Jason P. Berninger

Pharmaceuticals and Personal Care Products in the Environment: What Are the Big Questions?

Background: Over the past 10–15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment. Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas. Data sources: To better understand and manage the risks of PPCPs in the environment, we used the “key question” approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance. Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f ) antibiotic resistance, and g) risk management. Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.

Leveraging mammalian pharmaceutical toxicology and pharmacology data to predict chronic fish responses to pharmaceuticals.

Comparative pharmacology and toxicology approaches with fish models provide important linkages between the biomedical and environmental sciences. Because chronic fish responses to select pharmaceuticals are observed at very low (e.g., ng/L) concentrations, approaches are needed to identify therapeutics for robust environmental hazard and risk assessments. Whereas we observed no obvious relationship between acute toxicity data for rodent (LD(50)) and fish (LC(50)) models, using a probabilistic hazard evaluation approach, rodent and fish acute toxicity distributions predicted limited potential for acute toxicity at low concentrations, which is consistent with the peer-reviewed literature. Similar probabilistic distributions were developed to examine mammalian C(max) and an Acute to Therapeutic Ratio (ATR), a surrogate for mammalian therapeutic index that is similar to an Acute to Chronic Ratios (ACRs) commonly calculated for fish models. Probabilistic distributions of ATRs for fifteen drug classes were also examined, which showed specific groups with higher (e.g., reproductive hormones, corticosteroids, antihistamines) and lower (e.g., antibiotics, NSAIDs) ATR values than the distribution for all available pharmaceutical ATRs. A statistically significant relationship (r(2)=0.846, p<0.001) was determined between mammalian ATR and fish ACR values, which may support a screening approach to examine chronic pharmaceutical effects in fish based on the magnitude of mammalian ATR values.

Effects of the antihistamine diphenhydramine on selected aquatic organisms

In recent years pharmaceuticals have been detected in aquatic systems receiving discharges of municipal and industrial effluents. Although diphenhydramine (DPH) has been reported in water, sediment, and fish tissue, an understanding of its impacts on aquatic organisms is lacking. Diphenhydramine has multiple modes of action (MOA) targeting the histamine H1, acetylcholine (ACh), and 5-HT reuptake transporter receptors, and as such is used in hundreds of pharmaceutical formulations. The primary objective of this study was to develop a baseline aquatic toxicological understanding of DPH using standard acute and subchronic methodologies with common aquatic plant, invertebrate, and fish models. A secondary objective was to test the utility of leveraging mammalian pharmacology information to predict aquatic toxicity thresholds. The plant model, Lemna gibba, was not adversely affected at exposures as high as 10 mg/L. In the fish model, Pimephales promelas, pH affected acute toxicity thresholds and feeding behavior was more sensitive (no-observed-effect concentration = 2.8 µg/L) than standardized survival or growth endpoints. This response threshold was slightly underpredicted using a novel plasma partitioning approach and a mammalian pharmacological potency model. Interestingly, results from both acute mortality and subchronic reproduction studies indicated that the model aquatic invertebrate, Daphnia magna, was more sensitive to DPH than the fish model. These responses suggest that DPH may exert toxicity in Daphnia through ACh and histamine MOAs. The D. magna reproduction no-observed-effect concentration of 0.8 µg/L is environmentally relevant and suggests that additional studies of more potent antihistamines and antihistamine mixtures are warranted.

Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows

A need exists to better understand the influence of pH on the uptake and accumulation of ionizable pharmaceuticals in fish. In the present study, fathead minnows were exposed to diphenhydramine (DPH; disassociation constant = 9.1) in water for up to 96 h at 3 nominal pH levels: 6.7, 7.7, and 8.7. In each case, an apparent steady state was reached by 24 h, allowing for direct determination of the bioconcentration factor (BCF), blood-water partitioning (PBW,TOT), and apparent volume of distribution (approximated from the whole-body-plasma concentration ratio). The BCFs and measured PBW,TOT values increased in a nonlinear manner with pH, whereas the volume of distribution remained constant, averaging 3.0 L/kg. The data were then simulated using a model that accounts for acidification of the gill surface caused by elimination of metabolically produced acid. Good agreement between model simulations and measured data was obtained for all tests by assuming that plasma binding of ionized DPH is 16% that of the neutral form. A simpler model, which ignores elimination of metabolically produced acid, performed less well. These findings suggest that pH effects on accumulation of ionizable compounds in fish are best described using a model that accounts for acidification of the gill surface. Moreover, measured plasma binding and volume of distribution data for humans, determined during drug development, may have considerable value for predicting chemical binding behavior in fish.

