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Metformin is currently thought to be the highest drug by weight released into the aquatic environment, as a direct result of its widespread use in the treatment of a number of human health disorders. The removal of metformin from wastewaters is directly related to the formation of guanylurea (metformin's only known persistent degradation product), which is generally present at higher concentrations in surface waters than the parent compound. With metformin use rising steadily, it is important to characterize the effects of guanylurea on nontarget aquatic organisms. We recently demonstrated the effects of developmental exposure to environmentally relevant concentrations of metformin on the growth of early life stage (ELS) medaka as well as effects on the body weight of adult male fish following full‐life cycle exposures. In the present study, we describe similar effects of guanylurea exposure on these endpoints and life stages. Guanylurea led to effects on growth in a 28‐d ELS assessment that were similar to those of metformin; however, these effects occurred at concentrations in the ng/L range compared with the μg/L range for metformin. A possible sex‐dependent association with body weight changes was also observed in adults following a 165‐d full‐life cycle exposure to guanylurea alone or in a mixture with metformin. To our knowledge, the present is the first study to report the toxicity of guanylurea to nontarget aquatic organisms. Environ Toxicol Chem 2019;00:1–6. © 2019 SETAC

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Adult fish health surveys are part of Canada's Environmental Effects Monitoring (EEM) programs for both metal mining and pulp and paper sectors under Canada's Fisheries Act. Similar protocols are used within the Joint Oil Sands Monitoring (JOSM) plan to develop baseline health for fish populations within the lower Athabasca River, Fort McMurray. Results reported here focus on the health of white sucker at five sites including upstream reference sites outside of the oil sands formation, a site within the formation upstream of oil sands industrial activity, and sites within the formation downstream of oil sands development. The objective here was to provide baseline data addressing questions regarding fish health based on site location. Additionally, an assessment of reproductive function (circulating steroid levels, secondary sex characteristics, gonad size and total fecundity) was conducted. To accumulate a strong baseline of fish health at the five sites, fish were collected for three consecutive years (2011)(2012)(2013). Consistent changes in the health of white suckers within the formation itself were demonstrated with increased change documented downstream of oil sands development (2011)(2012). Fish within the formation and downstream of oil sands development had increased condition factor and increased levels of internal fat stores relative to fish upstream of the oil sands area, changes confirmed in our 2012 collections. Ethoxyresorufin-O-deethylase activity in the liver was induced in fish within the formation with some increases downstream of oil sands development indicating increased exposure to inducing compounds, such as polycyclic aromatic compounds. Reproductive endpoints were not consistently altered in fish collected within the formation or downstream of oil sands development. Follow-up studies in 2013 identified potential improvements in fish health both within the formation and downstream of oil sands development. With a strong baseline of fish health presented here, the program will use critical effects sizes to monitor future fish health.

Jackfish Bay is an isolated bay on the north shore of Lake Superior, Canada that has received effluent from a large bleached-kraft pulp mill since the 1940s. Studies conducted in the late 1980s found evidence of reductions in sex steroid hormone levels in multiple fish species living in the Bay, and increased growth, condition and relative liver weights, with a reduction in internal fat storage, reduced gonadal sizes, delayed sexual maturation, and altered levels of circulating sex steroid hormones in white sucker (Catostomus commersonii). These early studies provided some of the first pieces of evidence of endocrine disruption in wild animals. Studies on white sucker have continued at Jackfish Bay, monitoring fish health after the installation of secondary waste treatment (1989), changes in the pulp bleaching process (1990s), during facility maintenance shutdowns and during a series of facility closures associated with changing ownership (2000s), and were carried through to 2019 resulting in a 30-year study of fish health impacts, endocrine disruption, chemical exposure, and ecosystem recovery. The objective of the present study was to summarize and understand more than 75 physiological, endocrine, chemical and whole organism endpoints that have been studied providing important context for the complexity of endocrine responses, species differences, and challenges with extrapolation. Differences in body size, liver size, gonad size and condition persist, although changes in liver and gonad indices are much smaller than in the early years. Population modeling of the initial reproductive alterations predicted a 30% reduction in the population size, however with improvements over the last couple of decades those population impacts improved considerably. Reflection on these 30 years of detailed studies, on environmental conditions, physiological, and whole organism endpoints, gives insight into the complexity of endocrine responses to environmental change and mitigation.

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Metformin is routinely detected in aquatic ecosystems because of its widespread use as a treatment for Type 2 diabetes. Laboratory studies have shown that exposure to environmentally relevant concentrations of metformin can alter metabolic pathways and impact the growth of early life stage (ELS) fish; however, it is unknown whether these effects occur in wild populations. Herein, we evaluate whether findings from laboratory studies are representative and describe the relative sensitivities of both populations. Duplicate exposures (0, 5, or 50 μg/L metformin) were conducted using wild- and lab-spawned fathead minnow (Pimephales promelas) embryos. Apart from the water source, exposure conditions remained constant. Wild embryos were exposed to previously dosed lake water to account for changes in bioavailability, while reconstituted freshwater was used for the laboratory study. Developmental metformin exposure differentially impacted the growth and morphology of both cohorts, with energy dyshomeostasis and visual effects indicated. The fitness of wild-spawned larvae was impacted to a greater extent relative to lab-spawned fish. Moreover, baseline data reveal important morphological differences between wild- and lab-spawned ELS fatheads that may diminish representativeness of lab studies. Findings also confirm the bioavailability of metformin in naturally occurring systems and suggest current exposure scenarios may be sufficient to negatively impact developing fish.