Toxicokinetic Triage for Environmental Chemicals

Toxicokinetic (TK) models link administered doses to plasma, blood, and tissue concentrations. High-throughput TK (HTTK) performs in vitro to in vivo extrapolation to predict TK from rapid in vitro measurements and chemical structure-based properties. A significant toxicological application of HTTK has been “reverse dosimetry,” in which bioactive concentrations from in vitro screening studies are converted into in vivo doses (mg/kg BW/day). These doses are predicted to produce steady-state plasma concentrations that are equivalent to in vitro bioactive concentrations. In this study, we evaluate the impact of the approximations and assumptions necessary for reverse dosimetry and develop methods to determine whether HTTK tools are appropriate or may lead to false conclusions for a particular chemical. Based on literature in vivo data for 87 chemicals, we identified specific properties (eg, in vitro HTTK data, physico-chemical descriptors, and predicted transporter affinities) that correlate with poor HTTK predictive ability. For 271 chemicals we developed a generic HT physiologically based TK (HTPBTK) model that predicts non-steady-state chemical concentration time-courses for a variety of exposure scenarios. We used this HTPBTK model to find that assumptions previously used for reverse dosimetry are usually appropriate, except most notably for highly bioaccumulative compounds. For the thousands of man-made chemicals in the environment that currently have no TK data, we propose a 4-element framework for chemical TK triage that can group chemicals into 7 different categories associated with varying levels of confidence in HTTK predictions. For 349 chemicals with literature HTTK data, we differentiated those chemicals for which HTTK approaches are likely to be sufficient, from those that may require additional data

Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine?

Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep-wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical signs, EEG, heart rate, respiration and AChE activity in blood and brain after soman poisoning. The model allowed the determination of the therapeutic effects at the short-term of obidoxime, atropine and physostigmine. Obidoxime exerted the highest therapeutic efficacy at administration of the lowest dose (3.1 mg/kg i.m.), whereas two higher doses (9 and 18 mg/kg) were less effective on most parameters. Addition of atropine at 0.03 and 3 mg/kg (i.m.) to the treatment did not improve the therapeutic effects of obidoxime alone. Physostigmine (0.8 mg/kg im) at 1 min after poisoning increased mortality. Two lower doses (0.1 and 0.3 mg/kg i.m.) showed improvements on all parameters but respiration. The middle dose was most effective in preventing seizure development and therefore assessed as the most efficacious dose. Combined treatment of obidoxime and physostigmine shortened the duration of seizures, if present, from up to 80 min to ~10–15 min. In practice, treatment will be employed when toxic signs appear, with the presence of high levels of AChE inhibition in both blood and brain. Administration of physostigmine at that moment showed to be redundant or even harmful. Therefore, treatment of OP poisoning with a carbamate, such as physostigmine, should be carefully re-evaluated

The use of modelling and probabilistic methods in cumulative risk assessment

This thesis was realized as part of the EU integrated project SAFE FOODS, the overall objective of which was to change the scope of decision-making on food safety from single risks to considering foods as sources of risks, benefits and costs associated with their production and consumption, and taking into account the social context in which decisions are made. One of the main goals within this project was the development and application of new quantitative risk assessment methods that better meet these demands of decision-makers. These new methods should account for variability in consumer populations and uncertainties in the assessment, and they should be fit to address the exposure to combinations of various chemicals present in the diet. This thesis combines several contributions to the development of this new approach. Two different computational tools are used for this purpose. Biologically based mathematical models (or mechanistic models) are models that quantitatively describe the behavior of chemicals in a biological system by use of differential equations. In this thesis, these models have been used to study the combined effects of chemicals, and how these could be predicted from information of the chemicals individually. Probabilistic methods are computational methods that combine statistical distributions of variables instead of point estimates. These methods are incorporated in the risk assessment framework to account for the variability in a population and uncertainty in the assessment. The final result is an estimate of potential health risks that may occur in the population, and a statement on how precise that estimation is