An initial probabilistic hazard assessment of oil dispersants approved by the united states national contingency plan

Dispersants are commonly applied during oil spill mitigation efforts; however, these industrial chemicals may present risks to aquatic organisms individually and when mixed with oil. Fourteen dispersants are listed on the U.S. Environmental Protection Agency (U.S. EPA) National Oil and Hazardous Substances Pollution Contingency Plan (NCP). Availability of environmental effects information for such agents is limited, and individual components of dispersants are largely proprietary. Probabilistic hazard assessment approaches including Chemical Toxicity Distributions (CTDs) may be useful as an initial step toward prioritizing environmental hazards from the use of dispersants. In the present study, we applied the CTD approach to two acute toxicity datasets: NCP (the contingency plan dataset) and DHOS (a subset of NCP listed dispersants reevaluated subsequent to the Deepwater Horizon oil spill). These datasets contained median lethal concentration (LC50) values for dispersants alone and dispersant:oil mixtures, in two standard marine test species, Menidia beryllina and Mysidopsis bahia. These CTDs suggest that dispersants alone are generally less toxic than oil. In contrast, most dispersant:oil mixtures are more toxic than oil alone. For the two datasets (treated separately because of differing methodologies), CTDs would predict 95% of dispersant:oil mixtures to have acute toxicity values above 0.32 and 0.76 mg/L for Mysidopsis and 0.33 mg/L and 1.06 mg/L for Menidia (for DHOS and NCP, respectively). These findings demonstrate the utility of CTDs as a means to evaluate the comparative ecotoxicity of dispersants alone and in mixture with different oil types. The approaches presented here also provide valuable tools for prioritizing prospective and retrospective environmental assessments of oil dispersants.

Application of chemical toxicity distributions to ecotoxicology data requirements under REACH.

The European Unions REACH regulation has further highlighted the lack of ecotoxicological data for substances in the marketplace. The mandates under REACH (registration, evaluation, authorization, and restriction of chemicals) to produce data and minimize testing on vertebrates present an impetus for advanced hazard assessment techniques using read-across. Research in our group has recently focused on probabilistic ecotoxicological hazard assessment approaches using chemical toxicity distributions (CTDs). Using available data for chemicals with similar modes of action or within a chemical class may allow for selection of a screening point value (SPV) for development of environmental safety values, based on a probabilistic distribution of toxicity values for a specific endpoint in an ecological receptor. Ecotoxicity data for acetylcholinesterase inhibitors and surfactants in Daphnia magna and Pimephales promelas were gathered from several data sources, including the U.S. Environmental Protection Agencys ECOTOX and Pesticides Ecotoxicity databases, the peer-reviewed literature, and the Human and Environmental Risk Assessment (HERA) project. Chemical toxicity distributions were subsequently developed, and the first and fifth centiles were used as SPVs for the development of screening-predicted no-effect concentrations (sPNECs). The first and fifth centiles of these distributions were divided by an assessment factor of 1,000, as recommended by REACH guidance. Use of screening values created using these techniques could support the processes of data dossier development and environmental exposure assessment, allowing for rigorous prioritization in testing and monitoring to fill data gaps.

Pathway-based approaches for assessment of real-time exposure to an estrogenic wastewater treatment plant effluent on fathead minnow reproduction

Wastewater treatment plant (WWTP) effluents are known contributors of chemical mixtures into the environment. Of particular concern are endocrine-disrupting compounds, such as estrogens, which can affect the hypothalamic-pituitary-gonadal axis function in exposed organisms. The present study examined reproductive effects in fathead minnows exposed for 21 d to a historically estrogenic WWTP effluent. Fathead minnow breeding pairs were held in control water or 1 of 3 effluent concentrations (5%, 20%, and 100%) in a novel onsite, flow-through system providing real-time exposure. The authors examined molecular and biochemical endpoints representing key events along adverse outcome pathways linking estrogen receptor activation and other molecular initiating events to reproductive impairment. In addition, the authors used chemical analysis of the effluent to construct a chemical-gene interaction network to aid in targeted gene expression analyses and identifying potentially impacted biological pathways. Cumulative fecundity was significantly reduced in fish exposed to 100% effluent but increased in those exposed to 20% effluent, the approximate dilution factor in the receiving waters. Plasma vitellogenin concentrations in males increased in a dose-dependent manner with effluent concentration; however, male fertility was not impacted. Although in vitro analyses, analytical chemistry, and biomarker responses confirmed the effluent was estrogenic, estrogen receptor agonists were unlikely the primary driver of impaired reproduction. The results provide insights into the significance of pathway-based effects with regard to predicting adverse reproductive outcomes.

