The PhATE (Pharmaceutical Assessment and Transport Evaluation) model presented in this paper was developed as a tool to estimate concentrations of active pharmaceutical ingredients (APIs) in U.S. surface waters that result from patient use (or consumption) of medicines. PhATE uses a mass balance approach to model predicted environmental concentrations (PECs) in 11 watersheds selected to be representative of most hydrologic regions of the United States. The model divides rivers into discrete segments. It estimates the mass of API that enters a segment from upstream or from publicly owned treatment works (POTW) and is subsequently lost from the segment via in-stream loss mechanisms or flow diversions (i.e., man-made withdrawals). POTW discharge loads are estimated based on the population served, the API use per capita, the potential loss of the compound associated with human use (e.g., metabolism), and the portion of the API mass removed in the POTW. Simulations using three surrogate compounds showthat PECs generated by PhATE are generally within an order of magnitude of measured concentrations and that the cumulative probability distribution of PECs for all watersheds included in PhATE is consistent with the nationwide distribution of measured concentrations of the surrogate compounds. Model simulations for 11 APIs yielded four categories of results. (1) PECs fit measured data for two compounds. (2) PECs are below analytical method detection limits and thus are consistent with measured data for three compounds. (3) PECs are higher than (i.e., not consistent with) measured data for three compounds. However, this may be the consequence of as yet unidentified depletion mechanisms. (4) PECs are several orders of magnitude below some measured data but consistentwith most measured data forthree compounds. For the fourth category, closer examination of sampling locations suggests that the field-measured concentrations for these compounds do not accurately reflect human use. Overall, these results demonstrate that PhATE may be used to predict screening-level concentrations of APIs and related compounds in the environment as well as to evaluate the suitability of existing fate information for an API.

The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using > or = 42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence of fish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number of fish used from 3,822 to 1,025 (approximately 73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates.

An evaluation of measured and predicted concentrations of 17-ethinylestradiol in surface waters of the United States and Europe was conducted to develop expected long-term exposure concentrations for this compound. Measured environmental concentrations (MECs) in surface waters were identified from the literature. Predicted environmental concentrations (PECs) were generated for European and U.S. watersheds using the GREAT-ER and PhATE models, respectively. The majority of MECs are nondetect and generally consistent with model PECs and conservative mass balance calculations. However, the highest MECs are not consistent with concentrations derived from conservative (worst-case) mass balance estimates or model PECs. A review of analytical methods suggests that tandem or high-resolution mass spectrometry methods with extract cleanup result in lower detection limits and lower reported concentrations consistent with model predictions and bounding estimates. Based on model results using PhATE and GREAT-ER, the 90th-percentile low-flow PECs in surface water are approximately 0.2 and 0.3 ng/L for the United States and Europe, respectively. These levels represent conservative estimates of long-term exposure that can be used for risk assessment purposes. Our analysis also indicates that average concentrations are one to two orders of magnitude lower than these 90th-percentile estimates. Higher reported concentrations (e.g., greater than the 99th-percentile PEC of approximately 1 ng/L) could result from methodological problems or unusual environmental circumstances; however, such concentrations are not representative of levels generally found in the environment, warrant special scrutiny, and are not appropriate for use in risk assessments of long-term exposures.

No abstract

The pharmaceutical industry is conducting research to evaluate the pathways and fate of active pharmaceutical ingredients from the consumer to surface waters. One potential pathway identified by the researchers is the disposal of unused pharmaceutical products that are discarded by consumers in household trash and disposed of in municipal solid waste landfills. This study was designed to evaluate relative amounts of surface water exposures through the landfill disposal pathway compared to patient use and flushing of unused medicine pathways. The estimated releases to surface water of 24 example active pharmaceutical ingredients (APIs) in landfill leachate were calculated for 3 assumed disposal scenarios: 5%, 10%, and 15% of the total annual quantity of API sold is discarded and unused. The estimated releases from landfills to surface waters, after treatment of the leachate, were compared to the total amount of each example API that would be released to surface waters from publicly owned treatment works, generated by patient use and excretion. This study indicates that the disposal of unused medications in municipal solid waste landfills effectively eliminates the unused medicine contribution of APIs to surface waters; greater than 99.9% of APIs disposed of in a landfill are permanently retained. Integr Environ Assess Manag 2013;9:142-154. ß 2012 SETAC