Environmental Risk Assessment Of Chemicals Research Articles

Reprint of PopGen: A virtual human population generator

The risk assessment of environmental chemicals and drugs is moving towards a paradigm shift in approach which seeks the full replacement animal testing with high throughput, mechanistic, in vitro systems. This new vision will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of specific biochemical pathways are likely to lead to adverse health effects in an intact organism. Such an approach requires a framework, into which disparate data generated using in vitro, in silico and in chemico systems, can be integrated and utilised for quantitative in vitro-to-in vivo extrapolation (QIVIVE), ultimately to the human population level. Physiologically based pharmacokinetic (PBPK) models are ideally suited for this and are obligatory in order to translate in vitro concentration-response relationships to an exposure or dose, route and duration regime in people. In this report we describe PopGen a virtual human population generator which is a user friendly, open access web-based application for the prediction of realistic anatomical, physiological and phase 1 metabolic variation in a wide range of healthy human populations. We demonstrate how PopGen can be used for QIVIVE by providing input to a PBPK model, at an appropriate level of detail, to reconstruct exposure from human biomonitoring data. We discuss how the process of exposure reconstruction from blood biomarkers, in general, is analogous to exposure or dose reconstruction from concentration-response measurements made in proposed in vitro cell based systems which are assumed to be surrogates for target organs.

生活関連化学物質のヒト健康および環境影響に関するリスクアセスメント －in silico手法とモデル試験の活用による陽イオン界面活性剤の暴露評価－

生活関連化学物質のヒト健康および環境影響に関するリスクアセスメント －in silico手法とモデル試験の活用による陽イオン界面活性剤の暴露評価－

Implications of interacting microscale habitat heterogeneity and disturbance events onFolsomia candida(Collembola) population dynamics: A modeling approach

The authors implemented a fractal algorithm in a spatially explicit individual-based model to generate landscapes with different microscale patterns of habitat fragmentation and disturbance events and studied their effects on population dynamics of the collembolan Folsomia candida. Among human activities that may cause habitat destruction, the present study focused on agricultural practices. Soil organisms living in a cultivated field are subjected to habitat loss and fragmentation as well as disturbance events generated by the application of agrochemicals and related activities. In addition, they are exposed to natural stressors, which might influence the effects of chemicals on populations. The authors designed simulation experiments that incorporate these 3 factors and investigated their effects on populations of F. candida in the presence or absence of behavioral avoidance of contaminated habitat. Simulation results show that spatial autocorrelation of contamination has different effects on population growth and equilibrium size according to the percentage of clean habitat. This pattern changes when avoidance behavior is excluded from the model, as does population recovery after a series of disturbance events. The model suggests that a combination of heterogeneous contamination and multiple stressors can lead to unexpected effects of toxicants at the population level. Individual-based models can help to understand these effects and therefore add ecological realism to environmental risk assessment of chemicals and can help to explore the effects of different risk management options.

EFSA's 19th Scientific Colloquium on Biodiversity as protection goal in environmental risk assessment for EU agro‐ecosystems

