Estimation of seroconversion rates for infectious diseases: Effects of age and noise.

The presence of serum antibodies is a biomarker of past infection. Instead of seroclassification aimed at measuring seroprevalence a population sample of serum antibody levels may be used to estimate the incidence of seroconversion. This article expands an earlier study into seroincidence estimation, employing models of the seroresponse that include probability of escaping infection, as well as nonexponential decay kinetics and different sources of noise. As previously, a constant force of infection is assumed. When the seroconversion rate is low, a substantial fraction of the population may not be old enough to have experienced any seroconversions, causing underestimation of seroconversion rates that may be substantial at young ages. A correction is given that can be shown to remove such age dependent bias. Simulation studies show that the updated models provide accurate estimates of seroconversion rates, but also that the presence of noise, when unaccounted for, may introduce considerable bias, especially at low (< 0.1/yr) seroconversion rates and young ages. The revised serocalculator scripts can be used to update the R package "seroincidence."

Detection of titanium particles in human liver and spleen and possible health implications.

BACKGROUND: Titanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal studies. A health risk from nanosized TiO2 particle consumption could not be excluded then. RESULTS: Here we show the first quantification of both total titanium (Ti) and TiO2 particles in 15 post-mortem human livers and spleens. These low-level analyses were enabled by the use of fully validated (single particle) inductively coupled plasma high resolution mass spectrometry ((sp)ICP-HRMS) detection methods for total Ti and TiO2 particles. The presence of TiO2 in the particles in tissues was confirmed by Scanning Electron Microscopy with energy dispersive X-ray spectrometry. CONCLUSIONS: These results prove that TiO2 particles are present in human liver and spleen, with ≥24% of nanosize (< 100 nm). The levels are below the doses regarded as safe in animals, but half are above the dose that is deemed safe for liver damage in humans when taking into account several commonly applied uncertainty factors. With these new and unique human data, we remain with the conclusion that health risks due to oral exposure to TiO2 cannot be excluded.

Linking the seroresponse to infection to within-host heterogeneity in antibody production.

A recently published model for the serum antibody response to infection appeared well suited for use in statistical analyses of longitudinal serological data. The published model assumed exponential decay with fixed rates for pathogen and serum antibody kinetics, ignoring any within-host heterogeneity in the seroresponse. A bi-exponential model shows that there is rapid initial decay followed by a prolonged period of persistent low serum antibody concentrations. We propose a small modification of the decay model that greatly increases its flexibility by allowing for non-exponential antibody decay. The modified model produces power functions that may be interpreted as a mixture of exponential decay curves, with a mixing distribution representing the relative contribution of many centres of antibody production to the serum antibody concentration. Fitting the power function decay model to observed longitudinal data for pertussis shows improved goodness of fit compared to the exponential decay model, with estimates for the shape parameter (r=2.2; 95% CI (1.7-2.8)) that differ from exponential shape (r=1). The power function decay model predicts more persistent antibody concentrations in the long term (symptomatic threshold reached >30 years after infection) which, when used in biomarker studies, will lead to lower estimates of seroconversion rates compared to exponential antibody decay.

Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure.

INTRODUCTION: Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen). MATERIALS AND METHODS: We assessed the accuracy of the models' predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated. RESULTS: With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52-4.19mg/L with the Bos model, 1.42-4.04mg/L with the Mumtaz model, and 1.81-4.31mg/L with the Jongeneelen model compared to 0.27-5.44mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4-2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels. CONCLUSIONS: The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.

Toxicokinetic model assessment on the dechlorination of dietary toxaphene CHB-62 into CHB-44 in Atlantic salmon (Salmo salar L.).

European Union legislation on the upper limits of toxaphene in feed and food include the congeners CHB-26, CHB-62 and CHB-50 and is set at 50 µg kg⁻¹ feed for the sum of these three congeners. However, due to their elevated presence in fish, the congeners CHB-40 and CHB-41, CHB-44, and CHB-42 should also be included according to the European Food Safety Authority (EFSA) in 2005. Earlier trials with model zebra fish have shown in vivo dechlorination of dietary CHB-62 to CHB-44 and, to a lesser degree, of CHB-50 to CHB-40. Biomagnification patterns of Atlantic salmon, fed with technical toxaphene-enriched feeds, indicated that Atlantic salmon have a similar dechlorination. In the present study, a serial one-compartment physiological kinetic model, which includes differentiated growth of body components, is used to quantify the contribution of dechlorination to the congener-specific fillet accumulation of a mixture of dietary toxaphene congeners in Atlantic salmon. The model is assessed from experimental uptake and elimination kinetics of Atlantic salmon smolt fed with technical toxaphene for 122 days followed by a depuration period of 75 days in which the fish were fed toxaphene-free control feed. The serial one-compartment model shows that about 31% of CHB-44 that accumulated in the fillet originated from dietary CHB-62. In contrast, dechlorination of CHB-50 into CHB-40 is not significant. The results show that previously demonstrated in vivo dechlorination of CHB-62 into CHB-44 in zebra fish also occurs in the farmed fish species Atlantic salmon. This dechlorination can at least partly explain the relatively elevated CHB-44 observed in toxaphene fish surveys.

