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It is important that bathing water sites are free as possible from antibiotic resistant bacteria (ARB) to prevent the spread of difficult to treat infections throughout the population. This study examines the possible human exposure to antibiotic resistant Escherichia coli (AR-E. coli) through recreational activities at two different bathing water sites located near wastewater treatment plants (WWTPs). A quantitative risk assessment model was created to model the pathway of the AR-E. coli from the WWTPs effluent water through to the bathing water sites. Both sampling data and data from scientific literature were used. The main steps considered for the model were: the dilution and decay of the AR-E. coli from the WWTPs effluent water into the river; the dilution of the river into the bathing water sites and the human exposure to AR-E. coli through recreational activities at the bathing water sites (as a result of water ingestion). The results show the mean predicted human exposure levels ranged between 0.45 and 345.09 cfu/100 ml. A back calculation method determined that in accordance with the European Bathing Water Directive (2006/7/EC) (BWD) to be considered "poor" water quality, the concentration of AR-E. coli in WWTP effluent water would need to exceed 2.45 log cfu/ml at site 1 and exceed 2.71 log cfu/ml at site 2. This study provides valuable information for regulatory bodies and policy makers on the possible human exposure levels to AR-E. coli and the maximum permissible concentrations in WWTP effluent water to ensure compliance with relevant bathing water legislation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Body mass index (BMI) has not been shown to correlate with Patient Reported Outcome Measures (PROMs) following total knee arthroplasty (TKA). We investigated the relationship between weight, BMI, limb morphology, and Oxford Knee Score (OKS). Furthermore, the utility of a novel radiological measurement, the Knee Mass Index (KMI), was investigated., Methods: Data including weight, BMI, gender, preoperative and 12 month OKS were collected from an arthroplasty database that contained 268 patients who underwent TKA. Measurements of soft tissue and bone width were made from the preoperative radiograph and 'KMI' was calculated. Pearson correlation and multivariate regression analyses were used to assess the relationship between OKS and the above variables., Results: The novel measurement, KMI, was not a predictor of the OKS. The BMI was predictive of initial OKS (Odds Ratio (OR) -0.26 p < 0.001), 12 month OKS (OR -0.39 p < 0.001) and change in OKS (OR -0.39 p < 0.001). The initial OKS was predictive of 12 month OKS (OR 0.32 p < 0.001) and change in OKS (OR -0.68 p < 0.001)., Conclusions: The novel KMI metric was not useful in predicting function. Both the post-operative OKS and change in OKS are predicted by BMI and pre-operative OKS. This is one of the first studies to show a relationship between BMI and OKS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Antibiotic-resistant bacteria (ARB) are a potential threat to human health through drinking water with strong evidence of ARB presence in post treated tap water around the world. This study examines potential human exposure to antibiotic-resistant (AR) Escherichia coli (E. coli) through drinking water, the effect of different drinking water treatments on AR E. coli and the concentration of AR E. coli required in the source water for the EU Drinking Water Directive (DWD) (Council Directive 98/83/EC, 0CFU/100ml of E. coli in drinking water) to be exceeded. A number of scenarios were evaluated to examine different water treatment combinations and to reflect site specific conditions at a study site in Europe. A literature search was carried out to collate data on the effect of environmental conditions on AR E. coli, the effect of different water treatments on AR E. coli and typical human consumption levels of tap water. A human exposure assessment model was developed with probability distributions used to characterise uncertainty and variability in the input data. Overall results show the mean adult human exposure to AR E. coli from tap water consumption ranged between 3.44×10 -7 and 2.95×10 -1 cfu/day for the scenarios tested and varied depending on the water treatments used. The level of AR E. coli required in the source water pre-treatment to exceed the DWD varied between 1 and 5logcfu/ml, depending on the water treatments used. This can be used to set possible monitoring criteria in pre-treated water for potential ARB exposure in drinking water., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background & Aims: Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5beta-reductase., Methods: The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5beta-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice., Results: In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5beta-reductase (K(i) 9.19+/-0.40 microM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5beta-reductase activity, reduced urinary excretion of 3alpha,5beta-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5beta-reductase activity, supplementation of the fat-free diet with CDCA reduced 5beta-reductase activity, and urinary 3alpha,5beta-reduced corticosterone. Cholestasis in rats suppressed hepatic 5beta-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3alpha,5beta-tetrahydrocortisol was significantly lower than in healthy controls., Conclusion: These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic-pituitary-adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease., (Crown Copyright (c) 2010. Published by Elsevier B.V. All rights reserved.)

Clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, have revealed few side effects associated with its use. We here report a case of pancytopenia associated with the development of neutralizing antibodies to TPO that occurred in a patient who had undergone multicycle chemotherapy with multiple cycles of subcutaneous administration of pegylated recombinant human megakaryocyte growth and development factor. Samples of the patient's bone marrow showed trilineage hypoplasia with absence of myeloid, erythroid, and megakaryocyte progenitor cells but with elevated endogenous levels of erythropoietin, granulocyte colony-stimulating factor, and stem-cell factor. To our knowledge, this is the first report of an aplastic anemia-like syndrome associated with neutralizing antibodies to TPO.