EFSA Supporting PublicationsVolume 11, Issue 4 583E Event reportOpen Access EFSA's 19th Scientific Colloquium on Biodiversity as protection goal in environmental risk assessment for EU agro-ecosystems European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 14 April 2014 https://doi.org/10.2903/sp.efsa.2014.EN-583 Published date: 14 April 2014 Question number: EFSA-Q-2013-00912 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat VII. References AMIGA http://www.amigaproject.eu/project/objectives/. EFSA, 2010. Report on the PPR stakeholder workshop Protection goals for environmental risk assessment of pesticide: What and where to protect? EFSA Journal 2010; 8(7):1672, 46 pp. doi:10.2903/j.efsa.2010.1672. EFSA, 2011; Review of current practices of environmental risk assessment within EFSA. Supporting Publication: 2011:116. 39 p. EFSA GMO Panel (EFSA Panel on Genetically Modifed Organisms), 2010. Guidance on the environmental risk assessment of genetically modifed plants. EFSA Journal 2010; 8(11):1879. 111 pp. doi:10.2903/j.efsa.2010.1879. EFSA GMO Panel (EFSA Panel on Genetically Modifed Organisms), 2013. Guidance on the environmental risk assessment of genetically modifed animals. EFSA Journal 2013; 11(5):3200, 190 pp. doi:10.2903/j.efsa.2013.3200. EFSA PLH Panel (EFSA Panel on Plant Health), 2010. Guidance on a harmonised framework for pest risk assessment and the identifcation and evaluation of pest risk management options by EFSA. EFSA Journal 2010; 8(2):1495, 66 pp. doi:10.2093/j.efsa.2010.1495. EFSA PLH Panel (EFSA Panel on Plant Health), 2011. Guidance on the environmental risk assessment of plant pests. EFSA Journal 2011; 9(12):2460, 121 pp. doi:10.2093/j. efsa.2011.2460. EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), 2009. Guidance Document on Risk Assessment for Birds & Mammals on request from EFSA. EFSA Journal 2009; 7(12): 1438. doi:10.2903/j.efsa.2009.1438. EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), 2010. Scientifc Opinion on the development of specifc protection goal options for environmental risk assessment of pesticides, in particular in relation to the revision of the Guidance Documents on Aquatic and Terrestrial Ecotoxicology (SANCO/3268/2001 and SANCO/10329/2002). EFSA Journal 2010; 8(10):1821. 55 pp. doi:10.2903/j.efsa.2010.1821. EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), 2013. Guidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-feld surface waters. EFSA Journal 2013; 11(7):3290, 268 pp. doi:10.2903/j. efsa.2013.3290. Hommen U, Baveco JMH, Galic N and van den Brink PJ, 2010. Potential application of ecological models in the European environmental risk assessment of chemicals. I. Review of protection goals in EU directives and regulations. Integrated Environmental Assessment and Management, 6, 325– 337. Nienstedt KM, Brock TCM, van Wensem J, Montforts M, Hart A, Aagaard A, Alix A, Boesten J, Bopp SK, Brown C, Capri E, Forbes V, Koepp H, Liess M, Luttik R, Maltby L, Sousa J P, Streissl F and Hardy AR, 2012. Development of a framework based on an ecosystem services approach for deriving specifc protection goals for environmental risk assessment of pesticides. Sci Total Environ, 415, 31– 38. Rabinowitz D, 1981. Seven forms of rarity. Pages 205– 217 in H. Synge, editor. The biological aspects of rare plant conservation. Wiley, New York. Topping CJ, Kjær LJ, Hommen U, Høye TT, Preuss TG, Sibly RM and van Vliet P. 2014 in press. Recovery based on plot experiments is a poor predictor of landscape-level population impacts of agricultural pesticides. Environmental Toxicology and Chemistry. Accepted manuscript online: 5 Sep 2013, DOI: 10.1002/etc.2388. Volume11, Issue4April 2014583E This article also appears in:Scientific colloquia ReferencesRelatedInformation

Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study.Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism.Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability.Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability.Citation: Chiu WA, Campbell JL Jr, Clewell HJ III, Zhou YH, Wright FA, Guyton KZ, Rusyn I. 2014. Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456–463; http://dx.doi.org/10.1289/ehp.1307623

Combining high-resolution gross domestic product data with home and personal care product market research data to generate a subnational emission inventory for Asia

