretion under cold ambient conditions. Y. hyperborea showed low basal metabolism [0.051 ml O2 h−1·(g dry weight)−1, T=−1°C] and low ammonia excretion rates [4.212 µg·NH4-N·h−1·(g dry weight)−1, T=−1°C]. Low metabolic activity could prove a useful strategy during periods of low food availability. In addition, Y. hyperborea was able to regulate its O2 consumption rate at very low pO2 levels, which may be advantageous for a species that may experience periods of hypoxia.

Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.

We examined human adipose tissue, liver, and bile from humans in Japan to understand the contamination status, specific accumulation, and elimination of two newly identified environmental contaminants, tris(4-chlorophenyl)methane (TCPMe), tris(4-chlorophenyl)methanol (TCPMOH), and other persistent organochlorines such as polychlorinated biphenyls (PCBs), DDT and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), and chlordane compounds (CHLs). TCPMe and TCPMOH concentrations in Japanese human adipose tissue were slightly higher than those reported previously, indicating widespread exposure to these compounds in humans. Elevated residues of PCBs and DDTs are found in adipose tissue and liver. Concentrations in bile strongly correlated with concentrations in adipose fat and liver, which may suggest an equilibration in adipose fat/bile and liver/bile and possible biliary excretion of persistent organochlorines in humans. Composition of the organochlorines accumulated further indicates a metabolic capacity in humans higher than that of marine mammals. We observed age-dependent accumulation for TCPMe, TCPMOH, and other organochlorines, but there were no significant gender differences. p,p'-DDE and TCPMe were estimated to have low biliary excretion rate. Elimination potential of persistent organochlorines may be related to their octanol-water partition coefficient. The relationship between excretion rate and octanol-water partition coefficient may be used to predict the biliary excretion potential of some other lipophilic organochlorines such as dioxins and dibenzofurans in humans. The presence of organochlorines in bile suggests that the hepatic excretory system plays a major role in the elimination of xenobiotics in humans. To our knowledge, this is the first study of accumulation and elimination of TCPMe and TCPMOH in humans.

Kinetics of arsenic in human blood after a fish meal

It is well known that fish contains high amounts of arsenic (As) compounds (mean values per wet weight [mg x kg-1] Ballin [1]: 41; Falconer et al. [2]: 14; Staveland et al. [3]: 5.2), which are mainly represented by organic As compounds, especially by arsenobetaine. It is generally assumed that arsenobetaine is rapidly eliminated via the urine and therefore seems to be non-toxic for humans. However, the kinetics of arsenobetaine in human blood are unknown to date. Therefore, the following experiments were performed: 14 women of 24 to 32 years of age voluntarily ingested 179 to 292 g of cooked plaice fillet containing 44 (minimum) to 276 (maximum) mg As x kg-1 dry weight. Hence, the volunteers ingested 2.5 (minimum) to 20 (maximum) mg As per person, equivalent to 0.04 to 0.35 mg As x kg-1 body weight. The element As was measured by atomic absorption spectrometry using the graphite furnace technique in order to detect the total amount of As including that of the stable arsenobetaine. In the blood, the highest As values of 55 +/- 5.8 micrograms x L-1 (median) were found 2 hours after fish ingestion. Subsequently the As concentrations declined reaching 16 +/- 0.69 micrograms x L-1 (median) 48 hours after fish ingestion. In respect of the As values in blood recorded between 2 and 10 hours after fish ingestion, rapid elimination could be observed leading to a half-life of 7.1 hours (first value) recorded by linear regression analysis. With regard to the As values in blood between 10 and 48 hours after fish ingestion, a lower elimination rate was estimated with a longer half-life of 63 hours (second value). The reason for this delayed elimination of As is not known. The results indicate that As mainly absorbed as arsenonetaine due to ingestion of fish is not eliminated as fast as had been expected on the basis of published data. As long as it is not known what happens to arsenobetaine remaining for longer periods in the blood with a half-life of 63 hours, caution is advised regarding the general opinion that arsenobetaine is rapidly eliminated and non-toxic for human consumption.

Oral bioavailability and pharmacokinetics of elimination of 9-hydroxybenzo[a]pyrene and its glucoside and sulfate conjugates after administration to male and female American lobsters, Homarus americanus.

The pharmacokinetics of [(3)H]-9-hydroxybenzo[a]pyrene (9-OH-BaP), a highly lipophilic primary metabolite of benzo(a)pyrene, were examined after intrapericardial (iv) or oral doses of 50 or 200 microg/kg to intermolt American lobsters, Homarus americanus. Combining data for all lobsters, the average terminal elimination half-life of parent 9-OH-BaP was 97.3 h after iv and 56.5 h after oral administration, considerably less than found previously for benzo(a)pyrene (720 h). The oral bioavailability of parent 9-OH-BaP, calculated from the area under the hemolymph concentration curve, was 15.9%. The low bioavailability and variable elimination rates were attributed to extensive first-pass conjugation and sequestration in the hepatopancreas. BaP-9-sulfate was the major metabolite. Hemolymph concentrations of BaP-9-sulfate increased up to one day after the dose, and then decreased, with a terminal elimination half-life of 45 h. BaP 9-beta-D-glucoside was a minor metabolite in most hemolymph and tissue samples; an exception was hemolymph from the iv high-dose group. Concentrations of 9-OH-BaP and metabolites in the edible muscle tissue were similar to those in hemolymph, and 9-OH-BaP residues at 10 to 16 days after the dose were 3 to 12 ng/g muscle. Sulfotransferase and UDP-glucosyltransferase (UGT) activities with 9-OH-BaP were found in the antennal gland, intestinal mucosa, and hepatopancreas (UGT only). Sulfatase activity with BaP-9-sulfate, found in both the hepatopancreas and the antennal gland, was thought to contribute to metabolite cycling. These studies showed that 9-OH-BaP was readily conjugated to sulfate and glucose in the lobster, and that despite their high lipophilicity, 9-OH-BaP and conjugates were excreted from the lobster hemolymph and tissues much more rapidly than benzo[a]pyrene.

Renal NO production and the development of hypertension.

The juxtaglomerular apparatus (JGA) has the very important functions of detecting the fluid flow rate to the distal tubule and thus controlling the glomerular filtration rate (GFR) (tubuloglomerular feedback mechanism [TGF]) and renin release from the afferent arteriole. In studies of the TGF it has been evident that the sensitivity of this mechanism can be reset. Volume expansion will reset it to a low sensitivity leading to a high GFR and urine excretion rate, while dehydration will sensitize the TGF mechanism, giving rise to a low GFR and low urine excretion rate. Furthermore, we have found that in animals that spontaneously develop hypertension there is initially a sensitization of the TGF, leading to a reduced GFR and urine excretion rate, with fluid volume retention in the body and a consequent rise in blood pressure. When the pressure is raised, the TGF characteristics are normalized. In the macula densa (MD) cells in the JGA, there is a large production of NO from neuronal NOS. This production continuously reduces TGF sensitivity and is apparently impaired in animals that spontaneously develop hypertension. When we added an nNOS inhibitor to the drinking water for several weeks while measuring blood pressure, we found an increase in blood pressure after 3-4 weeks of treatment. This effect was abolished by a high salt diet. From these investigations, it also appeared as if nNOS-derived NO inhibited renin release. Experiments have also indicated that NO may resensitize inhibited G-protein coupled purinergic receptors.