Emissions of pharmaceuticals and plant protection products to the lagoon of Venice: development of a new emission inventory.

Estimating the emissions of chemical pollutants to water is a fundamental step for the development and application of effective and sustainable management strategies of water resources, but methods applied so far to build chemicals inventories at the European or national scale show several limitations when applied at the local scale. The issue is particularly relevant when considering contaminants of emerging concern (CECs), whose environmental releases and occurrence are still poorly studied and understood. In this work, an approach to estimate water emissions of nine active pharmaceutical ingredients (APIs) and ten most applied plant protection products (PPPs) is presented, considering proxy indicators (e.g., sales data and census information). The application area is the lagoon of Venice (Italy), a complex transitional environment highly influenced by anthropic pressures (e.g., agricultural and industrial activities, animal breeding, and wastewater discharge). The presented approach can be tailored to the information available for any local scale case study. Data on annual regional sales of PPPs and APIs were integrated with georeferenced demographic and economic statistics (such as census and land-use information) to estimate chemicals emissions to surface water and groundwater. A sensitivity and uncertainty analysis identified the main factors affecting emissions estimates, and those contributing more significantly to results uncertainty. Results showed the highest estimated emissions of APIs for antibiotics (i.e., amoxicillin, clarithromycin, azithromycin, and ciprofloxacin) used for humans and animals, while most of hormones' emission (i.e., 17- α-ethinylestradiol and 17-ß-estradiol) derived from animal breeding. Regarding PPPs, glyphosate and imidacloprid emissions were one to two orders of magnitude higher compared to the other chemicals. Uncertainty and sensitivity analysis showed that the variability of each parameter used to estimate emissions depends greatly both on the target chemical and the specific emission source considered. Excretion rates and removal during wastewater treatment were major key parameters for all the target pharmaceutical compounds, while for PPPs the key parameter was their loss into the natural waters after application.

Role of Physiologically Based Kinetic modelling in addressing environmental chemical mixtures - A review.

The role of Physiologically Based Kinetic (PBK) modelling in assessing mixture toxicology has been growing for the last three decades. It has been widely used to investigate and address interactions in mixtures. This review describes the current state-of-the-art of PBK models for chemical mixtures and to evaluate the applications of PBK modelling for mixtures with emphasis on their role in chemical risk assessment. A total of 35 mixture PBK models were included after searching web resources (Scopus, PubMed, Web of Science, and Google Scholar), screening for duplicates, and excluding articles based on eligibility criteria. Binary mixtures and volatile organic compounds accounted for two-thirds of the chemical mixtures identified. The most common exposure route and modelled system were found to be inhalation and rats respectively. Twenty two (22) models were for binary mixtures, 5 for ternary mixtures, 3 for quaternary mixtures, and 5 for complex mixtures. Both bottom-up and top-down PBK modelling approaches are described. Whereas bottom-up approaches are based on a series of binary interactions, top-down approaches are based on the lumping of mixture components. Competitive inhibition is the most common type of interaction among the various types of mixtures, and usually becomes a concern at concentrations higher than environmental exposure levels. It leads to reduced biotransformation that either means a decrease in the amount of toxic metabolite formation or an increase in toxic parent chemical accumulation. The consequence is either lower or higher toxicity compared to that estimated for the mixture based on the additivity principle. Therefore, PBK modelling can play a central role in predicting interactions in chemical mixture risk assessment.

Investigating cell type specific mechanisms contributing to acute oral toxicity.

The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 98 were identified with target organ specific effects, of which 93% were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% as non-toxic. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA.

The virtual cell based assay: Current status and future perspectives.