Environmental risk assessment of chemicals is reliant on good estimates of product usage information and robust exposure models. Over the past 20 to 30 years, much progress has been made with the development of exposure models that simulate the transport and distribution of chemicals in the environment. However, little progress has been made in our ability to estimate chemical emissions of home and personal care (HPC) products. In this project, we have developed an approach to estimate subnational emission inventory of chemical ingredients used in HPC products for 12 Asian countries including Bangladesh, Cambodia, China, India, Indonesia, Laos, Malaysia, Pakistan, Philippines, Sri Lanka, Thailand, and Vietnam (Asia-12). To develop this inventory, we have coupled a 1 km grid of per capita gross domestic product (GDP) estimates with market research data of HPC product sales. We explore the necessity of accounting for a population's ability to purchase HPC products in determining their subnational distribution in regions where wealth is not uniform. The implications of using high resolution data on inter- and intracountry subnational emission estimates for a range of hypothetical and actual HPC product types were explored. It was demonstrated that for low value products (<500 US$ per capita/annum required to purchase product) the maximum deviation from baseline (emission distributed via population) is less than a factor of 3 and it would not result in significant differences in chemical risk assessments. However, for other product types (>500 US$ per capita/annum required to purchase product) the implications on emissions being assigned to subnational regions can vary by several orders of magnitude. The implications of this on conducting national or regional level risk assessments may be significant. Further work is needed to explore the implications of this variability in HPC emissions to enable the HPC industry and/or governments to advance risk-based chemical management policies in emerging markets.

An energy budget agent-based model of earthworm populations and its application to study the effects of pesticides

Earthworms are important organisms in soil communities and so are used as model organisms in environmental risk assessments of chemicals. However current risk assessments of soil invertebrates are based on short-term laboratory studies, of limited ecological relevance, supplemented if necessary by site-specific field trials, which sometimes are challenging to apply across the whole agricultural landscape. Here, we investigate whether population responses to environmental stressors and pesticide exposure can be accurately predicted by combining energy budget and agent-based models (ABMs), based on knowledge of how individuals respond to their local circumstances. A simple energy budget model was implemented within each earthworm Eisenia fetida in the ABM, based on a priori parameter estimates. From broadly accepted physiological principles, simple algorithms specify how energy acquisition and expenditure drive life cycle processes. Each individual allocates energy between maintenance, growth and/or reproduction under varying conditions of food density, soil temperature and soil moisture. When simulating published experiments, good model fits were obtained to experimental data on individual growth, reproduction and starvation. Using the energy budget model as a platform we developed methods to identify which of the physiological parameters in the energy budget model (rates of ingestion, maintenance, growth or reproduction) are primarily affected by pesticide applications, producing four hypotheses about how toxicity acts. We tested these hypotheses by comparing model outputs with published toxicity data on the effects of copper oxychloride and chlorpyrifos on E. fetida. Both growth and reproduction were directly affected in experiments in which sufficient food was provided, whilst maintenance was targeted under food limitation. Although we only incorporate toxic effects at the individual level we show how ABMs can readily extrapolate to larger scales by providing good model fits to field population data. The ability of the presented model to fit the available field and laboratory data for E. fetida demonstrates the promise of the agent-based approach in ecology, by showing how biological knowledge can be used to make ecological inferences. Further work is required to extend the approach to populations of more ecologically relevant species studied at the field scale. Such a model could help extrapolate from laboratory to field conditions and from one set of field conditions to another or from species to species.

