Current and future perspectives for wastewater-based epidemiology as a monitoring tool for pharmaceutical use.

The medical and societal consequences of the misuse of pharmaceuticals clearly justify the need for comprehensive drug utilization research (DUR). Wastewater-based epidemiology (WBE) employs the analysis of human metabolic excretion products in wastewater to monitor consumption patterns of xenobiotics at the population level. Recently, WBE has demonstrated its potential to evaluate lifestyle factors such as illicit drug, alcohol and tobacco consumption at the population level, in near real-time and with high spatial and temporal resolution. Up until now there have been fewer WBE studies investigating health biomarkers such as pharmaceuticals. WBE publications monitoring the consumption of pharmaceuticals were systematically reviewed from three databases (PubMed, Web of Science and Google Scholar). 64 publications that reported population-normalised mass loads or defined daily doses of pharmaceuticals were selected. We document that WBE could be employed as a complementary information source for DUR. Interest in using WBE approaches for monitoring pharmaceutical use is growing but more foundation research (e.g. compound-specific uncertainties) is required to link WBE data to routine pharmacoepidemiologic information sources and workflows. WBE offers the possibility of i) estimating consumption of pharmaceuticals through the analysis of human metabolic excretion products in wastewater; ii) monitoring spatial and temporal consumption patterns of pharmaceuticals continuously and in near real-time; and iii) triangulating data with other DUR information sources to assess the impacts of strategies or interventions to reduce inappropriate use of pharmaceuticals.

Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid.

Given the important role of voltage-gated sodium (NaV) channel-modulating spider toxins in elucidating the function, pharmacology, and mechanism of action of therapeutically relevant NaV channels, we screened the venom from Australian theraphosid species against the human pain target hNaV1.7. Using assay-guided fractionation, we isolated a 33-residue inhibitor cystine knot (ICK) peptide (Ssp1a) belonging to the NaSpTx1 family. Recombinant Ssp1a (rSsp1a) inhibited neuronal hNaV subtypes with a rank order of potency hNaV1.7 > 1.6 > 1.2 > 1.3 > 1.1. rSsp1a inhibited hNaV1.7, hNaV1.2 and hNaV1.3 without significantly altering the voltage-dependence of activation, inactivation, or delay in recovery from inactivation. However, rSsp1a demonstrated voltage-dependent inhibition at hNaV1.7 and rSsp1a-bound hNaV1.7 opened at extreme depolarizations, suggesting rSsp1a likely interacted with voltage-sensing domain II (VSD II) of hNaV1.7 to trap the channel in its resting state. Nuclear magnetic resonance spectroscopy revealed key structural features of Ssp1a, including an amphipathic surface with hydrophobic and charged patches shown by docking studies to comprise the interacting surface. This study provides the basis for future structure-function studies to guide the development of subtype selective inhibitors.

Evaluating the stability of three oxidative stress biomarkers under sewer conditions and potential impact for use in wastewater-based epidemiology.

Wastewater contains a wealth of information about the population who contribute to it including biological and chemical markers of human activity and exposures. F2-isoprostanes have been proposed as oxidative stress biomarkers that can be measured in wastewater to provide a measure of oxidative stress at the population level. While an association between tobacco use and their level in wastewater has been demonstrated, an in-sewer stability assessment has not been conducted to support their use as oxidative stress biomarkers for wastewater-based epidemiology studies. In this study we investigated the stability of 8-iso-prostaglandin F2α (PGF2α), its metabolite dinor-11ß-Prostaglandin F2α (dnPGF2α) and Prostaglandin E2 (PGE2) (representative of other classes of prostaglandins) in laboratory-scale sewer reactors simulating real sewers. PGF2α, dnPGF2α and PGE2 were all found to be sufficiently stable under typical sewer conditions therefore satisfying the stability requirement of wastewater-based epidemiology population health biomarkers.

Trends in nicotine consumption between 2010 and 2017 in an Australian city using the wastewater-based epidemiology approach.

Monitoring smoking prevalence is key to assessing responses to tobacco control measures, and evaluating associated health and economic costs. Estimates of tobacco consumed in Australia are based on various data sources - tax excise clearances, sales, and self-report surveys. There are limitations with each of these data sources which makes triangulation of cigarette use estimates by multiple methods important. Wastewater-based epidemiology, the systematic sampling and analysis of wastewater, is now a routine method to measure and monitor human exposure to a range of chemicals. This study provides a high frequency long-term temporal assessment of exposure to nicotine, the main addictive component of tobacco, using this approach. 291 archived wastewater samples collected from a regional city catchment from 2010 to 2017 were analysed for human-specific nicotine metabolites (cotinine and trans-3'-hydroxycotinine), to estimate per capita nicotine use. Temporal trends in nicotine use determined by wastewater-based epidemiology were compared with national sales and survey data. Wastewater analysis showed a 25% reduction in the mean number of cigarette equivalents consumed from 2010 to 2017, representing a 3% annual decline. These findings are in good agreement with estimates based on surveys and sales data, indicating annual declines of 5% and 4%, respectively. Findings of this study demonstrate WBE to be a relatively cost-effective and objective approach to reporting long-term data on nicotine consumption. When combined with alternative data sources, and valuable sociodemographic information of surveys, wastewater-based epidemiology helps to refine our estimates and understanding of the total impacts of smoking.

Population histamine burden assessed using wastewater-based epidemiology: The association of 1,4­methylimidazole acetic acid and fexofenadine.

Systematic sampling and analysis of wastewater has become an important tool for monitoring consumption of drugs and other substances, and has been proposed as a method to evaluate aspects of population health using endogenous biomarkers. 1,4­methylimidazoleacetic acid (MIAA) is an endogenous biomarker and metabolite of histamine turnover. Its urinary excretion is elevated in conditions such as mastocytosis, hay fever, hives, food allergies and anaphylaxis. The aim of this study was to develop and apply methods for MIAA in wastewater and compare its occurrence with antihistamine use in wastewater. Consecutive daily samples were collected from seven catchments serving populations from 3000 to 2 million and covering rural and urban communities during the 2016 Census in Australia. MIAA and the antihistamines (ranitidine, fexofenadine, cetirizine) were quantified consistently. Per capita excretion of MIAA (mg/d/capita) estimated from the WW concentrations were consistent with findings from previous clinical studies. We found significant positive correlations between loads of MIAA and fexofenadine (R2 = 0.68, p < 0.0001) and cetirizine (R2 = 0.25, p = 0.03) across the various catchments. Sewer reactor experiments on the degradation of MIAA and the antihistamines found that fexofenadine is stable for at least 24 h while MIAA, ranitidine and cetirizine are subject to degradation, and this should be considered in interpretations. To the best of our knowledge, this study is the first wastewater study to introduce and monitor an endogenous metabolite of histamine, and the first study to monitor and relate proxies of disease and treatment of disease.