In order to replace the use of animals in toxicity testing, there is a need to predict in vivo toxic doses from concentrations that cause toxicological effects in relevant in vitro systems. The Virtual Cell Based Assay (VCBA) estimates time-dependent concentration of a test chemical in the cell and cell culture for a given in vitro system. The concentrations in the different compartments of the cell and test system are derived from ordinary differential equations, physicochemical parameters of the test chemical and properties of the cell line. The VCBA has been developed for a range of cell lines including BALB/c 3T3 cells, HepG2, HepaRG, lung A459 cells, and cardiomyocytes. The model can be used to design and refine in vitro experiments and extrapolate in vitro effective concentrations to in vivo doses that can be applied in risk assessment. In this paper, we first discuss potential applications of the VCBA: i) design of in vitro High Throughput Screening (HTS) experiments; ii) hazard identification (based on acute systemic toxicity); and iii) risk assessment. Further extension of the VCBA is discussed in the second part, exploring potential application to i) manufactured nanomaterials, ii) additional cell lines and endpoints, and considering iii) other opportunities.

Modeling the influence of climate change on the mass balance of polychlorinated biphenyls in the Adriatic Sea.

Climate forcing is forecasted to influence the Adriatic Sea region in a variety of ways, including increasing temperature, and affecting wind speeds, marine currents, precipitation and water salinity. The Adriatic Sea is intensively developed with agriculture, industry, and port activities that introduce pollutants to the environment. Here, we developed and applied a Level III fugacity model for the Adriatic Sea to estimate the current mass balance of polychlorinated biphenyls in the Sea, and to examine the effects of a climate change scenario on the distribution of these pollutants. The model's performance was evaluated for three PCB congeners against measured concentrations in the region using environmental parameters estimated from the 20th century climate scenario described in the Special Report on Emission Scenarios (SRES) by the IPCC, and using Monte Carlo uncertainty analysis. We find that modeled fugacities of PCBs in air, water and sediment of the Adriatic are in good agreement with observations. The model indicates that PCBs in the Adriatic Sea are closely coupled with the atmosphere, which acts as a net source to the water column. We used model experiments to assess the influence of changes in temperature, wind speed, precipitation, marine currents, particulate organic carbon and air inflow concentrations forecast in the IPCC A1B climate change scenario on the mass balance of PCBs in the Sea. Assuming an identical PCBs' emission profile (e.g. use pattern, treatment/disposal of stockpiles, mode of entry), modeled fugacities of PCBs in the Adriatic Sea under the A1B climate scenario are higher because higher temperatures reduce the fugacity capacity of air, water and sediments, and because diffusive sources to the air are stronger.

Modeling the global levels and distribution of polychlorinated biphenyls in air under a climate change scenario.

We used the multimedia chemical fate model BETR Global to evaluate changes in the global distribution of two polychlorinated biphenyls, PCB 28 and PCB 153, under the influence of climate change. This was achieved by defining two climate scenarios based on results from a general circulation model, one scenario representing the last twenty years of the 20th century (20CE scenario) and another representing the global climate under the assumption of strong future greenhouse gas emissions (A2 scenario). The two climate scenarios are defined by four groups of environmental parameters: (1) temperature in the planetary boundary layer and the free atmosphere, (2) wind speeds and directions in the atmosphere, (3) current velocities and directions in the surface mixed layer of the oceans, and (4) rate and geographical pattern of precipitation. As a fifth parameter in our scenarios, we considerthe effect of temperature on primary volatilization emissions of PCBs. Comparison of dynamic model results using environmental parameters from the 20CE scenario against historical long-term monitoring data of concentrations of PCB 28 and PCB 153 in air from 16 different sites shows satisfactory agreement between modeled and measured PCBs concentrations. The 20CE scenario and A2 scenario were compared using steady-state calculations and assuming the same source characteristics of PCBs. Temperature differences between the two scenarios is the dominant factor that determines the difference in PCB concentrations in air. The higher temperatures in the A2 scenario drive increased primary and secondary volatilization emissions of PCBs, and enhance transport from temperate regions to the Arctic. The largest relative increase in concentrations of both PCB congeners in air under the A2 scenario occurs in the high Arctic and the remote Pacific Ocean. Generally, higher wind speeds under the A2 scenario result in more efficient intercontinental transport of PCB 28 and PCB 153 compared to the 20CE scenario. Our modeling indicates that in a future impacted by climate change, we can expectincreased volatilization emissions and increased mobility of persistent organic pollutants with properties similar to those of PCBs.