Jon F. Ericson

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.

Exposure assessment of 17α-ethinylestradiol in surface waters of the United States and Europe†

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.

In vivo and in vitro liver and gill EROD activity in rainbow trout (Oncorhynchus mykiss) exposed to the beta-blocker propranolol

The conservation of common physiological systems across vertebrate classes suggests the potential for certain pharmaceuticals, which have been detected in surface waters, to produce biological effects in nontarget vertebrates such as fish. However, previous studies assessing the effects of such compounds in fish have not taken into account the potential for metabolism and elimination. This study aimed to assess if propranolol, a β‐adrenergic receptor antagonist or β‐blocker, could modulate EROD activity (indicative of CYP1A activity) in rainbow trout (Oncorhynchus mykiss) gills and liver. For this, an in vivo time course exposure with 1 mg/L was conducted. Additionally, using measured in vivo plasma concentrations, an in vitro exposure at human therapeutic levels was undertaken. This allowed comparison of in vitro and in vivo rates of EROD activity, thus investigating the applicability of cell preparations as surrogates for whole animal enzyme activity analysis. In vitro exposure of suspended liver and gill cells at concentrations similar to in vivo levels resulted in EROD activity in both tissues, but with significantly higher rates (up to six times in vivo levels). These results show that propranolol exposure elevated EROD activity in the liver and gill of rainbow trout, and that this is demonstrable both in vivo (albeit nonsignificantly in the liver) and in vitro, thus supporting the use of the latter as a surrogate of the former. These data also provide an insight into the potential role of the gill as a site of metabolism of pharmaceuticals in trout, suggesting that propranolol (and feasibly other pharmaceuticals) may undergo “first pass” metabolism in this organ.

Environmental Fate of Human Pharmaceuticals

In recent years, environmental fate information for human pharmaceuticals has become increasingly available in the peer-reviewed literature. However, we still only have a limited understanding of the many environmental fate and transport processes affecting exposure of pharmaceuticals in aquatic and terrestrial systems. Moreover, because the physical–chemical properties of human pharmaceuticals differ from more traditional contaminants, current experimental and modeling approaches for measuring or predicting underlying fate characteristics and subsequent exposure do not necessarily work well for pharmaceuticals. Therefore, in this chapter, we discuss those factors and processes affecting the fate and transport of pharmaceuticals in the environment. We discuss the suitability of existing ’fate testing and modeling methodologies and finally develop recommendations on future research to address some of the major knowledge gaps.

The value of repeating studies and multiple controls: replicated 28‐day growth studies of rainbow trout exposed to clofibric acid

Two studies to examine the effect of waterborne clofibric acid (CA) on growth-rate and condition of rainbow trout were conducted using accepted regulatory tests (Organisation for Economic Co-operation and Development [OECD] 215). The first study (in 2005) showed significant reductions after 21 d of exposure (21-d growth lowest-observed-effect concentration [LOEC] = 0.1 µg/L, 21-d condition LOEC = 0.1 µg/L) that continued to 28 d. Growth rate was reduced by approximately 50% (from 5.27 to 2.67% per day), while the condition of the fish reduced in a concentration-dependant manner. Additionally, in a concentration-dependent manner, significant changes in relative liver size were observed, such that increasing concentrations of CA resulted in smaller livers after 28-d exposure. A no-observed-effect concentration (NOEC) was not achieved in the 2005 study. An expanded second study (in 2006) that included a robust bridge to the 2005 study, with four replicate tanks of eight individual fish per concentration, did not repeat the 2005 findings. In the 2006 study, no significant effect on growth rate, condition, or liver biometry was observed after 21 or 28 d (28-d growth NOEC = 10 µg/L, 28-d condition NOEC = 10 µg/L), contrary to the 2005 findings. We do not dismiss either of these findings and suggest both are relevant and stand for comparison. However, the larger 2006 study carries more statistical power and multiple-tank replication, so probably produced the more robust findings. Despite sufficient statistical power in each study, interpretation of these and similar studies should be conducted with caution, because much significance is placed on the role of limited numbers of individual and tank replicates and the influence of control animals.

Degradation and transformation of 17α‐trenbolone in aerobic water–sediment systems

Synovex® ONE is an extended-release implant containing the active ingredients estradiol benzoate and trenbolone acetate for use in beef steers and heifers. Trenbolone acetate is rapidly hydrolyzed in cattle to form 17β-trenbolone and its isomer, 17α-trenbolone, which are further transformed to a secondary metabolite, trendione. As part of the environmental assessment for the use of Synovex ONE, data were generated to characterize the fate of 17α-trenbolone, which is the principal metabolite found in cattle excreta, in the environment. A study was conducted to determine the degradation and transformation of [14 C]-17α-trenbolone in 2 representative water-sediment systems under aerobic conditions. The same transformation products, 17β-trenbolone and trendione, were formed, principally in the sediment phase, in both systems. From the production of these transformation products, the 50% disappearance time (DT50) values of 17β-trenbolone and trendione were determined, along with the DT50 values of the parent compound and the total drug (17α-trenbolone + 17β-trenbolone + trendione). The DT50 values for the total system (aqueous and sediment phase) and for the total residues (17α-trenbolone + 17β-trenbolone + trendione) in the 2 systems were 34.7 d and 53.3 d, respectively. Environ Toxicol Chem 2017;36:630-635.

Degradation and transformation of 17α-estradiol in water-sediment systems under controlled aerobic and anaerobic conditions.

One of the principal metabolites in cattle excreta following the administration of Synovex® ONE, which contains estradiol benzoate and trenbolone acetate, is 17α-estradiol. As part of the environmental assessment of the use of Synovex ONE, data were generated to characterize the fate of 17α-estradiol in the environment. Studies were conducted to determine the degradation and transformation of 17α-[14 C]-estradiol in 2 representative water-sediment systems each under aerobic and anaerobic conditions. The same transformation products-estriol, 17β-estradiol, and estrone-were formed, principally in the sediment phase, under both conditions in both systems. From the production of these transformation products, the 50% disappearance time (DT50) values of estrone and 17β-estradiol were determined, along with the DT50 values of 17α-estradiol and the total drug (17α-estradiol + 17β-estradiol + estrone). The results indicate that 17 α-[14 C]-estradiol was more persistent under anaerobic conditions than under aerobic conditions and that 17 α-[14 C]-estradiol was less persistent than its transformation products. The DT50 values for the total system (aqueous and sediment phases) and for the total residues (17α-estradiol, 17β-estradiol, and estrone) were selected for use in modeling the environmental fate of estradiol benzoate. For aerobic degradation in the water-sediment system, the DT50 was 31.1 d, and it was 107.8 d for the anaerobic system. Environ Toxicol Chem 2017;36:621-629.

Respirometric protocol to evaluate acute microbial inhibition in activated sludge

In the past, biological treatment has proven to be an efficient and cost-effective means for the removal of synthetic organic chemicals from wastewaters. As a result, many wastewater treatment facilities have incorporated activated sludge (AS) technology. A drawback of AS systems is their susceptibility to influent toxicity resulting from discharges of inhibitory compounds or process-related wastestreams. It is, therefore, desirable to quantify AS system performance deterioration resulting from such discharges. Although several researchers have compiled listings of IC50 values for several organic chemicals to individual groups of microorganisms (Blum and Speece, 1990; Tang et al., 1992), it is preferable to evaluate a compound’s effect to a particular microbial consortium (e.g., AS community). Furthermore, the ability to obtain IC50 values for specific biokinetic parameters such as µ max and K s would be beneficial.