Establishing allometric relationships between microsomal protein and cytochrome P450 content with body weight in vertebrate species.

Data from in vitro studies are routinely used to estimate in vivo hepatic clearance of chemicals and this information is needed to parameterise physiologically based kinetic models. Such clearance data can be obtained from laboratory experiments using liver microsomes, hepatocytes, precision-cut liver slices or recombinant enzymes. Irrespective of the selected test system, scaling factors are required to convert the in vitro measured intrinsic clearance to a whole liver intrinsic clearance. Scaling factors such as the hepatic microsomal protein per gram of liver and/or the amount of cytochrome P450 per hepatocyte provide a means to calculate the whole liver intrinsic clearance. Here, a database from the peer-reviewed literature has been developed and provides quantitative metrics on microsomal protein (MP) and cytochrome P450 contents in vertebrate orders namely amphibians, mammals, birds, fish and reptiles. This database allows to address allometric relationships between body weight and MP content, and body weight and cytochrome P450 content. A total of 85 and 74 vertebrate species were included to assess the relationships between log10 body weight versus log10 MP, and between log10 body weight and log10 cytochrome P450 content, respectively. The resulting slopes range from 0.76 to 1.45 in a range of vertebrate species. Such data-driven allometric relationships can be used to estimate the MP content necessary for in vitro to in vivo extrapolation of in vitro clearance data. Future work includes applications of these relationships for different vertebrate taxa using quantitative in vitro to in vivo extrapolation models coupled to physiologically based kinetic models using chemicals of relevance as case studies including pesticides, contaminants and feed additives.

The impact of imidacloprid and thiacloprid on the mean species abundance in aquatic ecosystems.

Neonicotinoids are currently the most widely used and sold insecticides in the world, providing effective pest control. Risk assessment of these and other pesticides by lab-based indicators is common. Yet, empirically and theoretically underpinning of extrapolation to indicators used in field surveys is severely limited. Consequently, the aim of our study was to quantify the toxicological and ecological impact of the neonicotinoids imidacloprid and thiacloprid to aquatic invertebrates. We derived Species Sensitivity Distributions (SSDs) based on chronic LC50 data and Mean Species Abundance Relationships (MSARs), comparing these lab-based approaches to field data as well. MSARs are changes in mean species abundance (MSA) as a function of chemical exposure, providing insight into the overall decline of a community. The MSA expresses the mean abundance of species in disturbed conditions relative to their abundance in undisturbed habitat. The medians of the SSD of imidacloprid and thiacloprid for the different species were 16.45 µg/L and 26.40 µg/L, respectively. HC50s of the MSAR of imidacloprid and thiacloprid were 4.25 µg/L and 5.12 µg/L, respectively. The three taxonomic groups tested (insects, crustaceans and mollusks) did not differ significantly in sensitivity for imidacloprid and thiacloprid, both according to the SSDs and MSARs derived. Quantile exposure-response curves (99%-tile) were plotted showing the relative abundance (RA) of aquatic invertebrate species at increasing imidacloprid levels. The 99%-tile of the Relative Abundances (RA99) of species and corresponding imidacloprid concentrations monitored in field surveys in the Netherlands was significantly lower than the Potentially Affected Fraction (PAF) calculated from the SSD. Yet, the MSA was similar to the RA99, suggesting that MSAR is an ecologically meaningful relationship for toxic stress estimated from lab data. Future efforts should be directed to additional empirical underpinning as well as determining the relationship of PAF to other metrics for ecosystem diversity and productivity.

Ecological risks of imidacloprid to aquatic species in the Netherlands: Measured and estimated concentrations compared to species sensitivity distributions.

