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Compared to research on the occurrence of pharmaceuticals in aquatic systems, studies investigating the potential human health risks appear to have lagged behind those on ecological risk assessment. The US EPA risk assessment procedure is often used for health risk assessment (US EPA, 1989). The procedure involves the following steps: (1) hazard identification, (2) exposure assessment, (3) doe-response assessment, (4) risk characterization, and (5) uncertainty analysis. Human health risk assessment characterizes risk using a quotient derived from a health-based threshold value (e.g., therapeutic dose) and the calculated exposure value for the given exposure routes (Table 2.1). Threshold values commonly used include the clinical point of departure, acceptable daily intake, reference dose and threshold of toxicological concern (Yang et al., 2017; Boobis et al., 2017). However, this is beyond the scope of this review, although the use of varying approaches may present challenges (Sorell, 2015). The health-based threshold value in all the reviewed cases was higher than the calculated exposure value, for no health risk scenarios. The low concentrations of individual pharmaceuticals in different environmental media could be due the interplay of several factors: (1) extensive safety testing conducted during their development and stringent of regulatory and environmental protection frameworks (Shore et al., 2014), and (2) most pharmaceuticals are not high-production- and use-volume substances (Christensen et al., 1998).

Antimicrobial resistance in human infections is particularly singled out as a possible human health risk due to the presence of pharmaceuticals in the environment (Sayadi et al., 2010; Tarfiei et al., 2018). Antibiotics can be excreted and released into the environment unaltered, thereby increasing the rate of development of antimicrobial resistance in pathogenic microorganisms such as bacteria and viruses. Examples of such antibiotics promoting antimicrobial resistance include sulfamethoxazole, trimethoprim, erythromycin, and keflex (Sayadi et al., 2010). Moreover, when bacteria are exposed to low doses of pharmaceuticals, the bacteria become tolerant to the antimicrobial. This, in turn, means that, when humans are infected with the drug-resistant bacteria, the prescribed pharmaceuticals may become ineffective or high doses will be required to be effective (Sayadi et al., 2010). The subject of antimicrobial resistance and its human health effects is reviewed elsewhere (Gwenzi et al., 2018).

Table 2.1 gives a summary of human exposure pathways and associated human risks to pharmaceuticals in the environment from earlier studies. Barring antimicrobial resistance, the findings of almost all human health risk assessment studies for the period up to 2010 have indicated low to no appreciable human health risk associated with exposure to pharmaceuticals in aqueous systems (Kumar et al., 2010). This pharmaceuticals taken via ingestion of groundwater, surface water, tap water, human food such as fish, milk, meat, seafood, and dermal routes (Fent et al., 2006; Kummerer, 2008; Bottoni et al., 2010). Subsequent studies post-2010 to date have also confirmed the pre-2010 results (Letsinger and Kay, 2019; Fantuzi et al., 2018; Praveena et al., 2019); Sharma et al., 2019). However, a few studies had indicated potential health risks to children and infants associated with the consumption of contaminated crops or tap water for a few of pharmaceuticals studied. These pharmaceuticals include lamotrigine in crops (Malchi et al., 2014) and dimetridazole, thiamphenicol, sulfamethazine, and clarithromycin in tap water (Leung et al., 2013). Moreover, more recent have ascertained that there is no or low risk to human health for all age groups (Li et al., 2017; Fantuzi et al., 2018; Semerjian et al., 2018; Praveena et al., 2019). The negligible human health risk has been confirmed even in a few studies focusing on for mixture of pharmaceuticals (Houtman et al., 2014). These results are in agreement with the conclusion that there are no adverse human health effects due to chronic exposure to pharmaceuticals in drinking water (World Health Organization, 2012). Kummerer (2010) also indicated that short-term effects of pharmaceuticals on humans are not known. Further, no consensus has been reached by the scientific community on potential human health risks posed by pharmaceuticals and endocrine disruptors through drinking water and consumption of fish using available human data (Touraud et al., 2011). However, targeted research is required to ascertain risk to infants and children and to communities in developing countries where human health risks could be high. However, note that in reality, it may be problematic to study the effects of a suite of pharmaceuticals given that a single pharmaceutical is designed to have a particular effect/s at a particular dose. Yet, studies based on mixture of pharmaceuticals are closer to reality than single compound studies because these compounds will never occur in an environmental sample in isolation. Moreover, there is the uncertainty on whether the concentrations of pharmaceuticals detected in environmental media and humans is significant enough to cause biological dysfunction/disruption stands (Wilkinson et al., 2015). Other even question whether the human risk posed by pharmaceuticals is more of an environmental hygiene concern than a toxicological and pharmacological issue (Jones et al., 2004). However, literature appears to point to the potential longterm human exposure risks. In addition, the application of health risk assessment models developed in high-income countries in low-income settings remain largely undone. Compared to developed countries, the results could be different in developing countries due to (1) the availability of pharmaceuticals, their use and use data, (2) exposure conditions, (3) standards of living, and (4) environmental protection and regulatory frameworks.