To understand better the factors influencing the relationships among airborne particle exposure, lung burden, and fibrotic lung disease, we developed a biologically based kinetic model to predict the long-term retention of particles in the lungs of coal miners. This model includes alveolar, interstitial, and hilar lymph node compartments. The 131 miners in this study had worked in the Beckley, West Virginia, area and died during the 1960s. The data used to develop this model include exposure to respirable coal mine dust by intensity and duration within each job, lung and lymph node dust burdens at autopsy, pathological classification of fibrotic lung disease, and smoking history. Initial parameter estimates for this model were based on both human and animal data of particle deposition and clearance and on the biological and physical factors influencing these processes. Parameter estimation and model fit to the data were determined using least squares. Results show that the end-of-life lung dust burdens in these coal miners were substantially higher than expected from first-order clearance kinetics, yet lower than expected from the overloading of alveolar clearance predicted from rodent studies. The best-fitting and most parsimonious model includes processes for first-order alveolar-macrophage-mediated clearance and transfer of particles to the lung interstitium. These results are consistent with the particle retention patterns observed previously in the lungs of primates. The findings indicate that rodent models extrapolated to humans, without adjustment for the kinetic differences in particle clearance and retention, would be inadequate for predicting lung dust burdens in humans. Also, this human lung kinetic model predicts greater retained lung dust burdens from occupational exposure than predicted from current human models based on lower exposure data. This model is useful for risk assessment of particle-induced lung diseases, by estimating equivalent internal doses in rodents and humans and predicting lung burdens in humans with occupational dust exposures., (Copyright 2001 Academic Press.)

This presentation describes the development of a prototype Monte Carlo module for the physiologically-based pharmacokinetic (PBPK) model for lead, created by Dr Ellen O'Flaherty. The module uses distributions for the following: exposure parameters (soil and dust concentrations, daily soil and ingestion rate, water lead concentration, water ingestion rate, air lead concentration, inhalation rate and dietary lead intake); absoption parameters; and key pharmacokinetic parameters (red blood binding capacity and half saturation concentration). Distributions can be specified as time-invariant or can change with age. Monte Carlo model predicted blood levels were calibrated to empirically measured blood lead levels for children living in Midvale, Utah (a milling/smelting community). The calibrated model was then evaluated using blood lead data from Palmerton, Pennsylvania (a town with a former smelter) and Sandy, Utah, (a town with a former smelter and slag piles). Our initial evaluation using distributions for exposure parameters showed that the model accurately predicted geometric (GM) blood lead levels of Palmerton and Sandy and slightly over predicted the GSD. Consideration of uncertainty in red blood cell parameters substantially inflated the GM. Future model development needs to address the correlation among parameters and the use of parameters for long-term exposure derived from short-term studies.

Metastasis and the processes underlying this phenomenon make epithelial cancers so malignant. Local control of cancers by surgery is sometimes possible but locoregional and distant recurrence commonly lead to the failure of treatment with ensuing morbidity and mortality. Tumour cells express a range of new antigens during growth and there are opportunities for the host immune system to interact with these antigens. This immune interaction eliminates the tumour or allows selection of phenotypic variants. Cell phenotypes selected by an incomplete immune response resemble the cell type commonly associated with metastases. Thus we propose that the host immune system may be responsible for selection of this phenotype and progression of the disease.

This study examines time- and concentration-dependent changes in distribution of hexavalent chromium [Cr(VI)] and total chromium [Cr-(TOT)] in reconstituted human blood following addition of potassium dichromate. Fresh human blood stabilized with EDTA was obtained from human volunteers soon after meal ingestion and at 2.5 h after a light meal (herein defined as "2.5-h fasted" conditions). Cr(VI) spiked into plasma under 2.5-h fasting conditions at 3.0-12.5 micrograms/L was stable for several hours, indicating a lack of appreciable reductive capacity in isolated plasma. Spiked plasma following a recent meal exhibited immediate but variable reduction of Cr(VI) up to 300 micrograms/L. When the spiked plasma was recombined with the red blood cell (RBC) fraction, rapid reduction occurred in both the plasma and the RBC fractions based on measurement of Cr(VI) and Cr(TOT). The data indicate that plasma reduction capacity is enhanced by a recent meal, but may be overwhelmed at Cr(VI) concentrations between 2000 and 10,000 micrograms/L. These data also suggest that the RBC fraction apparently has the capacity to reduce Cr(VI) at concentrations in blood up to 15,000 micrograms/L, and that the rate of Cr(VI) uptake into RBCs may not exceed the rate of intracellular reduction at these concentrations.