Recent declines of insects' biomass have been a major point of interest. While several causes, including use of neonicotinoids like imidacloprid, have been suggested, scientific underpinning is limited. The aim of our study was to assess the potential risk of imidacloprid for freshwater fauna in the Netherlands and to validate the SimpleBox model to allow application elsewhere. To this end, we compared imidacloprid concentrations estimated from emissions using the SimpleBox model to measurements obtained from monitoring databases and calculated the ecological risk based on measured concentrations for aquatic fauna. Imidacloprid concentration estimations were within the range measured, opening opportunities for application of SimpleBox to regions where measurements are limited. Aquatic insects were found to be most sensitive to imidacloprid while amphibians and fish are least sensitive to imidacloprid. In particular, the ecological risk of measured imidacloprid concentration in the Netherlands was 1%, implying that concentrations frequently exceed levels that are lethal in short-term experiments. Hence, based on lab toxicity data, the present study suggests that imidacloprid concentrations can be high enough to explain insect decline observed in the same areas.

An open source physiologically based kinetic model for the chicken (Gallus gallus domesticus): Calibration and validation for the prediction residues in tissues and eggs.

Xenobiotics from anthropogenic and natural origin enter animal feed and human food as regulated compounds, environmental contaminants or as part of components of the diet. After dietary exposure, a chemical is absorbed and distributed systematically to a range of organs and tissues, metabolised, and excreted. Physiologically based kinetic (PBK) models have been developed to estimate internal concentrations from external doses. In this study, a generic multi-compartment PBK model was developed for chicken. The PBK model was implemented for seven compounds (with log Kow range -1.37-6.2) to quantitatively link external dose and internal dose for risk assessment of chemicals. Global sensitivity analysis was performed for a hydrophilic and a lipophilic compound to identify the most sensitive parameters in the PBK model. Model predictions were compared to measured data according to dataset-specific exposure scenarios. Globally, 71% of the model predictions were within a 3-fold change of the measured data for chicken and only 7% of the PBK predictions were outside a 10-fold change. While most model input parameters still rely on in vivo experiments, in vitro data were also used as model input to predict internal concentration of the coccidiostat monensin. Future developments of generic PBK models in chicken and other species of relevance to animal health risk assessment are discussed.

Generic physiologically based kinetic modelling for farm animals: Part I. Data collection of physiological parameters in swine, cattle and sheep.

Physiologically based kinetic (PBK) models for farm animals are of growing interest in food and feed safety with key applications for regulated compounds including quantification of tissue concentrations, kinetic parameters and the setting of safe exposure levels on an internal dose basis. The development and application of these models requires data for physiological, anatomical and chemical specific parameters. Here, we present the results of a structured data collection of anatomical and physiological parameters in three key farm animal species (swine, cattle and sheep). We performed an extensive literature search and meta-analyses to quantify intra-species variability and associated uncertainty of the parameters. Parameters were collected for organ weights and blood flows in all available breeds from 110 scientific publications, of which 29, 48 and 33 for cattle, sheep, and swine, respectively. Organ weights were available in literature for all three species. Blood flow parameter values were available for all organs in sheep but were scarcer in swine and cattle. Furthermore, the parameter values showed a large intra-species variation. Overall, the parameter values and associated variability provide reference values which can be used as input for generic PBK models in these species.

Generic physiologically based kinetic modelling for farm animals: Part II. Predicting tissue concentrations of chemicals in swine, cattle, and sheep.

The development of three generic multi-compartment physiologically based kinetic (PBK) models is described for farm animal species, i.e. cattle, sheep, and swine. The PBK models allow one to quantitatively link external dose and internal dose for risk assessment of chemicals relevant to food and feed safety. Model performance is illustrated by predicting tissue concentrations of melamine and oxytetracycline and validated through comparison with measured data. Overall, model predictions were reliable with 71% of predictions within a 3-fold of the measured data for all three species and only 6% of predictions were outside a 10-fold of the measured data. Predictions within a 3-fold change were best for cattle, followed by sheep, and swine (82%, 76%, and 63%). Global sensitivity analysis was performed to identify the most sensitive parameters in the PBK model. The sensitivity analysis showed that body weight and cardiac output were the most sensitive parameters. Since interspecies differences in metabolism impact on the fate of a wide range of chemicals, a key step forward is the introduction of species-specific information on transporters and metabolism including expression and activities.

Historical rise of waterpower initiated the collapse of salmon stocks.

