Integrated assessment of environmental and human health risks of antibiotic residues and resistance for environmental and health policy

Abstract: Background: Antibiotic resistance is a global health crisis and a serious threat to progress in achieving the Sustainable Development Goals. This requires a One Health response that recognises the link between human and animal health and the environment. While within One Health, human and animal health feature prominently in terms of research and implementation, the efforts to tackle antibiotic resistance in the environment lag far behind in attention, evidence base, and political commitment. The knowledge of the emergence of antibiotic residues and antibiotic resistance in the environment, and the magnitude of the human health risk posed by it, remain limited. Various anthropogenic sources such as the pharmaceutical industry, hospital, and municipal wastewater release antibiotic residues into the environment. To define the risks to the environment and human health and to inform policy, there is a particular need to assess antibiotic concentrations in the environment at which resistance might develop and pose a health threat. Aim: To assess the potential environmental and human health risks of exposure to antibiotic residues and antibiotic resistance in various environmental compartments of the Western Pacific Region (WPR) and South-East Asia Region (SEAR) of the World Health Organization, particularly China and India, and to develop methods for the prioritisation of antibiotics to deal with aspects of their resistance and the toxicity risks on human health and various aquatic environmental compartments. Methods: In Study I, quantitative methods to determine antibiotic concentrations in various environmental compartments in rural Shandong province in China were used, and risk assessment methods to characterise environmental and health risks of antibiotic residues were performed. In study II, quantitative methods to investigate antibiotic residue levels and water quality in the river water samples from the Kshipra river in India during different seasons, and sampling sites over a 3-year period were applied, and microbiological and molecular methods to test antibiotic resistant Escherichia coli (E. coli) and antibiotic resistance genes were used. In study III, I conducted a systematic review of the literature (WPR (n=218), SEAR (n=22), China (n=168), and India (n=15)) published between 2006 and 2019, to investigate the occurrence and concentration of the reported antibiotic residues in various aquatic environmental compartments of the WPR and SEAR. I also used risk assessment methods including Probabilistic Environmental Hazard Assessments, to assess antibiotic exposures in various aquatic environmental compartments for concentrations of antibiotic residues that are above Predicted No Effect Concentrations for resistance development. In Study IV, I developed an integrated environment–human risk approach for a quantitative environmental (resistance and ecotoxicity) and human health (resistance and toxicity) risk assessment of antibiotic residues and a prioritisation system thereof. I propose a risk-based approach; the approach combines data on the exposure, toxicity, resistance, and chemical structure of antibiotics with Probabilistic Environmental Hazard Assessments and a Threshold of Toxicological Concern. The utility of the approach and the system was demonstrated using data from China as an example. The proposed approach can be used for other settings. Findings: Antibiotic residues were present in various environmental compartments of the WPR, the SEAR, China, and India (Study I, Study II, and Study III). The concentration levels of enrofloxacin, levofloxacin, and ciprofloxacin in wastewater were estimated to pose environmental risks for the development of antibiotic resistant bacteria in the environment of Shandong province, in China (Study I). Antibiotic resistant E. coli were present in the water and sediment of the Kshipra river in India and showed significant seasonal and spatial variations over a 3-year period, and had varying associations with measured water quality parameters (Study II). In the WPR, 92 antibiotics were detected, and in the SEAR, 45 antibiotics were detected. Values of predicted threshold concentrations corresponding to different centiles for environmental exposure distributions of the maximum measured environmental concentrations of antibiotic residues, and the likelihood of exceedances of antibiotic Predicted No Effect Concentrations for resistance development of the WPR, the SEAR, China, and India were indicated (Study III). The highest environmental risks of antibiotic residues were observed in wastewater, and wastewater treatment plants’ influents and effluents (up to 100%) (Study III). Antibiotic residues appear to pose an appreciable human health risk from environmental exposure via drinking water of the WPR and China, and the highest risk was observed for ciprofloxacin (62.5%) (Study III). A list of priority antibiotics from different classes for China was developed by ranking antibiotics in descending order, based on their a) overall risk, b) resistance risk on environment, c) ecotoxicity risk, d) overall environmental risk, e) resistance risk on human health, f) toxicity risk on human health, and g) overall human health risk. Ciprofloxacin posed the greatest risk (Study IV). Conclusions: A novel assessment of the health risk due to the antibiotic residues in the aquatic environment of the WPR, the SEAR, China, and India were presented in this thesis. Antibiotic residues and antibiotic resistance were ubiquitous. There is evidence that residual concentrations of some antibiotics exceeded the thresholds for the development of resistance in various proportions of exposure in various aquatic environments of the WPR, the SEAR, China, and India, and posed an ecotoxicity effect. Wastewater and wastewater treatment plants serve as a hot spot for the development of antibiotic resistance in these regions. Antibiotic residues appear to pose an appreciable resistance and toxicity risk to human health from environmental exposure via drinking water. The emergence of antibiotic residues and resistance in drinking water further emphasises the need to place these threats to humans in the perspectives of environmental and health policy. These findings can help decision-makers to derive special risk reduction measures and focus mitigations towards priority antibiotics and high-risk sites, to decide the desired level of protection based on the proportions of exposure impacted, to implement eco-pharmacovigilance, and to help focus research efforts. This has the potential to assist decision-makers in efficiently allocating resources, which is especially vital for resource-poor settings e.g., in the WPR and SEAR.