Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead.

Context: Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans.

Context: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning.

Objective: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model.

Material And Methods: This was a kinetic modelling study.

Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations.

Titanium dioxide white pigment consists of particles of various sizes, from which a fraction is in the nano range (<100 nm). It is applied in food as additive E 171 as well as in other products, such as food supplements and toothpaste. Here, we assessed whether a human health risk can be expected from oral ingestion of these titanium dioxide nanoparticles (TiO NPs), based on currently available information.

Carry-over of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in dairy cows fed smoke contaminated maize silage or sugar beet pulp.

Fires and improper drying may result in contamination of feed with PCDD/Fs and PCBs. To predict the impact of elevated feed levels, it is important to understand the carry-over to edible products from food producing animals. Therefore, a carry-over study was performed with maize silage contaminated by a fire with PVC materials, and with sugar beet pulp contaminated by drying with coal, containing particles from a plastic roof.

Implementation of toxicokinetics in toxicity studies--Toxicokinetics of 4-methylanisole and its metabolites in juvenile and adult rats.

The current risk assessment of compounds is generally based on external exposure and effect relationships. External doses are often not representative for internal exposure concentrations. The aim of this study was to show how the implementation of toxicokinetics in a scheduled toxicity study contributes to improved data interpretation without additional use of animals and to the three goals of the 3R principles for animal testing.

Concentrations of dimethylaniline and other metabolites in milk and tissues of dairy cows treated with lidocaine.

Lidocaine is a topical anaesthetic drug used in dairy cows for laparotomy (caesarean section, abomasal displacement). Because there are no registered drugs for this indication, it can be applied under the so-called Cascade rules (off-label use), with the restriction that the off-label withdrawal periods of 7 days for milk and 28 days for meat are taken into account. In animals, lidocaine is rapidly metabolised into various metabolites, one being 2,6-dimethylaniline (DMA) which is reported to possess carcinogenic and mutagenic properties and detected also in milk.

Biokinetics of chlorpromazine in primary rat and human hepatocytes and human HepaRG cells after repeated exposure.

Since drug induced liver injury is difficult to predict in animal models, more representative tests are needed to better evaluate these effects in humans. Existing in vitro systems hold great potential to detect hepatotoxicity of pharmaceuticals. In this study, the in vitro biokinetics of the model hepatotoxicant chlorpromazine (CPZ) were evaluated in three different liver cell systems after repeated exposure in order to incorporate repeated-dose testing into an in vitro assay.

Carryover of cadmium from feed in growing pigs.

Growing male pigs were exposed to cadmium (Cd) at levels around 1 and 10 mg kg(-1) feed for up to 12 weeks, administered as CdCl2 or Cd-cysteine (CdCys). Pigs exposed to 10 mg kg(-1) showed decreased growth during the last 3 weeks. Liver and kidney concentrations of Cd continuously increased over the entire 12-week exposure, exceeding the European Union limits of 1.

Novel insights into the risk assessment of the nanomaterial synthetic amorphous silica, additive E551, in food.

This study presents novel insights in the risk assessment of synthetic amorphous silica (SAS) in food. SAS is a nanostructured material consisting of aggregates and agglomerates of primary particles in the nanorange (<100 nm). Depending on the production process, SAS exists in four main forms, and each form comprises various types with different physicochemical characteristics.

Infectious disease transmission as a forensic problem: who infected whom?

Observations on infectious diseases often consist of a sample of cases, distinguished by symptoms, and other characteristics, such as onset dates, spatial locations, genetic sequence of the pathogen and/or physiological and clinical data. Cases are often clustered, in space and time, suggesting that they are connected. By defining kernel functions for pairwise analysis of cases, a matrix of transmission probabilities can be estimated.

Benefit-risk assessment of plant sterols in margarine: a QALIBRA case study.

This paper presents the benefit-risk assessment of adding plant sterols to margarine as an illustration of the QALIBRA method and software. With the QALIBRA tool health effects, risks as well as benefits are expressed in a common metric (DALY) which allows quantitative balancing of benefits and risks of food intake. The QALIBRA software can handle uncertainties in a probabilistic simulation.

An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry.

We developed a population physiology model, physB, which provides a statistical description of the physiological characteristics in the human population, in terms of the physiological parameters that are needed in physiologically based pharmacokinetic modelling. The model predicts individual organ weights, blood flows and some respiratory parameters from anthropometric properties (body height and weight, age and gender). It draws on two existing models, PK-Pop and P(3)M, but various changes and improvements were made.

Transport of chlorpromazine in the Caco-2 cell permeability assay: a kinetic study.

The intestinal transport of compounds can be measured in vitro with Caco-2 cell monolayers. We took a closer look at the exposure and fate of a chemical in the Caco-2 cell assay, including the effect of protein binding. Transport of chlorpromazine (CPZ) was measured in the absorptive and secretory direction, with and without albumin basolaterally.

Fish consumption during child bearing age: a quantitative risk-benefit analysis on neurodevelopment.