The collapse of Atlantic salmon (Salmo salar) stocks throughout North-Western Europe is generally ascribed to large-scale river regulation, water pollution and over-fishing in the 19(th) and 20(th) century. However, other causes have rarely been quantified, especially those acting before the 19(th) century. By analysing historical fishery, market and tax statistics, independently confirmed by archaeozoological records, we demonstrate that populations declined by up to 90% during the transitional period between the Early Middle Ages (c. 450-900 AD) and Early Modern Times (c. 1600 AD). These dramatic declines coincided with improvements in watermill technology and their geographical expansion across Europe. Our extrapolations suggest that historical Atlantic salmon runs must have once been very abundant indeed. The historical perspective presented here contributes to a better understanding of the primary factors that led to major declines in salmon populations. Such understanding provides an essential basis for the effective ecological rehabilitation of freshwater ecosystems.

Circumpolar contaminant concentrations in polar bears (Ursus maritimus) and potential population-level effects.

Polar bears (Ursus maritimus) currently receive much attention in the context of global climate change. However, there are other stressors that might threaten the viability of polar bear populations as well, such as exposure to anthropogenic pollutants. Lipophilic organic compounds bio-accumulate and bio-magnify in the food chain, leading to high concentrations at the level of top-predators. In Arctic wildlife, including the polar bear, various adverse health effects have been related to internal concentrations of commercially used anthropogenic chemicals like PCB and DDT. The extent to which these individual health effects are associated to population-level effects is, however, unknown. In this study we assembled data on adipose tissue concentrations of ∑PCB, ∑DDT, dieldrin and ∑PBDE in individual polar bears from peer-reviewed scientific literature. Data were available for 14 out of the 19 subpopulations. We found that internal concentrations of these contaminants exceed threshold values for adverse individual health effects in several subpopulations. In an exploratory regression analysis we identified a clear negative correlation between polar bear population density and sub-population specific contaminant concentrations in adipose tissue. The results suggest that adverse health effects of contaminants in individual polar bears may scale up to population-level consequences. Our study highlights the need to consider contaminant exposure along with other threats in polar bear population viability analyses.

An allometric approach to quantify the extinction vulnerability of birds and mammals.

Methods to quantify the vulnerability of species to extinction are typically limited by the availability of species-specific input data pertaining to life-history characteristics and population dynamics. This lack of data hampers global biodiversity assessments and conservation planning. Here, we developed a new framework that systematically quantifies extinction risk based on allometric relationships between various wildlife demographic parameters and body size. These allometric relationships have a solid theoretical and ecological foundation. Extinction risk indicators included are (1) the probability of extinction, (2) the mean time to extinction, and (3) the critical patch size. We applied our framework to assess the global extinction vulnerability of terrestrial carnivorous and non-carnivorous birds and mammals. Irrespective of the indicator used, large-bodied species were found to be more vulnerable to extinction than their smaller counterparts. The patterns with body size were confirmed for all species groups by a comparison with IUCN data on the proportion of extant threatened species: the models correctly predicted a multimodal distribution with body size for carnivorous birds and a monotonic distribution for mammals and non-carnivorous birds. Carnivorous mammals were found to have higher extinction risks than non-carnivores, while birds were more prone to extinction than mammals. These results are explained by the allometric relationships, predicting the vulnerable species groups to have lower intrinsic population growth rates, smaller population sizes, lower carrying capacities, or larger dispersal distances, which, in turn, increase the importance of losses due to environmental stochastic effects and dispersal activities. Our study is the first to integrate population viability analysis and allometry into a novel, process-based framework that is able to quantify extinction risk of a large number of species without requiring data-intensive, species-specific information. The framework facilitates the estimation of extinction vulnerabilities of data-deficient species. It may be applied to forecast extinction vulnerability in response to a changing environment, by incorporating quantitative relationships between wildlife demographic parameters and environmental drivers like habitat alteration, climate change, or hunting.

Environmental contamination due to shale gas development.

