Natural clay as a sorbent to remove pharmaceutical micropollutants from wastewater.

Worldwide, the aquatic environment is contaminated by micro-pollutants, such as ingredients of personal care products, pesticides and pharmaceuticals. This contamination is one of the major environmental issues of global concern. Adsorption is one of approach, which has been most extensively discussed within recent years for the reduction of the input of micro-pollutants into the environment. In the present study, the natural clay classified as Na-montmorillonite, was characterized and tested for its potential to remove four model compounds representing different polarity and ionizability: i) diatrizoic acid (DAT), ii) iopamidol (IOP), iii) metformin (MTF), and iv) carbamazepine (CBZ). The adsorption efficiency of clay was evaluated by initial compound concentration, effect of pH, contact time and temperature. The results indicated that clay was able to remove the pharmaceuticals from aqueous medium with an efficiency of 70% for CBZ and MTF. In contrast, clay showed a lower removal of 30% for DAT and no removal for IOP. The results indicate that clay could rapidly and efficiently reduce the concentration of CBZ and MTF, which could provide a solution to remove some substances, without undesirable by-product generation. However, this study clearly demonstrated that removal rates strongly depend on the compound. Albeit chemical structure may play a role for the different degree of removal, this study could not completely explain the sorption mechanism between sorbent-sorbate interactions.

Hazard screening of photo-transformation products from pharmaceuticals: Application to selective ß1-blockers atenolol and metoprolol.

The identification of toxic components in cocktail mixtures of pollutants, their metabolites and transformation products (TPs) generated from environmental and treatment processes remains an arduous task. This study expanded in this area by applying a combination of chemical analytics, a battery of in vitro bioassays and an in silico "testing battery" to UV photolysis mixtures of active pharmaceutical ingredients. The objectives were to understand the toxic nature of the mixtures and to prioritize photo-TPs for risk analysis. The selective ß1-blockers Atenolol (ATL) and Metoprolol (MTL) that are ubiquitous in the aquatic environment were used as an example. The photolysis mixtures were cytotoxic to Vibrio fischeri and mammalian cells but not mutagenic in the Ames test or genotoxic in the in vitro micronucleus and umu tests. Potentially hazardous TPs were proposed by relating the observed effects to the kinetics of TP occurrence and applying in silico toxicity predictions for individual photo-TPs. This model study was done to identify principal mechanisms rather than accurately simulating environmental transformation processes. Several photo-TPs were proposed to present a greater hazard than the selected ß-blockers and therefore fate and toxicity assessments may be required to determine their environmental relevance.

Transformation products in the water cycle and the unsolved problem of their proactive assessment: A combined in vitro/in silico approach.

Transformation products (TPs) emerging from incomplete degradation of micropollutants in aquatic systems can retain the biological activity of the parent compound, or may even possess new unexpected toxic properties. The chemical identities of these substances remain largely unknown, and consequently, the risks caused by their presence in the water cycle cannot be assessed thoroughly. In this study, a combined approach for the proactive identification of hazardous elements in the chemical structures of TPs, comprising analytical, bioanalytical and computational methods, was assessed by the example of the pharmaceutically active micropollutant propranolol (PPL). PPL was photo-transformed using ultraviolet (UV) irradiation and 115 newly formed TPs were monitored in the reaction mixtures by LC-MS analysis. The reaction mixtures were screened for emerging effects using a battery of in vitro bioassays and the occurrence of cytotoxic and mutagenic activities in bacteria was found to be significantly correlated with the occurrence of specific TPs during the treatment process. The follow-up analysis of structure-activity-relationships further illustrated that only small chemical transformations, such as the hydroxylation or the oxidative opening of an aromatic ring system, could substantially alter the biological effects of micropollutants in aquatic systems. In conclusion, more efforts should be made to prevent the occurrence and transformation of micropollutants in the water cycle and to identify the principal degradation pathways leading to their toxicological activation. With regard to the latter, the judicious combination of bioanalytical and computational tools represents an appealing approach that should be developed further.

Re-Designing of Existing Pharmaceuticals for Environmental Biodegradability: A Tiered Approach with ß-Blocker Propranolol as an Example.