In Vitro Screening for Compounds That Enhance Human L1 Mobilization

The Long interspersed element 1 (LINE1 or L1) retrotransposon constitutes 17% of the human genome. There are currently 80–100 human L1 elements that are thought to be active in any diploid human genome. These elements can mobilize into new locations of the genome, resulting in changes in genomic information. Active L1s are thus considered to be a type of endogenous mutagen, and L1 insertions can cause disease. Certain stresses, such as gamma radiation, oxidative stress, and treatment with some agents, can induce transcription and/or mobilization of retrotransposons. In this study, we used a reporter gene assay in HepG2 cells to screen compounds for the potential to enhance the transcription of human L1. We assessed 95 compounds including genotoxic agents, substances that induce cellular stress, and commercially available drugs. Treatment with 15 compounds increased the L1 promoter activity by >1.5-fold (p<0.05) after 6 or 24 hours of treatment. In particular, genotoxic agents (benzo[a]pyrene, camptothecin, cytochalasin D, merbarone, and vinblastine), PPARα agonists (bezafibrate and fenofibrate), and non-steroidal anti-inflammatory drugs (diflunisal, flufenamic acid, salicylamide, and sulindac) induced L1 promoter activity. To examine their effects on L1 retrotransposition, we developed a high-throughput real-time retrotransposition assay using a novel secreted Gaussia luciferase reporter cassette. Three compounds (etomoxir, WY-14643, and salicylamide) produced a significant enhancement in L1 retrotransposition. This is the first study to report the effects of a wide variety of compounds on L1 transcription and retrotransposition. These results suggest that certain chemical- and drug-induced stresses might have the potential to cause genomic mutations by inducing L1 mobilization. Thus, the risk of induced L1 transcription and retrotransposition should be considered during drug safety evaluation and environmental risk assessments of chemicals.

PopGen: A virtual human population generator

The risk assessment of environmental chemicals and drugs is moving towards a paradigm shift in approach which seeks the full replacement animal testing with high throughput, mechanistic, in vitro systems. This new vision will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of specific biochemical pathways are likely to lead to adverse health effects in an intact organism. Such an approach requires a framework, into which disparate data generated using in vitro, in silico and in chemico systems, can be integrated and utilised for quantitative in vitro-to-in vivo extrapolation (QIVIVE), ultimately to the human population level. Physiologically based pharmacokinetic (PBPK) models are ideally suited for this and are obligatory in order to translate in vitro concentration–response relationships to an exposure or dose, route and duration regime in people. In this report we describe PopGen, a virtual human population generator which is a user friendly, open access web-based application for the prediction of realistic anatomical, physiological and phase 1 metabolic variation in a wide range of healthy human populations. We demonstrate how PopGen can be used for QIVIVE by providing input to a PBPK model, at an appropriate level of detail, to reconstruct exposure from human biomonitoring data. We discuss how the process of exposure reconstruction from blood biomarkers, in general, is analogous to exposure or dose reconstruction from concentration–response measurements made in proposed in vitro cell based systems which are assumed to be surrogates for target organs.

Geographically distributed classification of surface water chemical parameters influencing fate and behavior of nanoparticles and colloid facilitated contaminant transport

The current production and use of nanomaterials in consumer products have increased the concern about the possibility that these enter the rivers during their entire life cycle. Further, many aquatic contaminants undergo partitioning to the ubiquitous aquatic colloids. Here is presented the development of a set of European water types for environmental risk assessment of chemicals transported as nanovectors as is the case of environmental fate of manufactured nanoparticles and colloid-bound contaminants.A compilation of river quality geochemical data with information about multi-element composition for near 800 rivers in Europe was used to perform a principal component analysis (PCA) and define 6 contrasting water classes. With the aid of geographical information system algorithms, it was possible to analyse how the different sampling locations were predominantly represented within each European water framework directive drainage basin. These water classes and their associated Debye–Hückel parameter are determining factors to evaluate the large scale fate and behaviour of nanomaterials and other colloid-transported pollutants in the European aquatic environment.

Evolution of the sewage treatment plant model SimpleTreat: Applicability domain and data requirements

