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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Safety factors are used in ecological risk assessments to extrapolate from the toxic responses of laboratory test species to all species representing that group in the environment. More accurate extrapolation of species responses is important. Advances in understanding the mechanistic basis for toxicological responses and identifying molecular response pathways can provide a basis for extrapolation across species and, in part, an explanation for the variability in whole organism responses to toxicants. We highlight potential short- and medium-term development goals to meet our long-term aspiration of truly predictive in silico extrapolation across wildlife species' response to toxicants. A conceptual approach for considering cross-species extrapolation is presented. Critical information is required to establish evidence-based species extrapolation, including identification of critical molecular pathways and regulatory networks that are linked to the biological mode of action and species' homologies. A case study is presented that examines steroidogenesis inhibition in fish after exposure to fadrozole or prochloraz. Similar effects for each compound among fathead minnow, medaka, and zebrafish were attributed to similar inhibitor pharmacokinetic/pharmacodynamic distributions and sequences of cytochrome P45019A1/2 (CYP19A1/2). Rapid advances in homology modeling allow the prediction of interactions of chemicals with enzymes, for example, CYP19 aromatase, which would eventually allow a prediction of potential aromatase toxicity of new compounds across a range of species. Eventually, predictive models will be developed to extrapolate across species, although substantial research is still required. Knowledge gaps requiring research include defining differences in life histories (e.g., reproductive strategies), understanding tissue-specific gene expression, and defining the role of metabolism on toxic responses and how these collectively affect the power of interspecies extrapolation methods.

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Raloxifene hydrochloride is a selective estrogen receptor modulator (SERM) used for the prevention and treatment of osteoporosis in women. Excretion of raloxifene occurs through the feces of patients. Raloxifene has the potential to be discharged into waste treatment systems after therapeutic use. Raloxifene hydrochloride was investigated using a battery of studies designed to describe its physical/chemical characteristics and define its fate in the environment. The mean measured solubility of raloxifene hydrochloride (+/- standard deviation) was 345.2 +/- 15.6 microg/ml, 13.3 +/- 0.6 microg/ml, 0.9224 +/- 0.015 microg/ml, and 627.4 +/- 132.0 microg/ml in aqueous buffers at pH 5, 7, and 9 and in unbuffered water, respectively. Raloxifene exhibited a mean molar absorptivity of 34,000 and a wavelength absorbance maximum at 287 nm for pH 5 and 7 aqueous buffer solutions and 297 nm at pH 9. Mean measured Kow values were 516 +/- 17, 1,323 +/- 91, and 1,556 +/- 135 at pH 5, 7, and 9, respectively. After 5 d at 50 degrees C, raloxifene hydrolyzed 8.02, 10.61, and 23.81% in pH 5, 7, and 9 aqueous buffers, respectively. In a 28-d hydrolysis study at 25 degrees C, the calculated first-order hydrolysis rates were 6.92 x 10(-4), 1.70 x 10(-3), and 7.66 x 10(-3)/d, and the corresponding half-lives were 1,001, 410, and 90 d in pH 5, 7, and 9 aqueous buffers, respectively. Raloxifene sorbed significantly to sewage treatment solids with Freundlich isotherm adsorption coefficients K between 2,000 and 3,000. Raloxifene degraded rapidly in the presence of sewage solids. In a system containing 0.470 g/L sludge solids, the raloxifene biodegradation rate and half-life were 0.0966/h and 7.17 h, respectively. In a 28-d aerobic-aquatic biodegradation study containing 30 mg/L sludge solids, the raloxifene biodegradation rate and half-life were 0.0188/d and 37 d, respectively. Given the fate and behavior of raloxifene in these studies, it is anticipated that raloxifene would rapidly dissipate in the environment.