Model voor de schatting van de initiele lichaamsbelasting en de dagelijkse absorptie van lipofiele verontreinigingen in landbouwhuisdieren

Many lipophilic organic contaminants in the environment are toxic for humans and animals. The presence of this class of contaminants in animal products (meat and milk) intended for human consumption thus involves health risks to the general population. In order to assess these risks, concentrations of contaminants in domestic animals are monitored by occasional measurements on blood (plasma) or milk of living animals. A computer model to translate such measured concentrations into historical absorption and burden of the compound, and into the future residues expected in meat and milk products, is described. The methodology is based on a Physiologically Based Pharmaco Kinetic model for lipophilic contaminants in domestic animals. Validation of the proposed method was carried out using the results of experiments in which lactating and non-lactating cows were exposed to 2378-TCDD, and lactating and non-lactating goats to lindane and a number of PCB congeners. In the above-mentioned experiments, the animals were internally exposed by injecting known amounts of contaminant into their rumen. Concentration measurements were used to estimate the initial burden and the daily absorption of the PBPK model. Validation was carried out by comparing estimated initial burden and the daily absorption with the doses imposed in the experiment. The results show that the estimated initial body burdens are lower than the doses imposed by the bolus injection in the rumen. This indicates that absorption from the intestine is probably incomplete. The estimates of daily absorption correspond to zero or trace values for the stages in which the animals were fed with food devoid of the contaminant. The model is intended for use by veterinary services/inspections as a screening tool to estimate exposures and residues.Veel lipofiele organische milieucontaminanten zijn toxisch voor mens en dier. De aanwezigheid van deze contaminanten in vlees- en/of melkproducten bestemd voor menselijke consumptie kunnen daarom een gezondheidsrisico voor de bevolking vormen. Om de risico's te kunnen beoordelen worden incidenteel concentraties gemeten in bloedplasma of melk van levende dieren. Dit rapport presenteert een computer model om dergelijke metingen te vertalen naar de historische opname van de component en de te verwachten residuen in vlees en melk. De methodologie is gebaseerd op een "Physiologically Based Pharmaco Kinetic" model voor lipofiele contaminanten in landbouwhuisdieren. Validatie van de voorgestelde methode werd uitgevoerd m.b.v. de resultaten van experimenten waarin lacterende en niet-lacterende koeien werden blootgesteld aan 2378-TCDD en lacterende en niet-lacterende geiten aan lindaan en een aantal PCB congeneren. In de bovengenoemde studies werden de dieren blootgesteld door bekende hoeveelheden contaminant in het rumen te spuiten, waarna concentraties in melk, bloedplasma, of vet werden gemeten in de tijd. Deze metingen werden aangewend om de initikle belasting en de dagelijkse absorptie van de contaminant te schatten. Validatie vond plaats door de geschatte waarden te vergelijken met de initikle belasting en de dagelijkse absorptie die waren opgelegd in het experiment. De resultaten laten zien dat na een bolus injectie in het rumen de geschatte initikle belasting van het lichaam over het algemeen lager is dan de opgelegde hoeveelheid. Dit kan duiden op incomplete absorptie uit de darm. De geschatte dagelijkse absorptie was nul of bijna nul voor de perioden dat de dieren schoon voedsel aangeboden kregen. Het model is bedoeld om gebruikt te worden door veterinaire inspecties als een 'screening' instrument om een eerste indruk te krijgen van blootstellingen en residuen en de daarbij behorende gezondheidsrisico's

The Budget Impact of Oral Nutritional Supplements for Disease Related Malnutrition in Elderly in the Community Setting