SimpleTreat 3.1 is the sewage treatment plant (STP) model implemented in the European Union (EU) framework for the environmental risk assessment of chemicals. The model was originally designed for neutral hydrophobic chemicals, whereas many substances currently under regulatory scrutiny, are ionizable at environmental pH. Although the model has been adapted to describe ionization (SimpleTreat 3.1), the fate of organic ions is limited to the unbound aqueous phase, which seriously restricts the applicability domain. New regressions were implemented to estimate the sludge-water partition coefficient normalized to organic carbon (KOC ) of monovalent acids and bases from the octanol-water partition coefficient (KOW ), the dissociation constant (pKa) and the pH. We evaluated the updated model (SimpleTreat 3.2) with 10 test chemicals by comparing predictions with monitoring data collected from the literature. Test chemicals were specifically selected to challenge the applicability domain and to cover a wide range of functionality and physical-chemical properties. Although predicted effluent concentrations are generally conservative, SimpleTreat 3.2 provides reasonable estimates for use in lower-tier risk assessment for neutral and monovalent ionizable chemicals. The accuracy of the new KOC regressions is acceptable for monovalent acid but is lower for bases, for which measured sludge KOC is highly recommended. Measured KOC are also recommended for ionic surfactants and necessary for organic ligands, which may limit the applicability of SimpleTreat using a basic input data set. The conservative nature of model estimates reflects the default worst case, non-numerical parameterization of biodegradation rates and the assumption that biodegradation is limited to the unbound aqueous phase. The potential of refining the description of biodegradation using higher tier simulation tests is explored in a parallel article (Franco et al. this issue).

To the Editor

To the Editor

A list of fish species that are potentially exposed to pesticides in edge-of-field water bodies in the European Union--a first step towards identifying vulnerable representatives for risk assessment.

Surrogate species are used in standard toxicity tests for the environmental risk assessment of chemicals. Test results are then extrapolated to the situation in the field, which is often associated with a large degree of uncertainty. Since a vulnerable species in the field is not only characterised by its intrinsic sensitivity to a stressor but also by its potential for exposure and its population resilience, the identification of focal species based on these three components of vulnerability is needed for a more ecologically relevant risk assessment. This study listed European fish species that are susceptible to pesticide exposure in the field and thus achieved the first step towards identifying focal species for the risk assessment of pesticides for fish in Europe. A step-wise filtering approach was applied to list freshwater fish species that are native to Europe and widespread in the European Union, which inhabit streams, ditches or ponds in agricultural landscapes and therefore, are at an elevated risk of being exposed to pesticides. Out of the 579 fish species occurring in European freshwater, 27 species met the filtering criteria. The resulting list was verified based on monitoring studies that were conducted in agricultural landscapes over the past 20 years. Focal fish species that can be used for a more ecologically relevant environmental risk assessment of pesticides in Europe can be identified from the produced list of species by further assessing their ecological (life history and dispersal characteristics) and intrinsic sensitivities.Electronic supplementary material.The online version of this article (doi:10.1007/s11356-013-1471-x) contains supplementary material, which is available to authorized users.

Use of Early Juvenile Zebrafish Danio Rerio for In-Vivo Assessment of Endocrine Modulation by Xenoestrogens

Reliable and cost-effective early-life stage (ELS) bioassays incorporating practical experimentation without compromising scientific relevance are crucial in chemical risk assessment. This study investigated the use of 20 days-post-fertilization life stage (20dpfZF) of zebrafishDanio rerio to screen environmental chemicals known to be estrogenicin adult fish. Firstly, studies with key genes in steroidogenesis were conducted; the brain isoform of aromatase gene (cyp19a1b) being the most prominently expressed biomarker. Regulation of mRNA levels of molecular biomarkers, vitellogenin 1 gene (vtg1) and cyp19a1b were selected to assess the endocrine modulation by xenoestrogens, 17α-ethinylestradiol (EE2), 4-n-nonylphenol (NP), 4-t-octylphenol (OP) and bisphenol A (BPA). Groups of 20dpfZF (n=15) as three replicates were exposed to chemicals over a five-day period in aerated static setups. Exposure of 20dpfZF to sediment spiked with EE2 (nominal 3μg g-1dw) was also conducted to assess the sensitivity of this life-stage to sediment with estrogenic potency. Whole body homogenates of exposed juveniles showed the estrogenic potential of chemicals in the order: EE2 > OP > BPA > NP. Higher relative expression of cyp19a1b was noticed at lower ambient concentrations of EE2, although vtg1 showed more pronounced expression to it. The 20dpfZF responded in a dose-related way to sediment spiked with EE2, expanding its use as a general aquatic animal model. The suitability of 20dpfZF as an in vivo model, along with stable expression of reference genes was established. In addition to consistent expression pattern of key target genes on xenoestrogenicity, it serves as a practical screening model for the risk assessment of environmental chemicals and samples with estrogenic potential.