When considered from a public health perspective, the central question regarding chemical mixtures is deceptively simple: Are current approaches to risk assessment for chemical mixtures affording effective (adequate) and efficient (cost-effective) protection for members of our society? Answering this question realistically depends on an understanding of the hierarchical goals of public health (i.e. prevention, intervention, treatment) and an accurate evaluation of the extent to which these goals are being achieved. To allow decision makers to make informed judgments about the health risks of chemical mixtures, adequate scientific knowledge and understanding must be available to support risk assessment activities, which are an integral part of the regulatory decision making process. Designing and implementing relevant research depends on the existence of a feedback loop between researchers and regulators, where the information needs of regulators influence the nature and direction of research and the information and understanding generated by researchers improves the scientific basis for public health decisions. A clear, consistent, commonly accepted taxonomy for describing important mixture-related phenomena is a key factor in creating and maintaining the necessary feedback loop. Ultimately, both researchers and regulators share a common goal with regard to chemical mixtures; improving the state-of-the-science so that we can make informed decisions about protecting public health. A survey of research issues and needs that are crucial to attaining this goal is presented.

Physiologically-based models for metals differ in several key respects from models for organic compounds. Although sequestration by binding to specific metal-binding proteins in liver, kidney, and red cell may be important, neither the magnitude and pattern of metabolism nor potential accumulation in fat is a component of models of metal kinetics. In addition, the long residence times of bone-seeking elements require that bone turnover and metabolism be incorporated into physiologically-based models for these elements. Three mechanism (rapid exchange at bone/blood interfaces, trapping or incorporation with forming bone and loss with resorbing bone, and slow exchange throughout the total bone volume) are potentially important in the overall interchange of bone-seeking elements between blood and bone. Three examples are given of applications of physiologically-based kinetic models for the bone-seeking elements lead, chromium, and uranium to assist in answering practical questions relating to bioavailability, distribution, and data interpretation.

This study provided an assessment of the effects of lead on early growth in rats based on structural equation modeling and nested analysis of variance (ANOVA). Structural equation modeling showed that lead in drinking water (250, 500, or 1000 ppm) had a direct negative effect on body weight and tail length (i.e., growth) in female rats during the first week of exposure. During the following 2 weeks of exposure, high correlation between growth measurements taken over time resulted in reduced early postnatal growth. By the fourth week of exposure, reduced growth was not evident. Mating began after 8 weeks of exposure, and exposure continued during gestation. Decreased fetal body weight was detected when the effects of litter size, intrauterine position, and sex were controlled in a nested ANOVA. Lead exposure did not appear to affect fetal skeletal development, possibly because lead did not alter maternal serum calcium and phosphorus levels. The effect of lead on individual fetal body weight suggests that additional studies are needed to examine the effect of maternal lead exposure on fetal development and early postnatal growth.

Reduction of hexavalent chromium (Cr(VI) to trivalent chromium (Cr(III) and differential kinetics of Cr(III) and Cr(VI) are important determinants of the disposition and toxicity of chromium. A physiologically based model of chromium disposition in the rat has been developed. The model takes into account different absorption and reduction rates in the lung and gastrointestinal tract; different efficiencies of transfer of Cr(III) and Cr(VI) into tissues including erythrocytes, where Cr(VI) is reduced to Cr(III) and retained for an extended period of time; uptake and storage in bone; and reabsorption of chromium from the gastrointestinal tract. The model is shown to be capable of generating the observed distributions of chromium between plasma and erythrocytes in rats given Cr(VI) intragastrically, intraduodenally, or intratracheally.

A model of the growing small animal skeleton has been developed. The model accurately reproduces a variety of different kinds of measurements made at different ages in different species, as well as reproducing a precise and detailed series of measurements in the growing guinea pig. Of the multiple mechanisms responsible for transfer of bone-seeking elements from blood to bone and back again, several are quantitatively insignificant on a skeletal scale. Surface (rapid) exchange, diffuse (slow) exchange, and secretion of new bone during growth are the principal determinants of skeletal metabolism. Bone blood flow can probably by satisfactorily modeled as a combination of a basal flow rate plus an increment that is directly proportional to formation rate of new bone.

Net free fatty acid release from adipose tissue taken from male rats fed a stock diet unsupplemented with chromium was significantly greater than that from adipose tissue taken from chromium-supplemented rats. This enhanced net lipolysis was unaccompanied by any evidence of a compensatory increase in reesterification. Specifically, the glycerokinase-catalyzed direct phosphorylation of glycerol, which might have provided an alternate supply of alpha-glycerophosphate for reesterification in the absence of glycolytic production of alpha-glycerophosphate, was significantly reduced. These animals also showed an abnormal glucose tolerance response. In contrast, male rats fed a purified diet unsupplemented with chromium appeared to be marginally chromium-deficient as judged by a glucose tolerance test but did not show any alterations in adipose tissue metabolism attributable to the adequacy of chromium nutriture.