Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that could help in meeting these challenges. However, to use mechanistic data to support chemical assessments, there is a need for effective translation of this information into endpoints meaningful to ecological risk-effects on survival, development, and reproduction in individual organisms and, by extension, impacts on populations. Here we discuss a framework designed for this purpose, the adverse outcome pathway (AOP). An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. The practical utility of AOPs for ecological risk assessment of chemicals is illustrated using five case examples. The examples demonstrate how the AOP concept can focus toxicity testing in terms of species and endpoint selection, enhance across-chemical extrapolation, and support prediction of mixture effects. The examples also show how AOPs facilitate use of molecular or biochemical endpoints (sometimes referred to as biomarkers) for forecasting chemical impacts on individuals and populations. In the concluding sections of the paper, we discuss how AOPs can help to guide research that supports chemical risk assessments and advocate for the incorporation of this approach into a broader systems biology framework.

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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.

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Trenbolone acetate is a synthetic steroid that is extensively used in the United States as a growth promoter in beef cattle. The acetate is administered to livestock via slow-release implants; some is converted by the animal to 17-beta-trenbolone, a relatively potent androgen receptor agonist in mammalian systems. Recent studies indicate that excreted 17-beta-trenbolone is comparatively stable in animal waste, suggesting the potential for exposure to aquatic animals via direct discharge, runoff, or both. However, little is known concerning the toxicity of trenbolone to fish. Our goal was to assess the effects of 17-beta-trenbolone on reproductive endocrinology of the fathead minnow (Pimephales promelas). An in vitro competitive binding study with the fathead minnow androgen receptor demonstrated that 17-beta-trenbolone had a higher affinity for the receptor than that of the endogenous ligand, testosterone. Male and female fish were exposed for 21 d to nominal (target) concentrations of 17-beta-trenbolone ranging from 0.005 to 50 microg/L. Fecundity of the fish was significantly reduced by exposure to measured test concentrations > or = 0.027 microg/ L. The 17-beta-trenbolone was clearly androgenic in vivo at these concentrations, as evidenced by the de novo production in females of dorsal (nuptial) tubercles, structures normally present only on the heads of mature males. Plasma steroid (testosterone and beta-estradiol) and vitellogenin concentrations in the females all were significantly reduced by exposure to 17-beta-trenbolone. The 17-beta-trenbolone also altered reproductive physiology of male fathead minnows, albeit at concentrations much higher than those producing effects in females. Males exposed to 17-beta-trenbolone at 41 microg/L (measured) exhibited decreased plasma concentrations of 11-ketotestosterone and increased concentrations of beta-estradiol and vitellogenin. Overall, our studies indicate that 17-beta-trenbolone is a potent androgen and reproductive toxicant in fish. Given the widespread use of trenbolone acetate as a growth promoter, and relative stability of its metabolites in animal wastes, further studies are warranted to assess potential ecological risk.

Due to the time and expense associated with full life-cycle testing, most current toxicity tests with fish do not explicitly consider reproductive output as an endpoint but, rather, focus on early life-stage survival and development. However, some classes of chemicals could adversely impact reproduction at concentrations below those that affect development. Further, estimates of the effects of toxic compounds on reproductive output can be critical to the ecological risk assessment process. In this manuscript, we describe a short-term reproduction test with the fathead minnow (Pimephales promelas) and evaluate the test using two model reproductive toxicants, methoxychlor (an estrogenic compound) and methyltestosterone (an androgenic chemical). The test is initiated with reproductively mature animals and is comprised of a pre-exposure phase of 14 to 21 d, followed by a chemical exposure of up to 21 d. During and at completion of the test, several endpoints related to reproductive fitness and endocrine function are assessed. Both chemicals evaluated in our study caused a significant decrease in fecundity of the fish at nominal concentrations of 5.0 micrograms/L (methoxychlor) and 0.2 mg/L (methyltestosterone). Methoxychlor decreased plasma concentrations of one or more steroids (testosterone, 11-ketotestosterone, beta-estradiol) in both sexes and caused a significant induction of plasma vitellogenin in males, a response consistent with activation of the estrogen receptor by the pesticide (or its metabolites). Methyltestosterone decreased plasma concentrations of sex steroids and adversely affected gonadal status (as evaluated by relative weight and histopathology) in both sexes. The androgenic nature of methyltestosterone was clearly expressed as masculinization of exposed females via formation of nuptial tubercles, structures normally present only in reproductively active males. The chemical also caused a significant induction of plasma vitellogenin in both males and females; this unexpected estrogenic response was most likely due to aromatization of the androgen to a form capable of binding to the estrogen receptor. These studies demonstrate the utility of this short-term assay for identifying chemicals that exert reproductive toxicity through alterations in endocrine systems controlled by estrogens and androgens.