Modeling non-monotonic dose–response relationships: Model evaluation and hormetic quantities exploration

Non-monotonic (biphasic) dose–response relationships, known as hormetic relationships, have been observed across multiple experimental systems. Several models were proposed to describe non-monotonic relationships. However, few studies provided comprehensive description of hermetic quantities and their potential application. In this study, five biphasic models were used to fit five hormetic datasets from three different experimental systems of our lab. The bisection algorithm based on individual monotone functions was proposed to calculate arbitrary hormetic quantities instead of traditional methods (e.g., model reparameterization) which need complex mathematical manipulation. Results showed that all the five biphasic models could describe those datasets fairly well with coefficient of determination (R2adj) greater than 0.95 and root mean square error (RMSE) smaller than 0.10. The best-fit model could be selected based on R2adj, RMSE, and a supplemental criterion of Akaike information criterion (AIC). Hormetic quantities that trigger 10% stimulation at the left (ECL10) and right (ECR10) side of stimulatory peak were calculated and emphasized for their implication in hormesis exploration for the first time. Furthermore, the ECL10, proposed as an alarm threshold for hormesis, was expected to be useful in risk assessment of environmental chemicals. This study lays a foundation in the quantitative description of the low dose hormetic effect and the investigation of hormesis in environmental risk assessment.

Predicting Adult Fish Acute Lethality with the Zebrafish Embryo: Relevance of Test Duration, Endpoints, Compound Properties, and Exposure Concentration Analysis

The zebrafish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, which is required by various regulations for environmental risk assessment of chemicals. We investigated the reliability of the embryo test by probing organic industrial chemicals with a wide range of physicochemical properties, toxicities, and modes of toxic action. Moreover, the relevance of using measured versus nominal (intended) exposure concentrations, inclusion of sublethal endpoints, and different exposure durations for the comparability with reported fish acute toxicity was explored. Our results confirm a very strong correlation of zebrafish embryo to fish acute toxicity. When toxicity values were calculated based on measured exposure concentrations, the slope of the type II regression line was 1 and nearly passed through the origin (1 to 1 correlation). Measured concentrations also explained several apparent outliers. Neither prolonged exposure (up to 120 h) nor consideration of sublethal effects led to a reduced number of outliers. Yet, two types of compounds were less lethal to embryos than to adult fish: a neurotoxic compound acting via sodium channels (permethrin) and a compound requiring metabolic activation (allyl alcohol).

Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy

Pregnancy is associated with considerable changes in the physiological, anatomical and biochemical attributes in women. These may alter the exposure to xenobiotics between pregnant and non-pregnant women who receive similar doses, with implications for different susceptibility to environmental pollutants or therapeutic agents. Physiologically based pharmacokinetic (PBPK) models together with in vitro in vivo extrapolation (IVIVE) of absorption, distribution, metabolism and excretion (ADME) characteristics may capture the likely changes. However, such models require comprehensive information on the longitudinal variations of PBPK parameter values; a set of data that are as yet not available from a singular source. The aim of this article was to collect, integrate and analyse the available time-variant parameters that are needed for the PBPK modelling of xenobiotic kinetics in a healthy pregnant population. A structured literature search was carried out on anatomical, physiological and biochemical parameters likely to change in pregnancy and alter the kinetics of xenobiotics. Collated data were carefully assessed, integrated and analysed for trends with gestational age. Algorithms were generated to describe the changes in parameter values with gestational age. These included changes in maternal weight, the individual organ volumes and blood flows, glomerular filtration rates, and some drug-metabolising enzyme activities. Articles were identified using relevant keywords, quality appraised and data were extracted by two investigators. Some parameters showed no change with gestational age and for others robust data were not available. However, for many parameters significant changes were reported during the course of pregnancy, e.g. cardiac output, protein binding and expression/activity of metabolizing enzymes. The trend for time-variant parameters was not consistent (with respect to direction and mono-tonicity). Hence, various mathematical algorithms were needed to describe individual parameter values. Despite the limitations identified in the availability of some values, the collected data presented in this paper provide a potentially useful singular resource for key parameters needed for PBPK modelling in pregnancy. This facilitates the risk assessment of environmental chemicals and therapeutic drug dose adjustments in the pregnant population.