The fish ingredient N3-docosahexaenoic acid 22:6 n-3 (DHA) stimulates brain development. On the other hand methylmercury (MeHg) in fish disturbs the developing central nervous system. In this Context the IQ score in children is considered as an aggregate measure of in utero brain development.

Modelling approach to simulate reductions in LDL cholesterol levels after combined intake of statins and phytosterols/-stanols in humans.

Background: To examine the effects on LDL cholesterol of the combined use of statins and phytosterols/-stanols, in vivo studies and clinical trials are necessary. However, for a better interpretation of the experimental data as well as to possibly predict cholesterol levels given a certain dosing regimen of statins and phytosterols/-stanols a more theoretically based approach is helpful. This study aims to construct a mathematical model to simulate reductions in low-density lipoprotein (LDL) cholesterol in persons who combine the use of statins with a high intake of phytosterols/-stanols, e.

Disposition of smoked cannabis with high Δ(9)-tetrahydrocannabinol content: a kinetic model.

Introduction: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC).

Methods: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.

Effect of administration route on the biodistribution and shedding of replication-deficient AAV2: a qualitative modelling approach.

Gene therapy is a rapidly developing field in which recombinant nucleic acid sequences are introduced to individuals to regulate, repair, replace, add or delete a genetic sequence. Recombinant adeno-associated viral (AAV) vectors, especially AAV2, are frequently used in gene therapy. Knowledge on the biodistribution and potential shedding of AAV2 is crucial to evaluate the risks of infection with the viral vector for the patient and the environment.

Effect of administration route on the biodistribution and shedding of replication-deficient HAdV-5: a qualitative modelling approach.

Gene therapy is a rapidly developing field in which recombinant nucleic acid sequences are introduced to individuals. Its therapeutic, prophylactic or diagnostic effect relates directly to the sequence it contains or to the product of genetic expression of this sequence. Recombinant adenoviral vectors (in particular HAdV-5 vectors) are frequently used in gene therapy.

Kaolinic clay derived PCDD/Fs in the feed chain from a sorting process for potatoes.

At the end of 2004, during a routine monitoring project, high levels of PCDDs in milk from two farms were found. Using a bioassay and the congener patterns obtained by HRGC/HRMS, the source was traced back to the use of kaolinic clay for sorting potatoes in a production process of French fries. Rest products, especially peelings after scrubbing, were used as feed for dairy cows.

Dose addition and the isobole method as approaches for predicting the cumulative effect of non-interacting chemicals: a critical evaluation.

The prediction of the effect of cumulative exposure to similarly acting chemicals is commonly done by dose addition, such as in the relative potency factor approach. This can only be done under the assumption of zero interaction between the chemicals. The related, but not equivalent, isobole method is the most common criterion to judge whether interactions between similarly acting chemicals have taken place in a mixture experiment.

Toxicodynamic analysis of the inhibition of isolated human acetylcholinesterase by combinations of methamidophos and methomyl in vitro.

The applicability of dose addition to combinations of OP-esters and carbamates has been questioned based on theoretical considerations, but these have not been well supported by experimental findings. In the present study, the inhibition of AChE by combinations of methamidophos (an OP-ester) and methomyl (a carbamate) was examined in vitro. AChE inhibition was measured by the Ellman assay.

Toxicodynamic analysis of the combined cholinesterase inhibition by paraoxon and methamidophos in human whole blood.

Theoretical work has shown that the isobole method is not generally valid as a method for testing the absence or presence of interaction (in the biochemical sense) between chemicals. The present study illustrates how interaction can be tested by fitting a toxicodynamic model to the results of a mixture experiment. The inhibition of cholinesterases (ChE) in human whole blood by various dose combinations of paraoxon and methamidophos was measured in vitro.

Facilitated transport of polychlorinated biphenyls and polybrominated diphenyl ethers by dissolved organic matter.

The exchange rate of hydrophobic organic chemicals between the aqueous phase and a sorbent (e.g., soil, organism, passive sampler) is relevant for distribution processes between environmental compartments, including organisms.

Influence of albumin on sorption kinetics in solid-phase microextraction: consequences for chemical analyses and uptake processes.

Because of its simplicity, solid-phase microextraction (SPME) is an increasingly popular technique to use in experiments measuring freely dissolved concentrations of compounds in biological and environmental samples. However, a number of studies have shown that sorption kinetics of compounds in such SPME systems is dependent on the presence of a binding matrix. This affects the interpretability of nonequilibrium SPME data.

A simple steady-state model for carry-over of aflatoxins from feed to cow's milk.

A simple steady-state model is derived from two kinetic one-compartment models for the disposition of aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) in the lactating cow. The model relates daily intake of AFB1 in feed of dairy cattle and the cow's lactation status to resulting concentrations of AFM1 in milk. Moreover, assuming a linear relationship between the cow's lactation status and feed intake, the model relates daily milk production and AFB1 concentration in total feed to AFM1 levels in milk.