Table 2.1 Human exposure assessment and health risk assessment for pharmaceuticals in the environment.

Country	Study	Hazard identification	Exposure assessment	Dose-response relationship	Risk characterization	Risk management	Limitations/ Uncertainty analysis	Ref
United Arab Emirates	HRA	7 Antibiotics, 1 Analgesic, 1 ß-blocker, 1 Antipsychotic B, C, D, F, G, Sulphapyridine, Risperidone Sulphamethazine, Sulphadiazine, Metoprolol	Reclaimed wastewater Incidental ingestion Recreational dermal contact Occupational exposure Children and adults	Therapeutic dose vs. EDI	Cancer risk and non-cancer risk Risk quotients No associated health risks	-	Associated with toxicity and exposure assessment	Sermejian et al., 2018
Denmark	HRA	1 Sex hormone, 1 Antibiotic, 1 Antineoplastic A, E, Phenoxymethylpenieilin	Sewer, Household ingestion: leaf/root, crops, drinking water, fish, meat, dairy products, inhalation	Daily intake Local vs. Regional	Non-cancer risk Negligible risk	-	Local conditions, selection of drugs as ‘more potentially suspicious’	Christensen, 1998
USA	HRA	1 Analgesic, 1 anticancer, 1 Lipid regulator, 1 Anti-inflammatory A, Acetylsalicyclic acid, Clofibrate, Indomethacin	Ingestion of fish, Drinking water	Non-cancer: HBL vs. EDI For cancer: RSD vs. EDI	Cancer and noncancer risk No appreciable risk	-	Uncertainty factors used Analysis of parent drug (not metabolites) Limited data on methodology	Schulman et al., 2002
China	HRA	32 pharmaceutical drugs (human and veterinary) from 16 therapeutic classes	Household tap water Age-dependent seasonal exposures (carcinogenic and non-carcinogenic) Ingestion of tap water	Risk: Highest concentration vs. DWEL Age-related risk quotient	Low risk	Risk management and indicator monitoring framework	Age-dependent exposures used for uncertainties in exposure variations	Leung et al., 2013
Germany	EA	64 various pharmaceuticals from various therapeutic classes	Ingestion Drinking water	Reported concentrations vs. therapeutic dose	-	-	-	Webb et al., 2003
USA	EA	17 veterinary pharmaceuticals classes based on use	Pediatric exposure Various exposure sites Ingestion Dermal contact	-	-	Public awareness, home storage, appropriate product dispensing	Limitations: Data obtained from a single source, inconsistency in recording substance class	Tomasi et al., 2017
Israel	EA	Anticonvulsant: Carbamazepine	Reclaimed wastewater-irrigated vegetables, 34 volunteers, Ingestion	EDI vs. Therapeutic dose	-	-	Small and selective sample, potential for varying food preferences	Paltiel et al., 2016
Belgium	EA	Fentanyl (Analgesic)	Production site Dermal, Inhalation	-	-	-	Analytical procedure assumptions	Nimmen et al., 2006
Iran	EA	Penicillin	Production site Occupational exposure Inhalation	Exposed group vs. Not exposed group	-	-	Control group not measured, No standard sampling device	Farshad et al., 2016
Several studies used	HRA	Different classes of pharmaceuticals (Literature data used)	Crops: wastewater-irrigated, biosolids or manure-amended soil ingestion	Hazard quotient EDI vs. ADI	Minimal risk	-	Exposure to mixtures, All consumed crops assumed to contain the greatest concentrations	Prosser et al., 2015
USA	HRA	4 Antibiotics, 2 analgesics, 1 stimulant B, C, D, Ampicillin, Napoxen, caffeine, Trimethoprim	Domestic groundwater Ingestion ADI, DWEL	Average concentration in water vs. DWEL	Minimal risk	Routine water quality monitoring	Additive/synergistic effect of mixtures not addressed, Risk due to other exposure pathways were not considered	Kibuye et al., 2019
USA/Canada	EA	5 Antibiotics, 1 Analgesic, 1 Antidepressant, 1 hormone, 1 Anti-inflammatory, B, C, D, E, F, G, Fluoxetine, Ibuprofen, Azithromycin	Exposures: Children, recreational, ocupational, Dermal contact with biosolids Ingestion: Biosolids, crops, drinking water	The equivalent of one therapeutic dose or 1 d home exposure was used	-	-	Criteria developed to select representative pharmaceuticals for the study	Brown et al., 2019

ADI, Acceptable Daily Intake; EDI, Estimated Daily Intake; DWEL, Drinking Water Equivalent Level; HBL, Health-Based Level; RSD, Risk-Specific Dose; A, Cyclophosphamide; B, Ofloxacin; C, Acetaminophen; D, Sulphamethoxazole; E, 17α Ethinylestradiol; F, Erythromycin; G, Ciprofloxacin.

In aquatic systems and even in the human body, pharmaceuticals are modified by environmental stressors which subsequently change the exposure scenario (Oskarsson et al., 2014). Although individual pharmaceuticals are used in very small quantities (therapeutic dose), the presence of several similar pharmaceuticals (sharing same mode of action) may cause additive or synergistic exposures, and diversified stressor-receptor effects to non-target species (Daughton and Ternes, 1999). However as shown in Table 2.1, most studies on human health risks were conducted in developed countries (Shulman et al., 2002; Nimmen et al., 2006; Tomasi et al., 2016; Kibuye et al., 2019; Brown et al., 2019). This occurs despite the fact that the presence of pharmaceuticals in the environment is of global concern irrespective of level of industrialization (Kurster and Adler, 2014).

Research attention on human health risks should focus on Africa due to several risk factors (Gwenzi and Chaukura), including (1) reliance on untreated drinking water, (2) high levels of aquatic pollution caused by weak and poorly enforced regulations, and (3) lack of environmental and human health surveillance data. Human health risk assessment can be used to address, and minimize the potential human health risks highlighted in this chapter particularly in developing countries. The potential human health risks to guide research on human health effects associated with exposure to pharmaceuticals in the environment are shown in Table 2.1. Literature shows that the fate and behaviour of most pharmaceuticals entering the environment via numerous pathways remain poorly characterized (Kaczala and Blum, 2016). Further, the interactions of pharmaceuticals in various environmental media result in complex mixtures to which humans are exposed, not similar to actual doses as from on-the-counter prescriptions. This may imply that HRAs should also focus on mixtures of pharmaceuticals (Fent et al., 2006; Daughton, 2016). Data to allow metabolites and transformation products to be incorporated into human health risk assessments still lacking (Kummerer, 2010). Thus, the human health risks of pharmaceutical in the environment including aquatic systems require further investigation.