Shale gas development potentially contaminates both air and water compartments. To assist in governmental decision-making on future explorations, we reviewed scattered information on activities, emissions and concentrations related to shale gas development. We compared concentrations from monitoring programmes to quality standards as a first indication of environmental risks. Emissions could not be estimated accurately because of incomparable and insufficient data. Air and water concentrations range widely. Poor wastewater treatment posed the highest risk with concentrations exceeding both Natural Background Values (NBVs) by a factor 1000-10,000 and Lowest Quality Standards (LQSs) by a factor 10-100. Concentrations of salts, metals, volatile organic compounds (VOCs) and hydrocarbons exceeded aquatic ecotoxicological water standards. Future research must focus on measuring aerial and aquatic emissions of toxic chemicals, generalisation of experimental setups and measurement technics and further human and ecological risk assessment.

Low oxygen tolerance of different life stages of temperate freshwater fish species.

Data on low dissolved oxygen (DO2) tolerance of freshwater fish species of north-western Europe were used to create species sensitivity distributions (SSD). Lowest observed effect concentrations (LOEC) and 100% lethal concentrations (LC100) data were collected from the scientific literature. Comparisons were made among life stages as well as between native and exotic species. In addition, lethal DO2 concentrations were compared to oxygen concentrations corresponding to maximum tolerable water temperatures of the same species. Fish eggs and embryos were the least tolerant. Juveniles had a significantly lower mean LOEC than adults, but there was no difference in mean LC100 between the two groups. The difference in lethal oxygen concentrations between adults and juveniles was largest for three salmonids, although it remains uncertain if this was a result of smoltification. There were no significant differences between native and exotic species; however, data on exotics are limited. DO2 concentrations converted from maximum tolerable water temperatures were 3·9 times higher than the measured lethal DO2 concentrations, which may reflect changes in respiration rates (Q10) and may also relate to the simplicity of the model used.

Toxicity data for modeling impacts of oil components in an Arctic ecosystem.

Ecological impact assessment modeling systems are valuable support tools for managing impacts from commercial activities on marine habitats and species. The inclusion of toxic effects modeling in these systems is predicated on the availability and quality of ecotoxicology data. Here we report on a data gathering exercise to obtain toxic effects data on oil compounds for a selection of cold-water marine species of fish and plankton associated with the Barents Sea ecosystem. Effects data were collated from historical and contemporary literature resources for the endpoints mortality, development, growth, bioaccumulation and reproduction. Evaluating the utility and applicability of these data for modeling, we find that data coverage is limited to a sub-set of the required endpoints. There is a need for new experimental studies for zooplankton focused on the endpoints development and bioaccumulation and for larvae and juvenile fish focused on growth and development.

Combining monitoring data and modeling identifies PAHs as emerging contaminants in the arctic.

Protecting Arctic ecosystems against potential adverse effects from anthropogenic activities is recognized as a top priority. In particular, understanding the accumulation and effects of persistent organic pollutants (POPs) in these otherwise pristine ecosystems remains a scientific challenge. Here, we combine more than 20,000 tissue concentrations, a food web bioaccumulation model, and time trend analyses to demonstrate that the concentrations of legacy-POPs in the Barents/Norwegian Sea fauna decreased 10-fold between 1985 and 2010, which reflects regulatory efforts to restrict these substances. In contrast, concentrations of fossil fuel derived PAHs in lower trophic levels (invertebrates and fish) increased 10 to 30 fold over the past 25 years and now dominate the summed POP burden (25 POPs, including 11 PAHs) in these biota. Before 2000, PCBs dominated the summed POP burden in top predators. Our findings indicate that the debate on the environmental impacts of fossil fuel burning should move beyond the expected seawater temperature increase and examine the possible environmental impact of fossil fuel derived PAHs.

Organ-specific accumulation and elimination patterns of PCBs in adult seabass (Dicentrarchus labrax).