Persoonlijke verzorgingsproducten in het aquatisch milieu : een verkenning van het milieurisico van shampoo en tandpasta in het huishoudelijk afvalwater

Milieu Centraal is een consumentenorganisatie die de consument onder andere wil informeren over de milieubelasting van persoonlijke verzorgingsproducten en advies wil geven over de minst belastende producten. Hiervoor moet worden onderzocht welke componenten in persoonlijke verzorgingsproducten mogelijk schadelijk zijn voor het milieu. Een van de belangrijkste milieueffecten van het gebruik van persoonlijke verzorgingsproducten is waterverontreiniging. Producten als shampoo, zeep, badschuim en tandpasta komen na gebruik bijna geheel in het afvalwater terecht. Een deel wordt verwijderd in rioolwaterzuiveringsinstallaties, een ander deel eindigt in het oppervlaktewater. De Wetenschapswinkel Biologie van de Universiteit Utrecht heeft van Milieu Centraal de opdracht gekregen een verkenning uit te voeren van het risico van persoonlijke verzorgingsproducten in het aquatisch milieu. Badschuim lijkt qua samenstelling veel op shampoo, zeep bestaat voornamelijk uit goed afbreekbare componenten. Daarom beperkt dit onderzoek zich tot shampoo en tandpasta. Van 26 willekeurige soorten shampoos en 14 soorten tandpasta's is een lijst van ingrediënten gemaakt. Voor die componenten zijn in de literatuur toxiciteits- en afbreekbaarheidsgegevens verzameld. Op basis van hun chemische kenmerken en functie zijn de componenten ingedeeld in groepen, zoals oplosmiddelen, surfactanten (oppervlakte-actieve stoffen), conserveermiddelen, parfum en kleurstoffen. Onder de surfactanten en conserveermiddelen bleken mogelijk slecht afbreekbare, toxische componenten te zitten. Voor die groepen, en voor twee specifiek werkende componenten, is een risicoanalyse uitgevoerd. Voor de meeste surfactanten is het risicogetal veel kleiner dan één, dat wil zeggen dat de concentratie in het milieu veel kleiner is dan de effectconcentratie. Alleen de kationische surfactanten ATMAC en DADMAC, die in respectievelijk vier en twee van de onderzochte shampoos voorkwamen, hadden een risicogetal dicht bij één. Dat impliceert dat een nadelig effect in het aquatisch milieu op basis van deze studie niet kan worden uitgesloten. Van de onderzochte conserveermiddelen hadden alleen alkylparabens een risicogetal veel kleiner dan één. Deze componenten hebben op basis van het geschatte verbruik van shampoo en tandpasta een laag milieurisico. Voor de overige conserveermiddelen lagen de risicogetallen te dicht bij één om een schadelijk effect uit te sluiten. Deze werden echter in shampoos veel minder frequent aangetroffen dan parabens en niet in de onderzochte tandpasta’s

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Non-linearities occur no more frequently between microdose and therapeutic dose studies than in therapeutic range ascending-dose studies. Most non-linearities are due to known saturable processes, and can be foreseen by integrating commonly available preclinical data. The guidance presented here may support decision making on incorporating a microdosing study in drug development

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. Many who apply this latter method assume that it is applicable to any combination of substances, regardless of the shape of the dose-response curves of the individual substances or their underlying mechanism of action. Proponents commonly refer to the work of Berenbaum, who claimed to have proven the general applicability of the isobole method based on zero interaction. In this article, we argue that his argumentation is not generally valid. We further demonstrate that the isobole method, just like dose addition, has limited applicability. Using a physiologically based mathematical model, we provide a theoretical example of a combination of chemicals with zero interaction where the isobole method would result in the decision that they do interact. We discuss the implications for research focusing on detecting or defining interactions, and for the prediction of effects from combined exposures assuming zero interaction