Review articleMeasuring biomarkers in wastewater as a new source of epidemiological information: Current state and future perspectives
Introduction
Relevant epidemiological information about lifestyle habits, public health and wellbeing can be obtained from the chemical analysis of urban wastewater. This approach, called wastewater-based epidemiology (WBE), is based on the analysis of specific human metabolic excretion products (biomarkers) in wastewater as indicators of consumption or exposure of the population served by the sewer network under investigation to different substances. WBE has been successfully applied as a suitable approach for the estimation of illicit drugs consumption (Ort et al., 2014, Thomaidis et al., 2016, Thomas et al., 2012, van Nuijs et al., 2011a, Zuccato et al., 2008), but it has also recently been employed to assess other lifestyle-related factors such as alcohol (Rodríguez-Álvarez et al., 2015, Ryu et al., 2016), nicotine (Castiglioni et al., 2015b, Lopes et al., 2014, Rodríguez-Álvarez et al., 2014b), caffeine (Senta et al., 2015a) and new psychoactive substances (NPS) (Kinyua et al., 2015, Reid et al., 2014a, van Nuijs et al., 2014). WBE has also been applied to verify community-wide exposure to endocrine disruptors and antimicrobial agents in personal care and household products (O'Brien et al., 2015, Rydevik et al., 2015). The broad range of information that can be gathered from wastewater opens up the possibility of expanding WBE to other human biomarkers providing clues about diet, health, diseases and exposure to contaminants. For example by linking exposure to environmental or food contaminants with health outcomes such as diabetes or cancer.
In general, a human biomarker can be an endogenous compound (produced naturally in the body) or a metabolite of a xenobiotic/exogenous substance (produced through metabolic processes after intentional consumption of a substance, accidental exposure to environmental contaminants, as well as through diet or ingestion of a substance). Biomarkers can be classified on the basis of their function as biomarkers of exposure (compounds that give information about substances consumed or ingested) and biomarkers of effect (indicators of measurable changes or alterations in an organism that can be associated with health problems or wellbeing) and on the basis of biological nature (e.g. metabolites, hormones), or of the disease they can indicate (e.g. cardiovascular biomarkers, obesity biomarkers) (Pischon, 2009).
The selection of a specific biomarker is not an easy task, as it needs to satisfy different criteria (Fig. 1) (Castiglioni and Gracia-Lor, 2015, Gracia-Lor et al., 2016). From a WBE perspective, a suitable biomarker must be excreted mainly via urine and concentration levels in urine should be at least in the μg/L range to ensure its detection in raw wastewater after dilution (Chen et al., 2014).
A biomarker should also be sufficiently stable in wastewater during the transport (in-sewer stability) from the input (i.e. toilet) to the sampling point and during sampling, storage and analysis (in-sample stability) (McCall et al., 2016a). In wastewater biomarkers can undergo further transformation due to microbial activity (Mardal and Meyer, 2014) and/or sorption to particulate matter (Baker and Kasprzyk-Hordern, 2011, Daughton, 2012a, McCall et al., 2016a). The fate of biomarkers in the sewer can be also predicted by using mathematical models to simulate physicochemical and microbial processes (Bisceglia and Lippa, 2014, McCall et al., 2016b, Ramin et al., 2016). It is important to note that biomarker transformation pathways in the sewer might be different from human metabolic pathways.
Furthermore, a biomarker should preferably be specific to the compound under investigation and unique to human metabolism, thus ensuring that its presence only derives from human excretion and not from exogenous sources (Daughton, 2012b). Therefore, pharmacokinetic data on human metabolism are necessary but unfortunately this information is not always feasible as for many substances it is very limited or do not even exist. This information, however, is highly relevant not only to back-calculate the consumption/exposure of/to a certain substance by a community, but also to distinguish the amount of a substance originating from human metabolism or other sources. Unfortunately, pharmacokinetic studies are time-consuming and have to fulfil strict ethical rules. Alternative approaches, which allow for the identification and selection of appropriate biomarkers, are therefore required; for example, in-vitro studies using liver enzymes, which metabolize the parent compound, help in the elucidation of the chemical structure of the metabolites formed (i.e. possible biomarkers) formed (Mardal et al., 2016). Computer-based in-silico modelling also allows the prediction of pharmacokinetics (Reid et al., 2014a). However these alternatives provide qualitative information on metabolism, but not data regarding excretion rates of parent substances and their metabolites (Gracia-Lor et al., 2016).
