Default predicted no-effect target concentrations for antibiotics in the absence of data for the protection against antibiotic resistance and environmental toxicity.

The pharmaceutical manufacturing industry, via the AMR Industry Alliance, has developed and implemented steps to help minimize the potential impact of pharmaceutical manufacturing on the spread of antimicrobial resistance (AMR). One of these steps was to publish predicted no-effect concentrations (PNECs) to serve as targets for antibiotic manufacturing wastewater effluent risk assessments aimed to help protect environmental receptors and to mitigate against the spread of antibiotic resistance. Concentrations below which adverse effects in the environment are not expected to occur (PNECs) were first published in 2018 and are updated annually. The current list now stands at 125 antibiotics; however, it is recognized that this list does not encompass all manufactured antibiotics. Therefore, a statistical evaluation of currently available data was conducted and a default PNEC of 0.05 µg/L for antibiotics in the absence of other data was derived. Integr Environ Assess Manag 2022;18:863-867. © 2022 Merck, Sanofi, Johnson & Johnson Services, Inc, F.Hoffmann-La Roche Ltd, Teva Pharmaceuticals, GlaxoSmithKline, Novartis Pharma AG, and Pfizer lnc. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Science-based Targets for Antibiotics in Receiving Waters from Pharmaceutical Manufacturing Operations.

In 2016, the United Nations declared the need for urgent action to combat the global threat of antimicrobial resistance (AMR). In support of this effort, the pharmaceutical industry has committed to measures aimed at improving the stewardship of antibiotics both within and outside the clinic. Notably, a group of companies collaborated to specifically address concerns related to antibiotic residues being discharged from manufacturing sites. In addition to developing a framework of minimum environmental expectations for antibiotic manufacturers, science-based receiving water targets were established for antibiotics discharged from manufacturing operations. This paper summarizes the holistic approach taken to derive these targets and includes previously unpublished, company-generated, environmental toxicity data.

An International Perspective on the Tools and Concepts for Effluent Toxicity Assessments in the Context of Animal Alternatives: Reduction in Vertebrate Use.

Since the 1940s, effluent toxicity testing has been used to assess potential ecological impacts of effluents and help determine necessary treatment options for environmental protection prior to release. Strategic combinations of toxicity tests, analytical tools, and biological monitoring have been developed. Because the number of vertebrates utilized in effluent testing is thought to be much greater than that used for individual chemical testing, there is a new need to develop strategies to reduce the numbers of vertebrates (i.e., fish) used. This need will become more critical as developing nations begin to use vertebrates in toxicity tests to assess effluent quality. A workshop was held to 1) assess the state of science in effluent toxicity testing globally; 2) determine current practices of regulators, industry, private laboratories, and academia; and 3) explore alternatives to vertebrate (fish) testing options and the inclusion of modified/new methods and approaches in the regulatory environment. No single approach was identified, because of a range of factors including regulatory concerns, validity criteria, and wider acceptability of alternatives. However, a suite of strategies in a weight-of-evidence approach would provide the flexibility to meet the needs of the environment, regulators, and the regulated community; and this "toolbox" approach would also support reduced reliance on in vivo fish tests. The present Focus article provides a brief overview of wastewater regulation and effluent testing approaches. Alternative methodologies under development and some of the limitations and barriers to regulatory approaches that can be selected to suit individual country and regional requirements are described and discussed. Environ Toxicol Chem 2018;37:2745-2757. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

A risk-based approach to managing active pharmaceutical ingredients in manufacturing effluent.

The present study describes guidance intended to assist pharmaceutical manufacturers in assessing, mitigating, and managing the potential environmental impacts of active pharmaceutical ingredients (APIs) in wastewater from manufacturing operations, including those from external suppliers. The tools are not a substitute for compliance with local regulatory requirements but rather are intended to help manufacturers achieve the general standard of "no discharge of APIs in toxic amounts." The approaches detailed in the present study identify practices for assessing potential environmental risks from APIs in manufacturing effluent and outline measures that can be used to reduce the risk, including selective application of available treatment technologies. These measures either are commonly employed within the industry or have been implemented to a more limited extent based on local circumstances. Much of the material is based on company experience and case studies discussed at an industry workshop held on this topic.

Aqueous chlorination of levofloxacin: kinetic and mechanistic study, transformation product identification and toxicity.

The aim of this study was to gain further insight into the fate of levofloxacin during the chlorination process. First, a kinetic study was thus performed at pH 7.2, 20 °C and in the presence of an excess of total chlorine. A slower apparent removal of levofloxacin (k ~ 26 M(-1) s(-1)) was noted when sodium thiosulfate was used to stop the chlorination reaction compared to the degradation observed without using a reducing agent (k ~ 4400 M(-1) s(-1)). The formation of a chlorammonium intermediate which could be converted back into the parent compound through a reaction with thiosulfate was thus expected. This intermediate would result from an initial chlorine attack on the tertiary amine function of levofloxacin. Secondly, four chlorination transformation products were detected by LC/UV/MS analysis. The chemical structures of two of them are proposed. It was suggested that these compounds could come from a secondary reaction of the chlorammonium intermediate on levofloxacin. A reactional pathway is then proposed. Finally, a bioassay using Vibrio fisheri was carried out to study the toxicity pattern during levofloxacin chlorination. An increase in toxicity was observed during chlorination suggesting that the first transformations products formed were more toxic than the parent compound.

Levofloxacin oxidation by ozone and hydroxyl radicals: kinetic study, transformation products and toxicity.

This work was carried out to investigate the fate of the antibiotic levofloxacin upon oxidation with ozone and hydroxyl radicals. A kinetic study was conducted at 20 °C for each oxidant. Ozonation experiments were performed using a competitive kinetic method with carbamazepin as competitor. Significant levofloxacin removal was observed during ozonation and a rate constant value of 6.0×10(4) M(-1) s(-1) was obtained at pH 7.2. An H2O2/UV system was used for the formation of hydroxyl radicals HO. The rate constant of HO was determined in the presence of a high H2O2 concentration. The kinetic expressions yielded a [Formula: see text] value of 4.5×10(9) M(-1) s(-1) at pH 6.0 and 5.2×10(9) M(-1) s(-1) at pH 7.2. These results were used to develop a model to predict the efficacy of the ozonation process and pharmaceutical removal was estimated under different ozonation conditions (i.e. oxidant concentrations and contact times). The results showed that levofloxacin was completely degraded by molecular ozone during ozonation of water and that hydroxyl radicals had no effect in real waters conditions. Moreover, LC/MS/MS and toxicity assays using Lumistox test were performed to identify ozonation transformation products. Under these conditions, four transformation products were observed and their chemical structures were proposed. The results showed an increase in toxicity during ozonation, even after degradation of all of the observed transformation products. The formation of other transformation products not identified under our experimental conditions could be responsible for the observed toxicity. These products might be ozone-resistant and more toxic to Vibrio fisheri than levofloxacin.