Promoting effects on reproduction increase population vulnerability of Daphnia magna

Environmental risk assessment of chemicals is based on single species tests at the individual level with single compounds. However, the protection goal is the sustainability of a population, which faces several natural stressors and mixtures of chemicals in the environment. Therefore, experiments were undertaken to quantify the combined effects of chemicals with different modes of action on Daphnia magna populations. Populations continuously exposed to dispersogen A and at abundance equilibrium were treated with a 2-d pulse of p353-nonylphenol. In previous studies, dispersogen A was shown to act as a natural info-chemical, promoting the reproduction of daphnids (higher offspring quantity) coupled with reduced offspring fitness, whereas nonylphenol in pulsed-exposure caused size-selective mortality. Dispersogen A caused accelerated population growth to maximum abundance, shifted the population structure towards smaller individuals, and increased the population sensitivity to nonylphenol. The authors showed that a positive effect observed at the individual level can be transposed to a negative effect when monitored at the population level. So far, positive effects are not addressed in environmental risk assessment, and even in higher-tier testing, population structure is not quantified. Both factors indicate a potential mismatch between protection aim and risk assessment practice.

Risk Assessment of Environmental Chemicals: If It Ain't Broke …

Risk Assessment of Environmental Chemicals: If It Ain't Broke …

Fungal composition on leaves explains pollutant-mediated indirect effects on amphipod feeding

The energy stored in coarse particulate organic matter, e.g. leaf litter, is released to aquatic ecosystems by breakdown processes involving microorganisms and leaf shredding invertebrates. The palatability of leaves and thus the feeding of shredders on leaf material are highly influenced by microorganisms. However, implications in the colonization of leaves by microorganisms (=conditioning) caused by chemical stressors are rarely studied. Our laboratory experiments, therefore, investigated for the first time effects of a fungicide on the conditioning process of leaf material by means of food-choice experiments using Gammarus fossarum (Crustacea: Amphipoda). Additionally, microbial analyses were conducted to facilitate the mechanistic understanding of the observed behavior. Gammarids significantly preferred control leaf discs over those conditioned in presence of the fungicide tebuconazole at concentrations of 50 and 500 μg/L. Besides the decrease of fungal biomass with increasing fungicide concentration, also the leaf associated fungal community composition showed that species preferred by gammarids, such as Alatospora acumunata, Clavariopsis aquatica, or Flagellospora curvula, were more frequent in the control. Tetracladium marchalianum, however, which is rejected by gammarids, was abundant in all treatments suggesting an increasing importance of this species for the lower leaf palatability – as other more palatable fungal species were almost absent – in the fungicide treatments. Hence, the food-choice behavior of G. fossarum seems to be a suitable indicator for alterations in leaf associated microbial communities, especially fungal species composition, caused by chemical stressors. Finally, this or similar test systems may be a reasonable supplement to the environmental risk assessment of chemicals in order to achieve its protection goals, as on the one hand, indirect effects may occur far below concentrations known to affect gammarids directly, and on the other hand, the observed shifts in leaf associated microbial communities may have perpetuating implications in leaf shredding invertebrates.