A health economic analysis was performed to assess the economic impact on the national health care budget of using oral nutritional supplements (ONS), being a food for special medical purposes also known as medical nutrition, for the treatment of disease related malnutrition (DRM) in the community in the Netherlands. An economic model was developed to calculate the budget impact of using ONS in community dwelling elderly (>5 years) with DRM in the Netherlands. The model reflects the costs of DRM and the cost reductions resulting from improvement in DRM due to treatment with ONS. Using ONS for the treatment of DRM in community dwelling elderly, leads to a total annual cost savings of € 13 million (18.9% savings), when all eligible patients are treated. The additional costs of ONS (€ 57 million) are more than balanced by a reduction of other health care costs, e.g., re-/hospitalization (€ 70 million). Sensitivity analyses were performed on all parameters, including duration of treatment with ONS and the prevalence of DRM. This budget impact analysis shows that the use of ONS for treatment of DRM in elderly patients in the community may lead to cost savings in the Netherlands

First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development

Dose selection for “first in children” trials often relies on scaling of the pharmacokinetics from adults to children. Commonly used approaches are physiologically-based pharmacokinetic modeling (PBPK) and allometric scaling (AS) in combination with maturation of clearance for early life. In this investigation, a comparison of the two approaches was performed to provide insight into the physiological meaning of AS maturation functions and their interchangeability. The analysis focused on the AS maturation functions established using paracetamol and morphine paediatric data after intravenous administration. First, the estimated AS maturation functions were compared with the maturation functions of the liver enzymes as used in the PBPK models. Second, absolute clearance predictions using AS in combination with maturation functions were compared to PBPK predictions for hypothetical drugs with different pharmacokinetic properties. The results of this investigation showed that AS maturation functions do not solely represent ontogeny of enzyme activity, but aggregate multiple pharmacokinetic properties, as for example extraction ratio and lipophilicity (log P). Especially in children younger than 1 year, predictions using AS in combination with maturation functions and PBPK were not interchangeable. This highlights the necessity of investigating methodological uncertainty to allow a proper estimation of the “first dose in children” and assessment of its risk and benefits

Application of the Convection–Dispersion Equation to Modelling Oral Drug Absorption

Models of systemic drug absorption after oral administration are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict drug concentrations in blood plasma frequently yields a considerable mismatch between predicted and measured concentration profiles. This is particularly true for the upswing of the plasma concentration after oral administration. The current investigation explores an alternative model to describe the absorption rate based on the convection–dispersion equation describing the transport of chemicals through the GI tract. This equation is governed by two parameters, transport velocity and dispersion coefficient. One solution of this equation for a specific set of initial and boundary conditions was used to model absorption of paracetamol in a 22-year-old man after oral administration. The GI-tract passage rate in this subject was influenced by co-administration of drugs that stimulate or delay gastric emptying. The transport-limited absorption function is more accurate in describing the plasma concentration versus time curve after oral administration than the first-order model. Additionally, it provides a mechanistic explanation for the observed curve through the differences in GI-tract passage rate

Prediagnostic Serum Concentrations of Organochlorine Compounds and Risk of Testicular Germ Cell Tumors

BACKGROUND: Recent findings suggest that exposure to organochlorine (OC) compounds, chlordanes and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) in particular, may increase the risk of developing testicular germ cell tumors (TGCTs). OBJECTIVE: To further investigate this question, we conducted a nested case-control study of TGCTs within the Norwegian Janus Serum Bank cohort. METHODS: The study was conducted among individuals with serum collected between 1972 and 1978. TGCT cases diagnosed through 1999 (n = 49; 27-62 years of age at diagnosis) were identified through linkage to the Norwegian Cancer Registry. Controls (n =51) were matched to cases on region, blood draw year, and age at blood draw. Measurements of 11 OC insecticide compounds and 34 polychlorinated biphenyl (PCB) congeners were performed using gas chromatography/high-resolution mass spectrometry. Case-control comparisons of lipid-adjusted analyte concentrations were performed using the Wilcoxon signed-rank test. Odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles of analyte concentration were calculated using conditional logistic regression. RESULTS: TGCT cases had elevated concentrations of p,p′-DDE (tertile 3 vs. tertile 1 OR (ORT3) 2.2; 95% CI, 0.7-6.5; p Wilcoxon = 0.07), oxychlordane (ORT3 3.2; 95% CI, 0.6-16.8; pWilcoxon = 0.05), trans-nonachlor (ORT3 2.6; 95% CI, 0.7-8.9; pWilcoxon = 0.07), and total chlordanes (OR T3 2.0; 95% CI, 0.6-7.2; pWilcoxon = 0.048) compared with controls, although no ORs were statistically significant. Seminoma cases had significantly lower concentrations of PCB congeners 44, 49, and 52 and significantly higher concentrations of PCBs 99, 138, 153, 167, 183, and 195. CONCLUSIONS: Our study provides additional but qualified evidence supporting an association between exposures to p,p′-DDE and chlordane compounds, and possibly some PCB congeners, and TGCT risk

