Multi-parameter risk assessment of forty-one selected substances with endocrine disruptive properties in surface waters worldwide

Highlights

• Ecotoxicology and worldwide concentration data were collected for 53 most potent endocrine disruptors from 154 studies.

• Multi-parameter risk assessment identified 12 substances as high-risk.

• Risks of less researched compounds are currently greatly underestimated.

• A standardized methodology for data selection and assessment is necessary.

• A risk assessment platform for future prioritization of toxic substances is presented.

Abstract

The increasing use of substances with endocrine disruptive properties (EDs) not only impacts aquatic organisms but can also have a direct negative effect on human health. In this comprehensive worldwide review, we collected ecotoxicology and concentration data observed in surface water for 53 high-potency EDs and performed a risk assessment. The compounds were selected from the EU watchlist of priority substances, expanded with new compounds of emerging concern (total 41), where quantifiable data were available for the past three years (2018–2020). The risk quotients ranged from <0.01 for 22 substances to 1974 for tamoxifen. The frequency of samples in which the predicted no-effect concentrations were exceeded also varied, from 1.8% to 92.7%. By using the comprehensive multi-parameter risk assessment in our study, the most current to date, we determined that tamoxifen, imidacloprid, clothianidin, four bisphenols (BPA, BPF, BPS, and BPAF), PFOA, amoxicillin, and three steroid hormones (estriol, estrone, and cyproterone) pose significant risks in the environment. Comparing two structurally very similar bisphenols, BPA and BPB, suggested that the risk from BPB is currently underestimated by at least four orders of magnitude due to the lack of ecotoxicological data availability. The methodological limitations encountered suggest that a standardized methodology for data selection and assessment is necessary, highlighting the fact that some substances are currently under-represented in the field of ecotoxicological research. A new prioritization system is therefore presented, which provides a potential basis for new substances to be included in environmental monitoring lists.

Introduction

Substances that exhibit endocrine disruptive properties (most commonly denoted as endocrine disruptors, EDs) are one of the most important groups of contaminants of emerging concern in the aquatic environment, which is why their potential for causing adverse effects on aquatic organisms has attracted much attention from researchers globally. This is especially evident in research of endocrine disruption exhibited by pharmaceuticals, where many groups of drugs, used in both human and veterinary medicine, are known to have at least some form of endocrine effect: for example, hormonal drugs, antibiotics, and selective estrogen receptor modulators (SERMs) (Runnalls et al., 2013; Siegenthaler et al., 2017). Other environmental pollutants of high concern such as pesticides, bisphenols, and perfluorinated alkylated substances (PFAS), are also very important in terms of exposure, as they are used widely and are ubiquitous (Baines et al., 2017; Leemans et al., 2019; Mesnage et al., 2018). For example, the global estimated daily exposure to bisphenol A (BPA) for adults is more than 30 ng per kg of bodyweight (Huang et al., 2017). The same cannot yet be established for all other substances, as current understanding of the exposure parameters is incomplete (Sunderland et al., 2019).

The half-lives of EDs in the environment are usually relatively short, for example, <1 day for BPA (Corrales et al., 2015), compared with substances such as dioxins with environmental half-lives measured in years (Tuyet-Hanh et al., 2010). However, most are continually released into wastewater and sewage systems that frequently enter surface waters. Because of this, EDs are labeled as “pseudo-persistent” (Mackay et al., 2014). The main source of their entry into the aquatic environment is via incorrect medicine disposal, wastewater treatment plants, agriculture, run-offs, veterinary use, hospitals, and industrial manufacturing sites (Carraro et al., 2018; Gadipelly et al., 2014; Xu et al., 2018; Huang et al., 2020; Felis et al., 2020).

