Background: Over the past 10–15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment.Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas.Data sources: To better understand and manage the risks of PPCPs in the environment, we used the “key question” approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance.Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f ) antibiotic resistance, and g) risk management.Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.

The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using > or = 42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence of fish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number of fish used from 3,822 to 1,025 (approximately 73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates.

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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.

For many older pharmaceuticals, chronic aquatic toxicity data are limited. To assess risk during development, scale-up, and manufacturing processes, acute data and physicochemical properties need to be leveraged to reduce potential long-term impacts to the environment. Aquatic toxicity data were pooled from daphnid, fish, and algae studies for 102 active pharmaceutical ingredients (APIs) to evaluate the relationship between predicted no-effect concentrations (PNECs) derived from acute and chronic tests. The relationships between acute and chronic aquatic toxicity and the n-octanol/water distribution coefficient (D OW ) were also characterized. Statistically significant but weak correlations were observed between toxicity and log D OW , indicating that D OW is not the only contributor to toxicity. Both acute and chronic PNEC values could be calculated for 60 of the 102 APIs. For most compounds, PNECs derived from acute data were lower than PNECs derived from chronic data, with the exception of steroid estrogens. Seven percent of the PNECs derived from acute data were below the European Union action limit of 0.01 mg/L and all were anti-infectives affecting algal species. Eight percent of available PNECs derived from chronic data were below the European Union action limit, and fish were the most sensitive species for all but 1 API. These analyses suggest that the use of acute data may be acceptable if chronic data are unavailable, unless specific mode of action concerns suggest otherwise.

On 3 October 2007, 40 participants with diverse expertise attended the workshop Tamiflu and the Environment: Implications of Use under Pandemic Conditions to assess the potential human health impact and environmental hazards associated with use of Tamiflu during an influenza pandemic. Based on the identification and risk-ranking of knowledge gaps, the consensus was that oseltamivir ethylester-phosphate (OE-P) and oseltamivir carboxylate (OC) were unlikely to pose an ecotoxicologic hazard to freshwater organisms. OC in river water might hasten the generation of OC-resistance in wildfowl, but this possibility seems less likely than the potential disruption that could be posed by OC and other pharmaceuticals to the operation of sewage treatment plants. The work-group members agreed on the following research priorities: a) available data on the ecotoxicology of OE-P and OC should be published; b) risk should be assessed for OC-contaminated river water generating OC-resistant viruses in wildfowl; c) sewage treatment plant functioning due to microbial inhibition by neuraminidase inhibitors and other antimicrobials used during a pandemic should be investigated; and d) realistic worst-case exposure scenarios should be developed. Additional modeling would be useful to identify localized areas within river catchments that might be prone to high pharmaceutical concentrations in sewage treatment plant effluent. Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment.

Sulfamethoxazole (SMX) is an old sulfonamide antibiotic that was launched first in combination with trimethoprim in 1969 by F.Hoffmann-La Roche. Although sales figures for SMX have been declining over the past 20 yr, the compound is still widely used; moreover, many measured environmental concentrations (MECs) are available from Europe, the United States, Asia, Australia, and Africa. To assess aquatic risks of SMX in Europe, the exposure of European surface waters was predicted based on actual sales figures from IMS Health, incorporating environmental fate data on one side, and based on collated MECs representing more than 5500 single measurements in Europe on the other. Environmental effects were assessed using chronic and subchronic ecotoxicity data for 16 groups of aquatic organisms, from periphyton communities to cyanobacteria, algae, higher plants, various invertebrates, and vertebrates. Predicted no-effect concentrations (PNECs) were derived using both deterministic and probabilistic methodology.

An environmental risk assessment (ERA) was made for the old cytostatic active pharmaceutical ingredient 5-fluorouracil (5-FU) and for capecitabine (CAP), which is a prodrug of 5-FU. This ERA is based on published and company internal data as well as new test results for physicochemical, human metabolism, biodegradability, environmental partitioning and fate, and acute and chronic ecotoxicity properties of the active substance 5-FU as well as on use sales data for 5-FU and CAP in Europe. Predicted environmental concentrations (PECs) were extrapolated following the EMEA 2006 Guideline on ERA for human pharmaceuticals and the European Union 2003 Technical Guidance Document (TGD) for risk assessment as well as the TGD-based application EUSES v2.0. Actual amounts sold were taken from IMS Health Databases, in order to refine the default use and EMEA penetration factor as well as the PECs. Moreover, available measured environmental concentrations (MECs) were used to supplement PECs. A predicted no-effect concentration (PNEC) for 5-FU was derived from chronic ecotoxicity data. Except for the simplistic EMEA Phase I default PEC, the risk characterization by PEC:PNEC and MEC:PNEC ratios for various environmental compartments resulted in no significant risk. As the EMEA Phase I PEC does not integrate documented human metabolism and environmental degradation, in contrast to refined PEC derivations, it is inferred that the current use of CAP and 5-FU does not present any evident risk to the environment. An additional evaluation of persistence, bioaccumulation, and toxicity (PBT) properties supports the conclusion of no significant environmental risk for 5-FU and CAP.