The present manuscript emerges within the framework of the pan-European inter-disciplinary network (Sewage analysis CORE group-SCORE), which brings together experts from different disciplines interested in standardizing the WBE approach and in coordinating international studies (http://score-cost.eu/). The aim of this review is to describe the criteria for selecting suitable biomarkers and to give an overview of relevant human (urinary) metabolites and potential wastewater biomarkers. Biomarkers have been grouped in four sections: (i) those that provide estimates of lifestyle factors and substance use, (ii) those used to estimate the exposure to toxicants present in the environment and food, (iii) those giving information about public health and (iv) those used to estimate the population size. For each group and biomarker, a thorough review of the available pharmacokinetic data (i.e. metabolism and excretion profile) and stability in urine and wastewater (if known) is provided. This information can be used to evaluate their suitability according to the criteria described above. Finally, potential gaps or limitations are discussed and future research directions are proposed.
Section snippets
Lifestyle and substance use biomarkers
Initially, WBE was applied to evaluate lifestyle, in particular illicit drug use within a community. Its ability to deliver objective and near-real-time data on drug use, being able to detect changes over time and local patterns of use, suggests that this method can be used as a complementary and extended data source to existing epidemiological tools. WBE has been well established for monitoring the use of cocaine, cannabis, amphetamine, methamphetamine and MDMA
Exposure biomarkers from environment and food
Two important exposure pathways for potentially harmful compounds are the dietary intake and the exposure from the surrounding daily environment. The monitoring of various classes of compounds for which exposure commonly occurs through these routes is necessary to safeguard public health. Representative chemical classes have been chosen as examples for this paper. Pesticides, mycotoxins and parabens are three classes of compounds for which exposure occurs through the intake of contaminated food
Health biomarkers
Community health programs play an essential role for public health agencies to monitor and evaluate the present status of health in a community and measure the success of programs aimed at improving it. Current challenges mainly consist of the quick and reliable evaluation of the overall health of a population, and detect possible health and illness threats such as pandemics or higher prevalence of diabetes or cancer.
The quantitative measurement of specific exogenous and endogenous biomarkers
Population biomarkers
Accurate estimation of population size is necessary to normalize WBE data to the per capita level, which allows for temporal and spatial comparisons to be made (van Nuijs et al., 2011b). A review of all uncertainties associated with WBE found that there is a direct relationship between the uncertainty in measuring the population size and the uncertainty in the calculated daily loads of drugs (Castiglioni et al., 2013, Lai et al., 2015a). Therefore, accurate data on population size are needed to
Conclusions and future perspectives
WBE is a rapidly developing scientific discipline with a strong transdisciplinary character. It has shown great progress, and opens up many possibilities for expanding its application to provide relevant information about lifestyle and public health.
This review has outlined potential wastewater biomarkers of exposure or effect that could be used for future applications associated with lifestyle and wellbeing studies. However, it has also discussed limitations and highlighted that more research
Acknowledgements
This work was supported by the COST Action ES1307 “SCORE – Sewage biomarker analysis for community health assessment”. Emma Gracia-Lor is very grateful to Generalitat Valenciana, Conselleria d'Educació, Investigació, Cultura i Esport (APOSTD/2015, Programa VALi + d) for her post-doctoral contract. Lubertus Bijlsma acknowledges NPS-Euronet (HOME/2014/JDRUG/AG/DRUG/7086), co-funded by the European Union, for his post-doctoral fellowship. Erika Castrignanò, Richard Bade, Juliet Kinyua, Pedram Ramin,
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