Defining the data gap: What do we know about environmental exposure, hazards and risks of pharmaceuticals in the European aquatic environment?

Active pharmaceutical ingredients (APIs) and their transformation products inevitably enter waterways where they might cause adverse effects to aquatic organisms. Identifying the potential risks of APIs in the environment is therefore a goal and current strategic direction of environmental management described in the EU Strategic Approach to Pharmaceuticals in the Environment and the Green Deal. This is challenged by a paucity of monitoring and ecotoxicity data to adequately describe risks. In this study we analyze measured environmental concentrations (MECs) of APIs from 5933 sites in 25 European countries as documented in the EMPODAT database or collected by the German Environment Agency for the time period between 1997 and 2020. These data were compared with empirical data on the ecotoxicity of APIs from the U.S. EPA ECOTOX database. Although 1763 uniquely identifiable APIs are registered with the European Medicines Agency (EMA) for sale in the European Economic Area (EEA), only 312 (17.7%) of these are included in publicly available monitoring data, 36 (1.8%) compounds have sufficient ecotoxicological data to derive a PNEC, and only 27 (1.5%) compounds meet both the hazard and exposure data requirements required to to perform an environmental risk assessment according to EMA guidelines. Four of these compounds (14.8%) had a median risk quotient (RQ) > 1. Endocrine disruptors had the highest median RQ, with 7.0 and 5.6 for 17α-ethinyl-estradiol and 17ß-estradiol respectively. A comparison of in-silico and empirical exposure data for 72 APIs demonstrated the high protectiveness of the current EMA guidelines, with predicted environmental concentrations (PECs) exceeding median MECs in 98.6% of cases, with a 100-fold median increase. This study describes the data shortfalls hindering an accurate assessment of the risk posed to European waterways by APIs, and identifies 68 APIs for prioritized inclusion in monitoring programs, and 66 APIs requiring ecotoxicity testing to fill current data gaps.

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 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.

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.

Physiologically based kinetic models for farm animals: Critical review of published models and future perspectives for their use in chemical risk assessment.

Physiologically based kinetic (PBK) models in the 10 most common species of farm animals were identified through an extensive literature search. This resulted in 39 PBK models, mostly for pharmaceuticals. The models were critically assessed using the WHO criteria for model evaluation, i.e. 1) purpose, 2) structure and mathematical representation, 3) computer implementation, 4) parameterisation, 5) performance, and 6) documentation. Overall, most models were calibrated and validated with published data (92% and 67% respectively) but only a fraction of model codes were published along with the manuscript (28%) and local sensitivity analysis was performed without considering global sensitivity analysis. Hence, the reliability of these PBK models is hard to assess and their potential for use in chemical risk assessment is limited. In a risk assessment context, future PBK models for farm animals should include a more generic and flexible model structure, use input parameters independent on calibration and include assessment tools to assess model performance. Development and application of PBK models for farm animal species would furthermore benefit from the setup of structured databases providing data on physiological and chemical-specific parameters as well as enzyme expression and activities to support the development of species-specific QIVIVE models.

Comparing the effectiveness of interventions to improve ventilation behavior in primary schools.

UNLABELLED: Poor air quality in schools has been associated with adverse health effects. Indoor air quality can be improved by increasing ventilation. The objective of this study was to compare the effectiveness of different interventions to improve ventilation behavior in primary schools. We used indoor CO(2) concentrations as an indicator. In 81 classes of 20 Dutch primary schools, we applied three different interventions: (i) a class-specific ventilation advice; (ii) the advice combined with a CO(2) warning device and (iii) the advice combined with a teaching package. The effectiveness of the interventions was tested directly after intervention and 6 weeks after intervention by measuring the CO(2) concentrations and comparison with a control group (iv). Before intervention, the CO(2) concentration exceeded 1000 ppm for 64% of the school day. The class-specific ventilation advice without further support appeared an ineffective tool to improve ventilation behavior. The advice in combination with a CO(2) warning device or the teaching package proved effective tools and resulted in lower indoor CO(2) concentrations when compared with the control group. Ventilation was significantly improved, but CO(2) concentrations still exceeded 1000 ppm for more than 40% of the school day. Hence, until ventilation facilities are upgraded, the CO(2) warning device and the teaching package are useful low-cost tools. PRACTICAL IMPLICATIONS: To improve ventilation behavior and indoor air quality in schools, CO(2) warning device and teaching package combined with a class-specific ventilation advice, are effective tools, while giving the ventilation advice solely, is not effective. Although ventilation is significantly improved through behavioral change, the ventilation rate is still insufficient to maintain good air quality during the full school day. Therefore, the improvement of the ventilation facilities is recommended. Hence, until ventilation facilities in schools are upgraded, the CO(2) warning device and the teaching package are useful low-cost tools to improve current indoor air quality.

Human and environmental risk assessment of pharmaceuticals: differences, similarities, lessons from toxicology.

The presence of human and veterinary pharmaceuticals in the environment has caused increasing concern due their effects on ecological receptors. Improving the risk assessment of these compounds necessitates a quantitative understanding of their metabolism and elimination in the target organism (toxicokinetics), particularly via the ubiquitous cytochrome P-450 (CYP) system and their mechanisms of toxicity (toxicodynamics). This review focuses on a number of pharmaceuticals and veterinary medicines of environmental concern, and the differences and similarities between ecological and human risk assessment. CYP metabolism is discussed with particular reference to its ubiquity in species of ecological relevance. The important issue of pharmaceutical mixtures is discussed to assess how emerging technologies such as ecotoxicogenomics may assist in moving towards a more mechanism-based environmental risk assessment of pharmaceuticals.

Effluent standards for developing countries: combining the technology- and water quality-based approach.

It is a challenge for developing countries to realize socio-economical development without impairing water resources in an unacceptable way. A possible means for controlling water pollution is through defining, applying and enforcing effluent standards for wastewater discharges. However, in many developing countries the definition of effluent standards is still poor. They are either too stringent because they are based on standards from developed countries, or too relaxed and therefore they do not guarantee the safe intended uses of water. In order to define an approach for setting effluent standards that suits the needs and means of developing counties, water quality management practices in the USA, the EU, the New Independent States (NIS) and the Philippines were analyzed and compared. Four criteria (protection of the environment, technical viability, economic feasibility and institutional capacity requirements) were used to assess the suitability of these practices for developing countries. It is concluded that a combined approach that is based on best available technology not entailing excessive costs and environmental quality standards is the best way to define effluent standards that restrict water pollution against affordable costs.