Integrating human and environmental health in antibiotic risk assessment: A critical analysis of protection goals, species sensitivity and antimicrobial resistance

Abstract

Antibiotics are vital in the treatment of bacterial infectious diseases but when released into the environment they may impact non-target organisms that perform vital ecosystem services and enhance antimicrobial resistance development with significant consequences for human health. We evaluate whether the current environmental risk assessment regulatory guidance is protective of antibiotic impacts on the environment, protective of antimicrobial resistance, and propose science-based protection goals for antibiotic manufacturing discharges. A review and meta-analysis was conducted of aquatic ecotoxicity data for antibiotics and for minimum selective concentration data derived from clinically relevant bacteria. Relative species sensitivity was investigated applying general linear models, and predicted no effect concentrations were generated for toxicity to aquatic organisms and compared with predicted no effect concentrations for resistance development. Prokaryotes were most sensitive to antibiotics but the range of sensitivities spanned up to several orders of magnitude. We show reliance on one species of (cyano)bacteria and the 'activated sludge respiration inhibition test' is not sufficient to set protection levels for the environment. Individually, neither traditional aquatic predicted no effect concentrations nor predicted no effect concentrations suggested to safeguard for antimicrobial resistance, protect against environmental or human health effects (via antimicrobial resistance development). Including data from clinically relevant bacteria and also more species of environmentally relevant bacteria in the regulatory framework would help in defining safe discharge concentrations for antibiotics for patient use and manufacturing that would protect environmental and human health. It would also support ending unnecessary testing on metazoan species.

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

“…Comparison of these values to the available literature for microbial populations in natural conditions suggests that these published PNECs are a conservative estimate of the target for protection against resistance. However, it can be noted that NOECs or EC10 values derived for some species, especially cyanobacteria used to derive a PNEC‐ENV, may be lower than proposed criteria designed to be protective of AMR (i.e., the PNEC‐MIC) (Le Page et al ) (Table ). Another performance measure of antibiotic effectiveness is the minimum selective concentration (MSC). The MSC is defined as the minimum concentration at which the presence and expression of resistance genes provide bacteria an advantage due to fitness over nonresistance strains of the same species or strain (Le Page et al ).…”

“…However, it can be noted that NOECs or EC10 values derived for some species, especially cyanobacteria used to derive a PNEC‐ENV, may be lower than proposed criteria designed to be protective of AMR (i.e., the PNEC‐MIC) (Le Page et al ) (Table ). Another performance measure of antibiotic effectiveness is the minimum selective concentration (MSC). The MSC is defined as the minimum concentration at which the presence and expression of resistance genes provide bacteria an advantage due to fitness over nonresistance strains of the same species or strain (Le Page et al ). The MSC is a theoretical threshold that is determined in the laboratory for any microorganism and antibiotic pair (Singer et al ).…”

“…Comparison of these values to the available literature for microbial populations in natural conditions suggests that these published PNECs are a conservative estimate of the target for protection against resistance. However, it can be noted that NOECs or EC10 values derived for some species, especially cyanobacteria used to derive a PNEC‐ENV, may be lower than proposed criteria designed to be protective of AMR (i.e., the PNEC‐MIC) (Le Page et al ) (Table ).…”

“…Environmental predicted no‐effect concentration (PNEC‐ENV) values were derived from toxicity endpoint data with an assessment factor applied, consistent with European guidance (ECHA European Chemicals Agency ; EU WFD European Union Water Framework Directive ). Because cyanobacteria are considered most sensitive to antibiotics (EMA European Medicines Agency ; LePage et al ), data sets were considered complete if cyanobacteria data were available following the OECD 201 guideline, or equivalent (OECD 2011). If cyanobacteria data were not available, the lowest chronic no observed effect concentration (NOEC) or 10% effect concentration (EC10) was used when chronic data for 3 trophic levels were available.…”

Occurrence, Distribution, and Risk Assessment of Antibiotics in a Subtropical River-Reservoir System

“…Antibiotics have been extensively and effectively used for several decades not only to relieve symptoms and treat human and animal diseases, but also to promote growths in the livestock, aquaculture and plant agriculture [1,2]. Estimated annual antibiotic consumption in the world ranged from 100,000 to 200,000 tons, and antibiotic consumption is on the rise [3,4].…”