The occurrence of numerous EDs in surface waters has been extensively studied worldwide (Casado et al., 2019; Chen et al., 2018; Pan et al., 2018; Yao et al., 2018), with concentrations ranging from low-ng/L to μg/L. Although the reported amounts in the environment are relatively low compared with the typical dosage of pharmaceutical substances (MSD, 2021), many of them are highly effective and thus physiologically active even at such low concentrations. This is particularly the case due to their continuous presence in the environment and is why they have the potential to cause chronic effects related to long-term exposure. The impact of these effects on non-target aquatic organisms can be severe, such as the development of cancer and disorders of reproductive, neuroendocrine, and immune systems (Marmugi et al., 2014; Richmond et al., 2017). A major concern related to the presence of EDs in the aquatic environment is their ability to disrupt the homeostasis of the endocrine system (detrimental effects on reproduction and population numbers). Other important effects can also be observed, such as their influence on behavior, metabolism, bacterial resistance, and environmental adaptability of species, for example. The prevention of such effects is important not only in terms of ecological preservation of aquatic wildlife and biodiversity, but non-target long-term effects of EDs are also important in human health. This is mainly related to chronic exposure to contaminated waters, considering that the estrogenic hormonal system in advanced aquatic organisms (e.g. fish) is similar to that in humans (Gunnarsson et al., 2019). This poses a risk for negative effects on fertility rates and constitutes a serious modern public health issue as humans are exposed to contaminated water through ingestion of treated and untreated waters, contaminated food and dermal exposure (Marques-Pinto and Carvalho, 2013; Rattan et al., 2017; Arnold et al., 2013; Toner et al., 2018).

Studies on the ecotoxicological potential of substances traditionally used single-species high-dose acute toxicity testing as these tests are simple and quick to perform, despite their inadequacy in predicting possible chronic effects from long-term exposure of aquatic organisms to multiple EDs (Fent et al., 2006; Vestel et al., 2016).

Several different studies incorporating risk assessment methods already exist in the literature, as this field has gained importance in recent years, though most are more specific and are less comprehensive. Several risk assessment approaches are available, ranging from simpler ones such as the deterministic risk assessment to semi-probabilistic and multi-parameter assessments. All of the listed principles have been used in this study. Many studies found in the literature use the deterministic approach and evaluate only the quotient of the median concentration of a substance divided by its lowest applicable predicted no-effect value (PNEC) known as the risk quotient (RQ), and no other risk assessment parameters. This was already done on a selection of up to more than a hundred substances, but has been evaluated in just a few countries: RQs of 48 contaminants of emerging concern have been evaluated in two countries (Česen et al., 2019), 36 pharmaceuticals in three countries (Huber et al., 2016), or 75 pharmaceuticals and personal care products (PPCPs), pesticides, and industrial chemicals in a single lake (Kandie et al., 2020). In the EU, RQs have also been evaluated for 34 antihypertensives (Godoy et al., 2015), pesticides and veterinary drugs (Casado et al., 2019), and pharmaceuticals in 16 different therapeutic groups (Zhou et al., 2019). Globally, evaluation of RQs has included substances from a particular pharmaceutical group such as seven psychoactive drugs (Cunha et al., 2019) and 17 antibiotics (Van Doorslaer et al., 2014), or from two groups such as cardiovascular and lipid regulating drugs (Zhang et al., 2020).

Comprehensive risk assessment approaches have also been used, albeit with measurements from individual countries, such as for 27 pharmaceuticals (Palma et al., 2020) or 140 PPCPs (Liu et al., 2020a). A study with a global evaluation of over 700 substances also exists, but with a differently focused assessment method aimed predominantly at non-pharmaceuticals and with calculations based on high-dose acute toxicity rather than low-dose chronic data (Fang et al., 2019).

The aim of this study is therefore to provide a wider, globally comprehensive evaluation of the range of concentrations of substances of interest in surface waters in different compound groups. They were selected from priority substances in the EU (Vella, 2018) and expanded to include other pharmaceuticals with endocrine effect as they have the most potential for serious adverse effects at low doses. We also added bisphenols due to their structure and PFAS due to them being emerging contaminants, while both groups also being endocrinally active (Jensen and Leffers, 2008; Li et al., 2015; Rubin, 2011). For PFAS, to our knowledge, no multi-parameter risk assessment has yet been published. The expansion of the list was done with the intention of their comparison with substances present on the EU watchlist.

We have ranked substances according to their RQ, frequency of PNEC exceedance and their priority index. In addition, we critically assessed the differences in results obtained in the present study and compared them with results from other studies in the literature. In our study we used the most recently available data (2018–2020) on reported concentrations of substances in surface waters. Coupling these data with relevant data from ecotoxicological studies enabled us, with the use of multi-parameter risk assessment methodology, to assess the ecotoxicological risk for the most representative substances from pharmacological-toxicological groups that pose the greatest risk to aquatic organisms and consequently to humans.