Transfer of perfluorooctane sulfonic acid (PFOS) from contaminated feed to dairy milk.

Dietary intake is the predominant route for human exposure to perfluorooctane sulfonic acid (PFOS). Single pollution events may thus affect human exposure if polluted ground and water is used to produce animal feed or food. In this study, a physiologically based pharmacokinetic (PBPK-) model is derived that describes the uptake of PFOS from contaminated feed by cows and its subsequent elimination through the cows' milk. Parameter values of the model were estimated by fitting to experimental data of a cow feeding trial. Model calculations showed that almost all PFOS ingested is excreted through the cows' milk. The elimination rate, however, was low as the estimated half-life in the cow was 56days and it may, thus, take a long time after an initial pollution event to produce PFOS-free milk. The derived model can be used to estimate the transfer of PFOS through the dairy food chain and can be used for comparison of various contamination routes.

Biomarker dynamics: estimating infection rates from serological data.

The marginal distribution of serum antibody titres in a cross-sectional population sample can be expressed as a function of the infection rate, taking into account heterogeneity in peak levels and decay rates. This marginal model allows estimation of incidences, as well as simple tests for homogeneity across age, gender or geographic strata, using likelihood ratio tests. An example is given using Campylobacter serum antibody data. Using a hierarchical dynamic model to analyse data from a follow-up study in patients with symptomatic Campylobacter infection, we show that the serum antibody response consists of a rapid increase to peak levels followed by a slow decline with a geometric mean halftime of 1.4, 0.6 and 0.3 years for IgG, IgM and IgA, respectively. Antibody peak levels and decay rates were highly variable among subjects. Incidence estimates are consistent among different antibody classes (IgG, IgM and IgA). High seroconversion rates indicate that Campylobacter infection is a frequent event, occurring approximately once every year in any adult person, in the Netherlands, supporting the conclusion that a small fraction of infections leads to symptoms severe enough for notification.

Toxicokinetics and carry-over model of α-hexabromocyclododecane (HBCD) from feed to consumption-sized Atlantic salmon (Salmo salar).

A two-compartmental model for the kinetics of carry-over of the brominated flame retardant α-hexabromocyclododecane (HBCD) from feed to the fillet of farmed harvest-sized Atlantic salmon (Salmo salar L.) was developed. The model is based on a fat compartment for storage of the lipophilic α-HBCD and a central compartment comprising all other tissues. Specific for this model is that the salmon has a continuous growth and that fillet contaminant levels are explained by both the fat and the central compartments. The uptake and elimination kinetics are obtained from experimental data where consumer sized (start weight approximately 1 kg) Atlantic salmon was fed α-HBCD spiked feed (280 ± 11 µg kg(-1)) for 2 months followed by a depuration period of 3 months. The model was used to simulate the HBCD feed-to-fillet transfer in Atlantic salmon under realistic farming conditions such as the seasonal fluctuations in feed intake, growth and fillet fat deposition. The model predictions gave fillet concentrations of 0.2-1.8 µg kg(-1) depending on the level of fish oil inclusion in the salmon diets when using fish oil with high POP background levels. Model simulations show that currently farmed Atlantic salmon can contribute to a maximum of 6% of the estimated provisional food reference dose for HBCD.

The kinetics of the tissue distribution of silver nanoparticles of different sizes.

Blood kinetics and tissue distribution of 20, 80 and 110 nm silver nanoparticles were investigated in rats up to 16 days after intravenous administration once daily for 5 consecutive days. Following both single and repeated injection, silver nanoparticles disappeared rapidly from the blood and distributed to all organs evaluated (liver, lungs, spleen, brain, heart, kidneys and testes) regardless of size. The 20 nm particles distributed mainly to liver, followed by kidneys and spleen, whereas the larger particles distributed mainly to spleen followed by liver and lung. In the other organs evaluated, no major differences between the sizes were observed. Size-dependent tissue distribution suggests size-dependent toxicity and health risks. Repeated administration resulted in accumulation in liver, lung and spleen, indicating that these organs may be potential target organs for toxicity after repeated exposure. A physiologically based pharmacokinetic (PBPK) model for nanoparticles which describes the kinetics of silver nanoparticles was developed. Model parameter values were estimated by fitting to data. No clear relation between parameter values and corresponding particle diameters became apparent.