Abstract-In developing sediment quality criteria (SQC) for metals, it is essential that bioavailability be a prime consideration. Different studies have shown that while dry weight metal concentrations in sediments are not predictive of bioavailability, metal concentrations in interstitial (pore) water are correlated with observed biological effects. A key partitioning phase controlling cationic metal activity and toxicity in the sediment-interstitial water system is acid-volatile sulfide (AVS). Acid-volatile sulfide binds, on a mole-to-mole basis, a number of cationic metals of environmental concern (cadmium, copper, nickel, lead, zinc) forming insoluble sulfide complexes with minimal biological availability. Short-term (10-d) laboratory studies with a variety of marine and freshwater benthic organisms have demonstrated that when AVS concentrations in spiked or field-collected sediments exceed those of metals simultaneously extracted with the AVS, interstitial water metal concentrations remain below those predicted to cause effects, and toxicity does not occur. Similar observations have been made in life-cycle laboratory toxicity tests with amphipods and chironomids in marine and freshwater sediments spiked with cadmium and zinc, respectively. In addition, field colonization experiments, varying in length from several months to more than 1 year, with cadmium-or zinc-spiked freshwater and marine sediments, have demonstrated a lack of biological effects when there is sufficient AVS to limit interstitial water metal concentrations. These studies on metal bioavailability and toxicity in sediments serve as the basis for proposed SQC for the metals cadmium, copper, nickel, lead, and zinc. Specifically, four approaches for deriving criteria are described: (a) comparison of molar AVS concentrations to the summed molar concentration of the five metals simultaneously extracted with the AVS; (b) measurement of interstitial water metal concentrations and calculation of summed interstitial water criteria toxic units (IWCTU) for the five metals, based upon final chronic values from water quality criteria documents; (c) calculation of summed IWCTU based upon sediment AVS concentrations and metal-specific partitioning of the metals to organic carbon; and (d) calculation of summed IWCTU based upon partitioning of the metals to a minimum binding phase sorbent (chromatographic sand). For a number of reasons, SQC derived using these approaches generally should be considered ''no effect'' values, i.e., with these techniques it is possible to predict when sediment metals will not be toxic, but not necessarily when metal toxicity will be manifested. Currently, approaches (a) and (b) are the most useful in terms of predicting metal bioavailability and deriving SQC. Further research is required, however, to fully implement approaches (c) and (d). Additional research also is required to thoroughly understand processes controlling bioaccumulation of metals from sediments by benthic organisms, as well as accumulation of metals by pelagic s...

Incorporation of global climate change (GCC) effects into assessments of chemical risk and injury requires integrated examinations of chemical and nonchemical stressors. Environmental variables altered by GCC (temperature, precipitation, salinity, pH) can influence the toxicokinetics of chemical absorption, distribution, metabolism, and excretion as well as toxicodynamic interactions between chemicals and target molecules. In addition, GCC challenges processes critical for coping with the external environment (water balance, thermoregulation, nutrition, and the immune, endocrine, and neurological systems), leaving organisms sensitive to even slight perturbations by chemicals when pushed to the limits of their physiological tolerance range. In simplest terms, GCC can make organisms more sensitive to chemical stressors, while alternatively, exposure to chemicals can make organisms more sensitive to GCC stressors. One challenge is to identify potential interactions between nonchemical and chemical stressors affecting key physiological processes in an organism. We employed adverse outcome pathways, constructs depicting linkages between mechanism-based molecular initiating events and impacts on individuals or populations, to assess how chemical- and climate-specific variables interact to lead to adverse outcomes. Case examples are presented for prospective scenarios, hypothesizing potential chemical–GCC interactions, and retrospective scenarios, proposing mechanisms for demonstrated chemical–climate interactions in natural populations. Understanding GCC interactions along adverse outcome pathways facilitates extrapolation between species or other levels of organization, development of hypotheses and focal areas for further research, and improved inputs for risk and resource injury assessments. Environ. Toxicol. Chem. 2013;32:32–48. © 2012 SETAC