CDER researchers have recently assessed the potential of human pharmaceuticals, after bodily excretion and entry into wastewater, to affect the endocrine (hormonal) physiology of aquatic wildlife, an important environmental problem that is not easily studied in the wild. Drawing from open-source toxicology data and computational resources, the researchers predict that among 175 pharmaceuticals that can affect estrogen pathways, several manifest properties that warrant further investigation into their pharmacological activity in fish. The researchers’ methodology 1 should be of interest to environmental scientists as well as drug developers more broadly who must prioritize concerns surrounding the potential physiological effects of wastewater pharmaceuticals on wildlife.

Background

Human pharmaceuticals that find their way into wastewater—primarily through bodily excretion after patient use—can travel into streams, rivers, bays, and other aquatic environments. Fish and other aquatic vertebrates are known to be susceptible to wastewater contaminants, generated from a variety of industrial sources, that affect hormone pathways—and particularly those pathways regulated by the female hormone estrogen. The contribution of human pharmaceuticals to the disruption of estrogen activity in the wild has been difficult to assess, but we can reason that pharmaceuticals developed to modulate estrogen activity in humans should be prioritized for further investigation, especially if it can be determined that they reach significant levels in aquatic ecosystems.

The research undertaken by CDER scientists 1 supports statutory responsibilities that the FDA bears in reviewing new drug products for market approval. The agency is mandated to consider the potential environmental impact of product approval, particularly if drug concentrations ensuing from new product approvals are estimated to reach an established threshold—typically, 1 part per billion at the point of entry into the aquatic environment. Estrogen-disruptive drugs can in fact be pharmacologically active at or below this threshold level, 2 because estrogen receptors have evolved in animal species to bind to estrogen (and estrogen-mimicking drugs) with very high affinity. In addition, the fat-soluble nature of estrogen-like chemicals may promote their accumulation above this threshold level in animal tissues.

Study Methodology

To begin their investigation, the CDER scientists took advantage of a federally managed toxicological resource (Tox21) that includes data for some 1000 pharmaceuticals marketed in 2016. From these data they were able to identify over 150 pharmaceuticals that showed the most consistent evidence  of interacting with the human estrogen receptor. To extend their assessment even further, the researchers used a collaborative computational resource (known as CERAPP) to estimate the potencies of an additional 170 pharmaceuticals not represented by the open-source data. Based on estimates of how chemical structural variations might affect chemical behavior, computational analyses predicted that over a dozen of the additional 170 pharmaceuticals could possibly interact pharmacologically with the human estrogen receptor. The combined total of 175 pharmaceuticals identified through these methods included drugs indicated within a clinical endocrine context (such as reproductive hormone modulators) as well as many that had not been clinically studied to treat endocrine conditions (such as anti-infective agents).

It is crucial to understand that scientists generally measure the potential for any given chemical to interact pharmacologically with biological receptors (such as the human estrogen receptor) in terms of the concentration necessary to achieve a standard level of effect—generally, the standard level is 50% of maximal pharmacological effect (as measured, for instance, in an in vitro assay). By establishing whether a low concentration will be sufficient for a pharmaceutical to achieve the 50%-maximal effect, or whether a high concentration is required, pharmaceuticals can be ranked according to “potency.” With potency values thus in hand, the CDER researchers calculated whether the concentrations of wastewater pharmaceuticals accumulating in fish tissues would be comparable to concentrations necessary to elicit the standard “50%-level” of maximal pharmacological effect (i.e., comparable to potency values).

To calculate drug concentrations at the point of entry into local aquatic environments, the researchers obtained commercial data of sales volumes (pertaining to 2016) and then assumed the entire volume to be utilized by patients over the course of the year and excreted (unmetabolized) into the annual US volume of wastewater discharged (without treatment or remediation) from sewage treatment plants. Other assumptions included no drug dilution in surface waters and no environmental drug metabolism, degradation, or adsorption. Based on these assumptions (and using a published model pertaining to fish), the researchers calculated the concentration that each of the 175 pharmaceuticals would reach in fish tissue. The equations used for these calculations also took factors into consideration such as the fat-solubility of each pharmaceutical, which directly predicts the tendency of the pharmaceutical to distribute from the aqueous environment into the relatively fatty constitution of fish tissue.

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Key Findings

Of the 175 drugs predicted to have pharmacological activity at estrogen receptors, approximately one-third were identified as estrogen agonists and two-thirds were identified as estrogen antagonists. Two FDA-approved estrogen agonists—17α-ethinylestradiol and 17β-estradiol—showed the potential to reach drug concentrations in fish tissue that exceed concentrations estimated to activate estrogen receptors in fish.  17α-ethinylestradiol is a widely used oral contraceptive. 17β-estradiol is used to treat some menopausal symptoms and ovary failure or removal. Similarly, two FDA-approved antagonists—raloxifene, a drug used in the treatment and prevention of osteoporosis, and bazedoxifene, a medication used to help prevent osteoporosis—showed the potential to reach drug concentrations in fish tissue that exceed potency levels. 

Implications

The analytic power of modern technologies allows for the detection of very low levels of many pharmaceuticals that enter aquatic environments, and in many instances, we can conclude that the levels, though detectable, are too low to affect human or wildlife biology. The CDER research discussed above explores some of the fundamental issues that environmental scientists must confront when highly potent drug products are widely used. The research furthermore exemplifies the challenges that the FDA and drug developers face when assessing the potential environmental impact of new drug applications, and it underscores the importance of developing new tools that can inform appropriate regulatory decisions.

The Spotlight series presents generalized perspectives on ongoing research- and science-based activities within CDER. Spotlight articles should not be construed to represent FDA’s views or policies.

• 1. a. b. Pinto CL, Bloom, RA, Laurenson, JP. An approach for using in vitro and in silico data to identify pharmaceuticals with potential (anti-)estrogenic activity in aquatic vertebrates at environmentally relevant concentrations. Environ Toxicol Chem;2019 (Doi: 10.1002/etc.4533).
• 2. Laurenson JP, Bloom RA, Page S, Sadrieh N. Ethinylestradiol and other human pharmaceutical estrogens in the aquatic environment: a review of recent risk assessment data. AAPS J 2014;16:299-310.