The present study quantifies and explains the differences between measured organ-specific polychlorinated biphenyls (PCBs) accumulation and elimination kinetics in seabass (Dicentrarchus labrax), comparing these results with calculations using the generic model OMEGA. Specimens of approximately 250 g were selected and fed with contaminated food with PCBs 18, 44, 49, 52, 101, 105, 118, 138, 180 and 187. The OMEGA model was applied using a measured biomass (re)production coefficient and the food ingestion coefficient. It produced estimations of total body concentrations within a factor between 1.5 and 7.0 times of the measured and it also reproduced the general trend of the PCB concentrations during the experiment. This study allows us to confirm that internal distribution of PCBs is slow, producing significant differences in the tissues elimination rate constants and consequently in tissues bioaccumulation factors (BAF). The distribution of PCBs within the organism was slower than reported before, due to the bigger body size and the high lipid content of these fish.

Comparison of three fish bioaccumulation models for ecological and human risk assessment and validation with field data.

This article compares two bioconcentration Quantitative Structure Activity Relationships (QSARs) for fish applied in human risk assessments with the mechanistic bioaccumulation model OMEGA and field data. It was found that all models are virtually similar up to a Kow of 10(6). For substances with a Kow higher than 10(6), the fish bioconcentration curve in the risk assessment model EUSES decreases parabolically. In contrast, OMEGA bioaccumulation outcomes approximately show a linear increase, based on mechanistic bioconcentration and biomagnification properties of chemicals. The OMEGA-outcomes are close to the fish bioconcentration outcomes of the risk assessment model CalTOX. For very hydrophobic substances, field accumulation data in freshwater and marine fish species are closer to OMEGA- and CalTOX-outcomes compared to EUSES. The results also show that it is important to include biomagnification in fish and lipid content of fish in human exposure models.

Probability and determinants of relapse after discontinuation of inhaled corticosteroids in patients with COPD treated in general practice.

OBJECTIVE: The objective of the study was to assess the probability, and explore determinants of adverse respiratory outcome after discontinuation of inhaled corticosteroid (ICS) treatment in subjects with chronic obstructive pulmonary disease (COPD) diagnosed and treated in general practice. DESIGN: Prospective unblinded ICS withdrawal study. SUBJECTS: 201 ICS treated COPD patients with various degrees of airflow limitation from 45 Dutch general practices. MAIN OUTCOME MEASURES: Probability of and time to exacerbation or unremitting worsening of respiratory symptoms after ICS discontinuation. RESULTS: Mean age was 60.6 (S.D. 9.5) years, post-bronchodilator forced expiratory volume in 1s (FEV1) 65.6 (S.D. 15.7) % predicted. Overall probability of adverse respiratory outcome after ICS discontinuation was 0.37 (95% confidence interval (CI) 0.31, 0.44). Survival analysis showed that age, gender, smoking status and reversibility of airflow limitation were independent predictors of adverse respiratory outcome. For females, the adjusted hazard ratio was 2.14 (95% CI 1.31, 3.50) compared to males. For age, the hazard ratio was 1.05 (95% CI 1.02, 1.08) per year lived. CONCLUSION: Discontinuation of inhaled corticosteroids may harm patients with COPD. The probability of an adverse respiratory outcome may be higher in women, elderly patients, smokers and patients with higher bronchodilator reversibility while on inhaled steroid treatment.

Estimating biotransformation rate constants of organic chemicals from modeled and measured elimination rates.

In this study, biotransformation rate constants are estimated for a large set of organic compounds. Biotransformation (km) is considered part of the total elimination, further consisting of physico-chemical elimination to water (kw), depuration by feces (kf) and growth dilution (gamma). Existing models are used to estimate kw and kf, and gamma. The difference between measured elimination rate constants and the sum of predicted elimination rate constants for water, feces and growth indicates the ration of biotransformation in the total elimination. In all examined animal classes, polycyclic aromatic hydrocarbons seem to be metabolized at an intermediate rate. Because of the relative low hydrophobicity of some of the studied compounds, their physico-chemical elimination rate constant is relatively high, and the relative contribution of metabolism to total elimination of these compounds is therefore relatively low. Fish seem to be capable of metabolizing chlorodibenzo-p-dioxins and -furans, DDT, chloroanilines and phenol.

