John L. Wilkinson

Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world's rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.

Pharmaceuticals and personal care products (PPCPs), other emerging contaminants (ECs), and metabolites thereof are ubiquitous in the environment, both built and natural. While such compounds have been environmentally present for some time, new pharmaceuticals and replacements for other ECs phased out due to regulatory limitations are continually being introduced to market. Non-target lower organisms are exposed through affected water, atmospheric emissions, precipitation, sediments, among other routes. Biological disruption/dysfunction (such as endocrine, developmental, and epigenetic disruption) has been reported in lower organisms exposed to trace levels of PPCPs and other ECs. Such disruption/dysfunction may not be exclusively present as traditional toxic response (e.g., cancer or death) but may only slightly alter natural biological processes as a result of exposure to an exogenous chemical (e.g., an increased heart rate or altered size of dorsal fat pads in fish). The epigenome and endocrine system appear to be relatively sensitive to many PPCPs/ECs, particularly during early development.Humans are exposed to ECs such as plasticizers and perfluorinated compounds (PFCs) mainly through ingestion (food and contaminated liquid) as well as interaction with day-to-day products (detergents, musk compounds in fragrances, etc.). Few, if any, studies have investigated trace-level toxicity of such ECs to humans as direct-exposure trials are highly unethical. However, numerous epidemiological links exist between the presence of contaminants in humans (blood, urine, and tissues) and the occurrence of diseases or other phenotypic alterations. Despite mounting interest and research, such trace-level effects on humans are greatly debated and often criticized.This paper reviews the current understanding of PPCP/EC toxicity. Discussion of general biological disruption/dysfunction of the following seven classes of PPCP/ECs is included: analgesics, antibiotics, antineoplastic compounds, beta-blockers, endocrine disrupting compounds, PFCs, and plasticizers. A review of receptor-mediated toxicity, non-monotonic dose response relationships, developmental toxicity, and environmental epigenetics is also included. Lastly, an overview of the proposed toxicity to humans is provided including discussion of significant criticism and direction of future research.

The spatial distribution of pharmaceuticals, personal care products (PPCPs) and other emerging contaminants (ECs) such as plasticisers, perflourinated compounds (PFCs) and illicit drug metabolites in water and bound to suspended particulate material (SPM) is not well-understood. Here, we quantify levels of thirteen selected contaminants in water (n=88) and their partition to suspended particulate material (SPM, n=16) in three previously-unstudied rivers of Greater London and Southern England during a key reproduction/spawning period. Analysis was conducted using an in-house validated method for Solid Phase Extraction followed by High-Performance Liquid Chromatography-Tandem Mass-Spectrometry. Analytes were extracted from SPM using an optimised method for ultrasonic-assisted solvent extraction. Detection frequencies of contaminants dissolved in water ranged from 3% (ethinylestradiol) to 100% (bisphenol-A). Overall mean concentrations in the aqueous-phase ranged from 14.7ng/L (benzoylecgonine) to 159ng/L (bisphenol-A). Sewage treatment works (STW) effluent was the predominant source of pharmaceuticals, while plasticisers/perfluorinated compounds may additionally enter rivers via other sources. In SPM, detection frequencies ranged from 44% (PFOA) to 94% (hydroxyacetophenone). Mean quantifiable levels of analytes bound to SPM ranged from 13.5ng/g dry SPM (0.33ng bound/L water) perfluorononanoic acid to 2830ng/g dry SPM (14.3ng bound/L water) perfluorooctanesulfonic acid. Long chain (>C7) amphipathic and acidic PFCs were found to more preferentially bind to SPM than short chain PFCs and other contaminants (Kd=34.1-75.5 vs <5 respectively). Per capita daily contributions of studied contaminants entering rivers ranged from 0.157μg/person/day of benzoylecgonine (cocaine metabolite) to 58.6μg/person/day of bisphenol-A. The large sample size of this work (n=104) enabled ANOVA followed by Tukey HSD post-hoc tests to establish significant trends in PPCP/EC spatial distribution from headwaters through downstream stretches of studied rivers. Novel findings include environmental Kd calculations, the occurrence of contaminants in river headwaters, increases in contaminant metabolite concentrations downstream of STW effluents revealing possible in-river degradation or de-conjugation, the influence of polarity and acidity in the partition of contaminants to particulate-material, among others.