Worldwide, contamination of aquatic systems with micropollutants, including pharmaceuticals, is one of the challenges for sustainable management of water resources. Although micropollutants are present at low concentrations, many of them raise considerable toxicological concerns, particularly when present as components of complex mixtures. Recent research has shown that this problem cannot be sustainably solved with advanced effluent treatment. Therefore, an alternative that might overcome these environmental problems is the design of new pharmaceutical molecules or the redesign of existing pharmaceutical molecules that present the functionality needed for their application and have improved environmental biodegradability. Such redesigning can be performed by small molecular changes in the drug molecule with intact drug moiety which could incorporate the additional attribute such as biodegradability while retaining its pharmacological potency. This proof of concept study provides an approach for the rational redesign of a given pharmaceutical (Propranolol as an example). New derivatives with small molecular changes as compared to propranolol molecule were generated by a nontargeted photolysis process. Generated derivatives with intact drug moieties (an aromatic ring and a ß-ethanolamine moiety) were further screened for aerobic biodegradability and pharmacological potency. The feasibility of the approach of redesigning an existing pharmaceutical through nontargeted generation of new derivatives with intact drug moiety and through subsequent screening was demonstrated in this study. Application of such approaches in turn might contribute to the protection of water resources in a truly sustainable manner.

Designing green derivatives of ß-blocker Metoprolol: a tiered approach for green and sustainable pharmacy and chemistry.

The presences of micro-pollutants (active pharmaceutical ingredients, APIs) are increasingly seen as a challenge of the sustainable management of water resources worldwide due to ineffective effluent treatment and other measures for their input prevention. Therefore, novel approaches are needed like designing greener pharmaceuticals, i.e. better biodegradability in the environment. This study addresses a tiered approach of implementing green and sustainable chemistry principles for theoretically designing better biodegradable and pharmacologically improved pharmaceuticals. Photodegradation process coupled with LC-MS(n) analysis and in silico tools such as quantitative structure-activity relationships (QSAR) analysis and molecular docking proved to be a very significant approach for the preliminary stages of designing chemical structures that would fit into the "benign by design" concept in the direction of green and sustainable pharmacy. Metoprolol (MTL) was used as an example, which itself is not readily biodegradable under conditions found in sewage treatment and the aquatic environment. The study provides the theoretical design of new derivatives of MTL which might have the same or improved pharmacological activity and are more degradable in the environment than MTL. However, the in silico toxicity prediction by QSAR of those photo-TPs indicated few of them might be possibly mutagenic and require further testing. This novel approach of theoretically designing 'green' pharmaceuticals can be considered as a step forward towards the green and sustainable pharmacy field. However, more knowledge and further experience have to be collected on the full scope, opportunities and limitations of this approach.

Qualitative environmental risk assessment of photolytic transformation products of iodinated X-ray contrast agent diatrizoic acid.

Recent studies have confirmed that the aquatic ecosystem is being polluted with an unknown cocktail of pharmaceuticals, their metabolites and/or their transformation products (TPs). Although individual chemicals are typically present at low concentrations, they can interact with each other resulting in additive or potentially even synergistic mixture effects. Therefore it is necessary to assess the environmental risk caused by these chemicals. Data on exposure is required for quantitative risk assessment of TPs and/or metabolites. Such data are mostly missing because of the non-availability of TPs and very often metabolites for experimental testing. This study demonstrates the application of different in silico tools for qualitative risk assessment using the example of photodegradation TPs (photo-TPs) of diatrizoic acid (DIAT), which itself is not readily biodegradable. Its photolytic transformation was studied and the photodegradation pathway was established. The aerobic biodegradability of photo-TPs under the conditions of an aquatic environment was assessed using standardized OECD tests. The qualitative risk assessment of DIAT and selected photo-TPs was performed by the PBT approach (i.e. Persistence, Bioaccumulation and Toxicity), using experimental biodegradation test assays, applying different QSAR models with several different toxicological endpoints and in silico read-across approaches. The qualitative risk assessment pointed out that the photo-TPs were less persistent compared to DIAT and none of them possessed any bioaccumulation threat. However, a few photo-TPs were predicted to be active for mutagenicity and genotoxicity, which indicate the need for further testing to confirm these predictions. The present study demonstrates that in silico qualitative risk assessment analysis can increase the knowledge space about the environmental fate of TPs.