Perspectives on Human Pharmaceuticals in the Environment

Human interaction with the environment remains one of the most pervasive facets of modern society. Whereas the anthropocene is characterized by rapid population growth, unprecedented global trade and digital communications, energy security, natural resource scarcities, climatic changes and environmental quality, emerging diseases and public health, biodiversity and habitat modifications are routinely touted by the popular press as they canvas global political agendas and scholarly endeavors. With a concentration of human populations in urban areas unlike any other time in history, the coming decades will be defined by “A New Normal,” as proposed by Sandra Postel, where the interplay among sustainable human activities and natural resource management will inherently determine the regional fates of human societies. In recent years, few topics have captured the public’s attention like the presence of human pharmaceuticals in environment. But why have citizens been so engaged by fish on Prozac and drug residues in drinking water? Because pharmacotherapy is now entrenched in everyday life, a realization that common drugs are found in the water we drink or the fish we eat likely produces a boomerang effect, where our daily reliance on well-accepted therapies is concretely linked in a new way with their potential consequences to the natural world. On an increasingly urban planet, pharmaceutical residues and traces of other contaminants of emerging concern represent signals of the rapidly urbanizing water cycle and harbingers of the “New Normal.” This volume examines current issues and provides timely future perspectives on human pharmaceuticals in the environment. We further provide a novel prediction that 10% of pharmaceuticals may result in internal fish plasma concentrations equaling the human Cmax value at or below an environmentally relevant concentration of 29 ng/L.

Prioritization of pharmaceuticals for potential environmental hazard through leveraging a large‐scale mammalian pharmacological dataset

The potential for pharmaceuticals in the environment to cause adverse ecological effects is of increasing concern. Given the thousands of active pharmaceutical ingredients (APIs) that can enter the aquatic environment through human and/or animal (e.g., livestock) waste, a current challenge in aquatic toxicology is identifying those that pose the greatest risk. Because empirical toxicity information for aquatic species is generally lacking for pharmaceuticals, an important data source for prioritization is that generated during the mammalian drug development process. Applying concepts of species read-across, mammalian pharmacokinetic data were used to systematically prioritize APIs by estimating their potential to cause adverse biological consequences to aquatic organisms, using fish as an example. Mammalian absorption, distribution, metabolism, and excretion (ADME) data (e.g., peak plasma concentration, apparent volume of distribution, clearance rate, and half-life) were collected and curated, creating the Mammalian Pharmacokinetic Prioritization For Aquatic Species Targeting (MaPPFAST) database representing 1070 APIs. From these data, a probabilistic model and scoring system were developed and evaluated. Individual APIs and therapeutic classes were ranked based on clearly defined read-across assumptions for translating mammalian-derived ADME parameters to estimate potential hazard in fish (i.e., greatest predicted hazard associated with lowest mammalian peak plasma concentrations, total clearance and highest volume of distribution, half-life). It is anticipated that the MaPPFAST database and the associated API prioritization approach will help guide research and/or inform ecological risk assessment.

Linking field‐based metabolomics and chemical analyses to prioritize contaminants of emerging concern in the Great Lakes basin

The ability to focus on the most biologically relevant contaminants affecting aquatic ecosystems can be challenging because toxicity-assessment programs have not kept pace with the growing number of contaminants requiring testing. Because it has proven effective at assessing the biological impacts of potentially toxic contaminants, profiling of endogenous metabolites (metabolomics) may help screen out contaminants with a lower likelihood of eliciting biological impacts, thereby prioritizing the most biologically important contaminants. The authors present results from a study that utilized cage-deployed fathead minnows (Pimephales promelas) at 18 sites across the Great Lakes basin. They measured water temperature and contaminant concentrations in water samples (132 contaminants targeted, 86 detected) and used 1 H-nuclear magnetic resonance spectroscopy to measure endogenous metabolites in polar extracts of livers. They used partial least-squares regression to compare relative abundances of endogenous metabolites with contaminant concentrations and temperature. The results indicated that profiles of endogenous polar metabolites covaried with at most 49 contaminants. The authors identified up to 52% of detected contaminants as not significantly covarying with changes in endogenous metabolites, suggesting they likely were not eliciting measurable impacts at these sites. This represents a first step in screening for the biological relevance of detected contaminants by shortening lists of contaminants potentially affecting these sites. Such information may allow risk assessors to prioritize contaminants and focus toxicity testing on the most biologically relevant contaminants. Environ Toxicol Chem 2016;35:2493-2502. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.