A risk-based approach to managing active pharmaceutical ingredients in manufacturing effluent.

The present study describes guidance intended to assist pharmaceutical manufacturers in assessing, mitigating, and managing the potential environmental impacts of active pharmaceutical ingredients (APIs) in wastewater from manufacturing operations, including those from external suppliers. The tools are not a substitute for compliance with local regulatory requirements but rather are intended to help manufacturers achieve the general standard of "no discharge of APIs in toxic amounts." The approaches detailed in the present study identify practices for assessing potential environmental risks from APIs in manufacturing effluent and outline measures that can be used to reduce the risk, including selective application of available treatment technologies. These measures either are commonly employed within the industry or have been implemented to a more limited extent based on local circumstances. Much of the material is based on company experience and case studies discussed at an industry workshop held on this topic.

Environmental fate and chemistry of raloxifene hydrochloride.

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.

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.

Species extrapolation for the 21st century.

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.

Human health risk assessments for three neuropharmaceutical compounds in surface waters.

Enhanced sensitivity of analytical chemistry methods has enabled the detection of low-levels of pharmaceuticals in the environment, resulting in questions about the safety of surface waters used for drinking supplies. Human health risk assessments were performed to evaluate the risks from residues of atomoxetine, duloxetine, and olanzapine, which might be found in surface waters. Preclinical safety studies and human clinical data were used to determine an acceptable daily intake (ADI) for each compound: atomoxetine, 1.4 microg/kg/day; duloxetine, 1.8 microg/kg/day; and olanzapine, 1.4 microg/kg/day. The calculated predicted no-effect concentrations (PNECs) for children were 25.7, 19.1, and 35.9 microg/L for atomoxetine, duloxetine, and olanzapine, respectively. Estimated exposure concentrations determined using United States Food and Drug Administration guidelines and predicted exposure concentrations from the PhATE model were compared with each PNEC to determine margins of safety, which ranged from 147 to 642. Based on currently available data used in this assessment, no appreciable human health risks exist from exposure to the highest 99th percentile of predicted residue levels of atomoxetine, duloxetine or olanzapine in surface waters under low-flow conditions.

Human pharmaceuticals in US surface waters: a human health risk assessment.

The detection of low levels of pharmaceuticals in rivers and streams, drinking water, and groundwater has raised questions as to whether these levels may affect human health. This report presents human health risk assessments for 26 active pharmaceutical ingredients (APIs) and/or their metabolites, representing 14 different drug classes, for which environmental monitoring data are available for the United States. Acceptable daily intakes (ADIs) are derived using the considerable data that are available for APIs. The resulting ADIs are designed to protect potentially exposed populations, including sensitive sub-populations. The ADIs are then used to estimate predicted no effect concentrations (PNECs) for two sources of potential human exposure: drinking water and fish ingestion. The PNECs are compared to measured environmental concentrations (MECs) from the published literature and to maximum predicted environmental concentrations (PECs) generated using the PhATE model. The PhATE model predictions are made under conservative assumptions of low river flow and no depletion (i.e., no metabolism, no removal during wastewater or drinking water treatment, and no instream depletion). Ratios of MECs to PNECs are typically very low and consistent with PEC to PNEC ratios. For all 26 compounds, these low ratios indicate that no appreciable human health risk exists from the presence of trace concentrations of these APIs in surface water and drinking water.

Extending the threshold of regulation concept: de minimis limits for carcinogens and mutagens.

Risk assessment processes for carcinogens are highly developed but risk assessment processes for mutagens are not well established. In the pharmaceutical industry, risk associated with exposure to carcinogens is tightly controlled. It is desirable to control risk associated with exposure to mutagens also, in spite of the greater uncertainty associated with the risk. In this paper, a published cancer potency database is used to frame the risk and to support risk management decisions. A de minimis exposure for mutagens is proposed and a decision matrix is presented to align available data with risk assessment approaches for carcinogens and mutagens.

Aerobic degradation of tylosin in cattle, chicken, and swine excreta.

Tylosin, a fermentation-derived macrolide antibiotic, was tested to determine its aerobic degradation rate in cattle, chicken, and swine excreta. For chicken, excreta from a hen administered 14C-tylosin as part of a metabolism study were used. For cattle and swine, 14C-tylosin was added to control excreta. The formation of 14C volatile breakdown products and 14CO2 was not observed throughout the study. Material balance for the carbon-14 label ranged between 94% and 104%. Initial, day-0, concentrations of tylosin-A averaged 119.52+/-4.39, 35.01+/-1.34, and 62.82+/-2.11 microg/g (dry weight basis) for cattle, chicken, and swine excreta samples, respectively. After 30 days, samples averaged 4.16+/-0.69 and 4.11+/-0.69 microg/g tylosin-A in cattle and swine excreta, respectively. No residues of tylosin-A or its factors were apparent in the chicken excreta samples after 30 days of incubation. In each case, tylosin declined to less than 6.5% of the initial level after 30 days. Calculated first-order half-lives under the test conditions were 6.2 days, <7.6 days, and 7.6 days for cattle, chicken, and swine excreta, respectively. The results indicate that tylosin residues degrade rapidly in animal excreta. Therefore, tylosin residues should not persist in the environment.