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Endocrine disrupting chemicals (EDCs) are substances that alter the function of the endocrine system and consequently cause adverse effects to humans or wildlife. The release of particular EDCs into the environment has been shown to negatively affect certain wildlife populations and has led to restrictions on the use of some EDCs. Current chemical regulations aim to balance the industrial, agricultural and/or pharmaceutical benefits of using these substances with their demonstrated or potential harm to human health or the environment. A summary is provided of the natural science evidence base informing the regulation of chemicals released into the environment that may have endocrine disrupting effects on wildlife. This summary is in a format (a 'restatement') intended to be policy-neutral and accessible to informed, but not expert, policy-makers and stakeholders.

The goal of protecting the aquatic environment through testing thousands of chemicals against hundreds of aquatic species with thousands of endpoints while also considering mixtures is impossible given the present resources. Much of the impetus for studies on micropollutants, such as pharmaceuticals, came from the topic of endocrine disruption in wild fish. But despite concern over reductions in fish fertility, there is little evidence that fish populations are in peril. Indeed, fish biologists suggest that many cyprinid populations have been recovering for the past 30 to 40 yr. The central assumption, key to current risk assessment, that effects observed in the laboratory or predicted by models are readily transferrable to the population level, is therefore questionable. The neglect in monitoring wildlife populations is the key weakness in environmental protection strategies. If we do not know whether aquatic wildlife species are declining or increasing, how valuable are our other ecotoxicological activities? Environ Toxicol Chem 2016;35:1609-1616. © 2016 SETAC., (© 2016 SETAC.)

The global water availability assessment (GWAVA) model, incorporating regional water abstractions and reservoir information, was used to model the human-sourced steroid estrogens estrone (E1) and estradiol (E2) in the Yellow River catchment (China). The river flows in the main stem were calibrated using gauged flows. Following a review of Chinese data on estrogen discharge from a range of sewage treatment plants, low, median, and high discharge rates were identified and used as best, expected, and worst-case scenarios, respectively. For any given location, the temporal variation of modeled estrogen levels was summarized using the mean and upper 90th percentile, which is where the model predicts 90% of values would be below this concentration. The predicted means and 90th percentiles for E1 were comparable to previous E1 measurements reported in the river. For the whole catchment, only 19% (mean value) of the river system by length was predicted to exceed 1 ng/L E2 equivalents (EEQs) using expected estrogen sewage discharge. Only 3% of the network by length was predicted to exceed the dangerously high 10 ng/L EEQ when considering 90th percentile concentrations. The highest exposures were in the Fen and Wei tributaries. Endocrine disruption risk from estrogens was predicted to be minimal in the main stem. Only in the worst-case discharge scenario and 90th percentile predicted concentrations were the most downstream river reaches of the main stem predicted to be at risk. Reservoirs appeared to be helpful in reducing estrogen concentrations thanks to longer water residence facilitating biodegradation., (© 2015 SETAC.)

In an effort to assess the combined risk estrone (E1), 17β-estradiol (E2), 17α-ethinyl estradiol (EE2), and estriol (E3) pose to aquatic wildlife across United States watersheds, two sets of predicted-no-effect concentrations (PNECs) for significant reproductive effects in fish were compared to predicted environmental concentrations (PECs). One set of PNECs was developed for evaluation of effects following long-term exposures. A second set was derived for short-term exposures. Both sets of PNECs are expressed as a 17β-estradiol equivalent (E2-eq), with 2 and 5 ng/L being considered the most likely levels above which fish reproduction may be harmed following long-term and short-term exposures, respectively. A geographic information system-based water quality model, Pharmaceutical Assessment and Transport Evaluation (PhATE™), was used to compare these PNECs to mean and low flow concentrations of the steroid estrogens across 12 U.S. watersheds. These watersheds represent approximately 19% of the surface area of the 48 North American states, contain 40 million people, and include over 44,000 kilometers of rivers. This analysis determined that only 0.8% of the segments (less than 1.1% of kilometers) of these watersheds would have a mean flow E2-eq concentration exceeding the long-term PNEC of 2.0 ng/L; only 0.5% of the segments (less than 0.8% of kilometers) would have a critical low flow E2-eq exceeding the short-term PNEC of 5 ng/L. Those few river segments where the PNECs were exceeded were effluent dominated, being either headwater streams with a publicly owned treatment works (POTW), or flowing through a highly urbanized environment with one or several POTWs. These results suggest that aquatic species in most U.S. surface waters are not at risk from steroid estrogens that may be present as a result of human releases., (Copyright © 2012 SETAC.)

The predicted aquatic estrogen concentrations for the whole of England and Japan were determined and compared using population and flow data. The overall value for English surface waters was 0.9 ng/L estradiol equivalents (EEQ) compared to 0.1 ng/L overall for Japan. Available dilution of sewage effluent was considered to be more important than contraceptive pill usage in this relative risk. A national survey of Japanese rivers using the yeast estrogen assay (YES) gave a median value of 0.27 ng/L EEQ which, while higher than that predicted, confirmed an overall low endocrine disruption risk. Using local population and flow data for 27 separate catchments, the predicted EEQ and measured EEQ (YES) values compared well, confirming the national picture that endocrine disruption would not be a widespread phenomena in Japan. Simple predictions based on population and flow can give an appropriate "ball park" value for catchments and even nations for concentrations of polar organic contaminants which have a majority human origin.

Endocrine disruption in the aquatic environment has been a much-researched topic worldwide for the last fifteen years. We have not attempted to write a traditional review of the topic with this paper. Instead, based on unpublished reports and our own personal memories, we provide a history of the development of endocrine disruption research in the last 30 years, since the initial, accidental discovery of intersex fish in an English river in 1978. We focus on how the key questions were tackled, and the often surprising answers to some of these questions. We cover what we now know, and what we still do not know. Based on our current understanding, we emphasize the crucial role played by interdisciplinary research in moving the issue forward. The paper concludes with a selection of general messages about chemicals in the environment which have emerged from endocrine disruption research, and how these have changed our understanding of chemicals in the environment. If lessons have been learnt, and are acted upon when the next chemical 'scare' emerges (as it inevitably will), then it should be possible to act more efficiently and effectively to better protect the environment than was achieved during the "oestrogens in the environment" era.

For endocrine disrupting chemicals in the environment, concerns arise primarily from the effects that may be induced in wildlife. A well studied example is estrogenic chemicals in the aquatic environment and their effects on fish. Directly measuring effects, in fieldwork studies, is an expensive and time-consuming approach that is fraught with many difficulties, ranging from study design right through to data analysis and interpretation. An alternative approach would be to predict the scale of effect(s) using suitable modeling techniques. We have attempted to do this using estrogenic chemicals as an example. We chose this group of aquatic pollutants because of the current considerable interest in them and the wealth of biological data available on them. Using the established GREAT-ER hydrological model,we have first predicted the concentrations and then the estrogenic effects on fish, of estrone, estradiol, ethinyl estradiol, and nonylphenol individually throughout an entire river catchment. We then show that knowledge of the biological responses of fish to mixtures of these chemicals can be used to predict the effect of environmentally realistic mixtures of them. To determine the degree of risk posed by this group of chemicals, it was necessary to take into account mixture effects: assessment on a chemical by chemical basis led to underestimations of the risk. Finally, we show that the approach can be used to predict how the risk will be affected by changes in the concentration of one chemical in the mixture. Although we have used only one endpoint (vitellogenin induction as an estrogenic response) and one group of similarly acting chemicals, we suggest that this general approach could prove extremely useful to regulatory authorities and other parties charged with protecting aquatic wildlife from adverse effects caused by chemicals in their environment.

In the past 10 years, many thousands of research papers covering the many different aspects of endocrine disruption in the environment have been published. What has been learned from all this research? We have tried to reduce this very large volume of research into a relatively small number of "lessons". Hence, this paper is not a typical review, but instead it summarizes our personal opinions on what we consider are the major messages to have come from all this research. We realize that what has been a lesson to us may have been obvious from the outset to someone more knowledgeable on that particular aspect of the burgeoning field of endocrine disruption. In addition, it is inevitable that others will consider that we have "missed" some lessons that they would have expected to find included in our list. If so, we encourage them to submit them as responses to our paper. Our own lessons range widely, from the design and interpretation of data from fieldwork studies, through some key messages to come out of the very many laboratory studies that have been conducted, to issues around the sources and fates in the environment of endocrine-disrupting chemicals, and finally to the key role of sewage treatment in controlling the concentrations of these chemicals in the aquatic environment. Having (hopefully) learned our lessons, we have then applied them to the difficult issue of how best to approach future concerns about the potential impacts of other new and emerging contaminants (e.g., pharmaceuticals) on wildlife.

Diethylhexyl phthalate (DEHP) is considered to be an endocrine disruptor, which unlike other chemicals that have either non-specific (e.g., narcotics) or more generalized reactive modes of action, affect the Hypothalamic-pituitary-gonadal (HPG) axis and tend to have specific interactions with particular molecular targets within biochemical pathways. Responding to this challenge, a novel method for deriving predicted no-effect concentration (PNEC) and probabilistic ecological risk assessment (PERAs) for DEHP based on long-term exposure to potentially sensitive species with appropriate apical endpoints was development for protection of Chinese surface waters. PNECs based on potencies to cause lesions in reproductive tissues of fishes, which ranged from 0.04 to 0.20 μg DEHP L −1 , were significantly less than those derived based on other endpoints or other taxa, such as invertebrates. An assessment of risks posed by DEHP to aquatic organisms in surface waters of China showed that 88.17% and 78.85% of surface waters in China were predicted to pose risks to reproductive fitness of fishes with thresholds of protection for aquatic organisms based on 5% (HC 5 ) and 10% (HC 10 ), respectively. Assessment of risks of effects based on effects mediated by the HPG-axis should consider effects on chronic, non-lethal endpoints for specific taxa, especially for reproductive fitness of fishes. [ABSTRACT FROM AUTHOR]

The occurrence of intersex fish is widespread in the rivers of England andWales. The extent of intersex in fish populations is believed to be strongly linked to their exposure to steroid estrogens. The present study presents, to our knowledge, the first national, catchment-based risk assessment for steroid estrogens in the world. A graphical information system-based model predicted the concentrations of estradiol (E2), estrone, and ethinylestradiol, which were combined and compared with known biological effect levels to predict the risk of endocrine disruption for 10,313 individual river reaches (21,452 km) receiving effluent from more than 2,000 sewage treatment plants serving more than 29 million people. The large scale of this assessment underlines the usefulness of computer-based risk assessment methods. Overall, 39% of the modeled reaches (all percentages are in terms of the total river length modeled) in England and Wales were predicted to be not at risk from endocrine disruption (mean concentrations, <1 ng/L E2 equivalents). A large range existed in the percentage of river reaches at risk in the various regions, from 5% in Wales to 67% in the Thames catchment. Important factors influencing this proportion are the population density, particularly their location, and the available dilution. A very small proportion of reaches (∼1-3%) were predicted to be at high risk (>10 ng/L E2 equivalents). Many of these high-risk reaches, however, were ditches, which were composed almost entirely of sewage effluent. The model could be applied equally well to any other chemical of concern emanating from the human population that would be impractical to assess by measurement. [ABSTRACT FROM AUTHOR]

Abstract: Effluent discharges at Rodbourne sewage treatment works (STWs) were assessed using chemical and in vitro biological analysis as well as modelling predictions. Results showed that Rodbourne STW discharged less estrone (E1) than expected, but similar 17β-estradiol (E2) and 17α-ethinyl estradiol (EE2) to those predicted by a widely cited effluent prediction model. The Exposure Analysis Modelling System (EXAMS) model was set up using measured effluent concentrations as its starting point to predict estrogen concentrations along a 10km length of the receiving water of the River Ray. The model adequately simulated estrogen concentrations along the river when compared to July 2007 measured data. The model predicted combined estrogen equivalents in reasonable agreement with estrogenicity as measured by passive sampler (POCIS) extracts using the yeast estrogen screen. Using gauged mean flow values for 2007 the model indicated that the most important determinand for estrogen exposure in the Ray was not season, but proximity to the Rodbourne effluent. Thus, fish in the first 3km downstream of Rodbourne were typically exposed to two or even three times more estrogens than those living 7–10km further downstream. The modelling indicated that, assuming the effluent estrogen concentrations measured in February 2008 were typical, throughout the year the whole length of the Ray downstream of Rodbourne would be estrogenic, i.e. exceeding the 1ng/L E2 equivalent threshold for endocrine disruption. [ABSTRACT FROM AUTHOR]

In this study, the risks to aquatic organisms posed by 12 commonly detected pharmaceuticals and personal care products (PPCPs) and endocrine disrupting chemicals (EDCs) that are extensively used in Bohai coastal region of China were examined. These were linear alkylbenzene sulfonate (LAS), nonylphenol (NP), diethylhexyl phthalate (DEHP), norfloxacin (NOR), sulfamethoxazole (SMX), erythromycin (ERY), bisphenol A (BPA), ofloxacin (OFL), carbamazepine (CBZ), naproxen (NPX), atenolol (ATL) and metoprolol (MET). Their relative risk was ranked based on the proximity between the medians of the reported effect concentrations and measured river or lake water concentrations. The surfactants (LAS) and endocrine disrupting chemicals NP (a breakdown product of the surfactant nonylphenol polyethoxylate) and DEHP (a plasticizer) were identified as posing the greatest risk from this range of chemicals. LAS had a hundred-fold higher risk than any of the pharmaceuticals. The highest risk ranked pharmaceuticals were all antibiotics. Zinc (Zn) and mercury (Hg) were added to the comparison as representative heavy metals. Zn posed a risk higher than all the organics. The risk posed by Hg was less than the surfactants but greater than the selected pharmaceuticals. Whereas LAS and DEHP could cause harmful effects to all the wildlife groups, NP and BPA posed the greatest risk to fish. Antibiotics showed the highest risk to algae. Spatial and temporal distributions of PPCPs and EDCs were conducted for risk identification, source analysis and seasonal change exploration. Municipal sewage effluent linked to urban areas was considered to be the major source of pharmaceuticals. With regard to seasonal influence the risk posed by LAS to the aquatic organisms was significantly affected by wet and dry seasonal change. The dilution effects were the common feature of LAS and ERY risks. The difference in LAS and ERY risk patterns along the rivers was mainly affected by the elimination process. [ABSTRACT FROM AUTHOR]