Nutrition screening tools used to identify malnutrition risk in hospitalized patients: a systematic review and meta-analysis protocol

Background: Malnutrition is a clinical problem with a high prevalence in hospitalized adult patients. Many nutritional screening tools have been developed but there is no consensus on which 1 is more useful. The purpose of this review protocol is to provide an overview of which nutritional screening tool is most valid to identify malnutritional risk in hospitalized adult patients and to analyze the sensitivity and specificity of the different tools. Methods: The protocol of this systematic review and meta-analysis was registered on the INPLASY website (https://inplasy.com/inplasy-2020-9-0028/) and INPLASY registration number is INPLASY202090028. We will perform a systematic literature search of main databases: PubMed, EMBASE, CINAHL and Web of Science and the Cochrane database. Also, grey literature will be search. Peer-reviewed studies published in English, Portuguese or Spanish language will be selected. Screening of titles, abstract and full text will be assessed for eligibility by 2 independent blinded reviewers and any discrepancies will be resolved via consensus. After screening the studies, a meta-analysis will be conducted, if it is possible. Results: Results from this systematic review will help health professionals to identify malnutrition in hospitalized patients and to make decisions to prevent or treat it as well as provide new clues to researchers. Conclusion: Our systematic review will provide aknowledge about the most valid malnutrition risk screening tool in hospitalized adult patients

Extensions to the Visual Predictive Check to facilitate model performance evaluation

The Visual Predictive Check (VPC) is a valuable and supportive instrument for evaluating model performance. However in its most commonly applied form, the method largely depends on a subjective comparison of the distribution of the simulated data with the observed data, without explicitly quantifying and relating the information in both. In recent adaptations to the VPC this drawback is taken into consideration by presenting the observed and predicted data as percentiles. In addition, in some of these adaptations the uncertainty in the predictions is represented visually. However, it is not assessed whether the expected random distribution of the observations around the predicted median trend is realised in relation to the number of observations. Moreover the influence of and the information residing in missing data at each time point is not taken into consideration. Therefore, in this investigation the VPC is extended with two methods to support a less subjective and thereby more adequate evaluation of model performance: (i) the Quantified Visual Predictive Check (QVPC) and (ii) the Bootstrap Visual Predictive Check (BVPC). The QVPC presents the distribution of the observations as a percentage, thus regardless the density of the data, above and below the predicted median at each time point, while also visualising the percentage of unavailable data. The BVPC weighs the predicted median against the 5th, 50th and 95th percentiles resulting from a bootstrap of the observed data median at each time point, while accounting for the number and the theoretical position of unavailable data. The proposed extensions to the VPC are illustrated by a pharmacokinetic simulation example and applied to a pharmacodynamic disease progression example

Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

Introduction. A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods. Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg j1 of fluvoxamine. Analysis. With increasing dose a disproportional increase in brain concentrations was observed. Th

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Background & Aims: Excess liver iron content is common and is linked to hepatic and extrahepatic disease risk. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals in UK Biobank with MRI quantified liver iron, and validated our findings in an independent cohort (n=1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 29 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 anthropometric traits and diseases. Results: We identified three independent genetic variants (rs1800562 (C282Y) and rs1799945 (H63D) in HFE and rs855791 (V736A) in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p<5x10-8). The two HFE variants account for ~85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases