is still lacking. Dermal contact and inhalation were mentioned in just a few studies as routes of exposure (Heron et al., 2003; Daughton et al., 2009). Although pharmaceuticals can be released in sweat and urine (Daughton et al., 2009), epidemiological evidence which shows that the significance of human exposure to such excretions and associated risks appears limited. Two studies have also investigated occupational exposure using concentrations of pharmaceutical in the environment reported in literature (Nimmen et al., 2006; Sermejain et al., 2018). In the same studies, the human health risks were insignificant. However, such studies often focus on a few pharmaceuticals while excluding several others detected in aquatic systems.
Figure 2.2 Human exposure pathways to pharmaceuticals in the environment.
Human exposure via drinking water has been shown to present the highest hazard of all these human exposure pathways (Kumar and Xagoraraki et al., 2010; Bordin et al., 2014; Miller et al., 2018). This risk is particularly high in cases where communities rely on untreated water for drinking purposes. Compared to conventional treatment processes, drinking water treated by membrane separation processes including reverse osmosis (RO), membrane distillation, and nanofiltration (NF) have been shown to have lower concentrations of pharmaceuticals (Licona et al., 2018; Foureaux et al., 2019; Couto et al., 2020). Thus, such drinking water may present lower toxicological and human health risks than raw water and treated water from conventional water treatment methods.
2.3.2 Potential Human Health Risks
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
|