Clearance and clearance inhibition of the HIV-1 protease inhibitors ritonavir and saquinavir in sandwich-cultured rat hepatocytes and rat microsomes.

The metabolism and active transport of ritonavir and saquinavir were studied using sandwich-cultured rat hepatoyctes and rat liver microsomes. For ritonavir four comparable metabolites were observed in the sandwich-culture and in microsomes. For saquinavir eight metabolites were observed in sandwich-culture and 14 different metabolites in microsomes. Ketoconazole did not affect the metabolism of ritonavir in sandwich-culture or microsomes and slightly inhibited the metabolism of saquinavir in sandwich-culture. This inhibition resulted in a different metabolite profile for saquinavir in microsomes. Ritonavir had a pronounced inhibiting effect on the metabolism of saquinavir and affected the hydroxylation of 6beta-testosterone negatively. In the active transport studies, cyclosporin A and PSC833 enhanced the metabolism of ritonavir, suggesting that ritonavir is normally excreted into the bile canaliculi. Verapamil, showed no effect on the metabolism of ritonavir. The intrinsic clearance was estimated at 1.65 and 67.5 microl/min/1 x 10(6) cells and the hepatic metabolism clearance at 0.017 and 6.83ml/min/SRW for ritonavir and saquinavir respectively. In conclusion, for saquinavir the metabolism rate and the amount of metabolites produced was higher than for ritonavir. Ritonavir had a strong inhibitory effect on the metabolism of saquinavir and seemed to be excreted into the bile.

A novel source for dioxins present in recycled fat from gelatin production.

Within a survey on dioxins in animal fat used as feed ingredient, a sample originating from pigs offal was shown to contain 50 ng Toxic Equivalents (TEQ) PCDD/PCDFs kg(-1) fat. Further investigation revealed fat samples with levels as high as 440 ng TEQ kg(-1) fat and contaminated feed with a highest level of 8.4 ng TEQ kg(-1) feed. The congener pattern was dominated by 1,2,3,7,8-PeCDD and 2,3,7,8-TCDD, and was not recognized from any previous incident or known dioxin source. Remarkably, 2,3,7,8-substituted congeners were much more abundant than their non-2,3,7,8-substituted counterparts. The sampled fat was derived from a gelatin production plant. Broken filters, used to clean the hydrochloric acid (HCl) used in the process, caused the dioxin contamination. The fat was primarily used for pig feed. A new physiologically-based pharmacokinetic (PBPK) model for lipophilic contaminants in growing slaughter pigs predicted levels at slaughter varying between 40 pg TEQ g(-1) fat (worst-case) and 2.5-7pgTEQ g(-1) fat under more realistic scenarios. Almost 300 farms were temporarily blocked. Many fat samples of pigs were analyzed using a combined approach of DR CALUX and GC/HRMS. Levels in contaminated pig fat were around the EU-limit of 1 pg TEQ g(-1) fat, with some samples up to 2-3 pg TEQ g(-1) fat. Of 80 negative samples analyzed by DR CALUX and GC/HRMS no false-negatives were obtained, whereas 36 and 62 of the 80 samples classified suspected with the bioassay had GC/HRMS levels above respectively the tolerance and action limits. It is concluded that novel and unexpected dioxin sources remain a threat to the food chain and require the proper evaluation and monitoring of production processes, including chemicals used therein.

A toxicokinetic model for the carry-over of dioxins and PCBs from feed and soil to eggs.

A mathematical model for the kinetics of carry-over of dioxins and dioxin-like PCBs from feed mixed with contaminated oil to eggs has been developed. This model incorporates uptake of the compounds over the gut wall and their subsequent transport by blood, distribution over the body, hepatic metabolism and excretion through egg yolk fat. The model is analysed with respect to the possibility of identifying as yet unknown model parameters by fitting these to the experimental data. The model was fitted to the experimental data on the carry-over from feed to eggs. The calibrated model was applied to calculate the steady-state concentrations in eggs which were compared to European Maximum Residue Levels for dioxins in feed and eggs, showing that these limits do not match. The feed limit of 0.75 ng TEQ/kg should be reduced to about 0.17 ng TEQ/kg in order to guarantee egg levels below the residue limit of 3 pg TEQ/g fat. Experimental results of carry-over from contaminated soil were used to estimate the absorption of dioxin-like compounds from soils as compared to the absorption from feed, resulting in a value around 40 to 60% absorption from soil as compared to around 90% absorption from feed.