The power of size. 1. Rate constants and equilibrium ratios for accumulation of organic substances related to octanol-water partition ratio and species weight.

Most of the thousands of substances and species that risk assessment has to deal with are not investigated empirically because of financial, practical, and ethical constraints. To facilitate extrapolation, we have developed a model for accumulation kinetics of organic substances as a function of the octanol-water partition ratio (Kow) of the chemical and the weight, lipid content, and trophic level of the species. The ecological parameters were obtained from a previous review on allometric regressions. The chemical parameters, that is, resistances that substances encounter in water and lipid layers of organisms, were calibrated on 1,939 rate constants for absorption from water for assimilation from food and for elimination. Their ratio was validated on 37 laboratory bioconcentration and biomagnification regressions and on 2,700 field bioaccumulation data. The rate constant for absorption increased with the hydrophobicity of the substances with a Kow up to about 1,000 and then leveled off, decreasing with the weight of the species. About 39% of the variation was explained by the model, while deviations of more than a factor of 5 were noted for labile, large, and less hydrophobic molecules as well as for algae, mollusks, and arthropods. The efficiency for assimilation of contaminants from food was determined mainly by the food digestibility and thus by the trophic level of the species. A distinction was made between substances that are stable, that is, with a minimum elimination only, and those that are labile, that is, with an excess elimination probably largely due to biotransformation. The rate constant for minimum elimination decreased with the hydrophobicity of the substance and the weight of the species. About 70% of the variation was explained by the model, while deviations of more than a factor of 5 were noted for algae, terrestrial plants, and benthic animals. Labile substances were eliminated faster than isolipophilic stable compounds, but differences in laboratory elimination and accumulation were small compared with those in field accumulation. Excess elimination by vertebrates was faster than by invertebrates. Differences between terrestrial and aquatic species were attributed to water turnover rates, whereas differences between trophic levels were due to the food digestibility. Food web accumulation, expressed as organism-organic solids and organism-food concentrations ratios could be largely explained by ecological variables only. The model is believed to facilitate various types of scientific interpretation as well as environmental risk assessment.

The power of size. 2. Rate constants and equilibrium ratios for accumulation of inorganic substances related to species weight.

Most of the thousands of substances and species that risk assessment has to deal with are not investigated empirically because of financial, practical, and ethical constraints. To facilitate extrapolation, we have developed a model for concentration kinetics of inorganic substances as a function of the exposure concentration of the chemical and the weight and trophic level of the species. The ecological parameters and the resistances that substances encounter during diffusion in water layers were obtained from previous reviews. The other chemical parameters (the resistances for permeation of lipid layers) were calibrated in the present study on 1,062 rate constants for absorption from water, for assimilation from food, and for elimination. Data on all elements and species were collected, but most applied to aquatic species, in particular mollusks and fish, and to transition metals, in particular group IIB (Zn, Cd, Hg). Their ratio was validated on 92 regressions and nine geometric averages, representing thousands of (near-)equilibrium accumulation ratios from laboratory and field studies. Rate constants for absorption and elimination decreased with species weight at an exponent of about -0.25, known from ecological allometry. On average, uptake-rate constants decreased with about the reciprocal square root of the exposure concentration. About 71 and 30% of the variation in absorption and elimination was explained by the model, respectively. The efficiency for assimilation of elements from food appeared to be determined mainly by the food digestibility and the distribution over egested and digested fractions. (Near-)equilibrium accumulation and magnification ratios also decreased with the reciprocal square root of the exposure concentration. The level of the organism-solids concentrations ratios roughly varied between one and two orders of magnitude, depending on the number of elements and species groups investigated. Metal concentrations did not increase at higher trophic levels, with the exception of (methyl-)mercury. Organism-solids concentration ratios for terrestrial species tended to be somewhat lower than those for their aquatic equivalents. Food web accumulation, expressed as organism-organic solids and organism-food concentrations ratios, can therefore be only partly explained by ecological variables. The model is believed to facilitate various types of scientific interpretation as well as environmental risk assessment.