Evaluation of the reproductive effects of tamoxifen citrate in partial and full life‐cycle studies using fathead minnows (Pimephales Promelas)

Abstract

Laboratory studies were conducted to investigate potential adverse effects on development, growth, reproduction and biomarker responses (vitellogenin [VTG] and gonad histology) in fathead minnows (Pimephales promelas) exposed to tamoxifen citrate. Based on the results of a partial life cycle study (nominal [mean measured] concentrations ranged from 0.18 [0.11] to 18 [15.74] microg/L), a 284-d fish full life-cycle (FFLC) flow-through study was conducted using newly fertilized embryos (<24 h postfertilization) exposed to nominal (mean measured) concentrations of 14C-tamoxifen citrate that ranged from 0.01 (0.007) to 5.12 (4.08) microg/L. Triethylene glycol (2.0 microl/L) was used as a solvent carrier, with 17beta-estradiol (E2) as a positive control (nominal 0.1 microg/L). Among the biomarkers measured, significant effects on VTG and gonad histology were observed, although these results required care in their interpretation. Among important population-relevant endpoints, no effects on reproduction were observed at nominal concentrations < or = 5.12 microg/L. Effects on growth (length and weight) were observed in some treatments; however, some of these showed irregular concentration-response relationships, which made interpretation uncertain, or were deemed transient in nature (e.g., reduction in growth of F1 28-d posthatch larval fish at nominal concentrations of 0.08, 0.64, and 5.12 microg/L) and judged not to be biologically significant. Interpretation of results from fish chronic studies is challenging and frequently calls for scientific judgement about statistical and biological significance and what constitutes an adverse effect. Using the principles used in mammalian toxicology studies, data from partial and FFLC studies were evaluated from both statistical and biological perspectives in order to determine no-observed-adverse effect concentrations (expressed as (adverse)NOEC) for use in environmental risk assessment. Careful consideration of both biological and statistical outcomes from these studies suggested overall (adverse)NOEC concentration and lowest-observed-effect concentration ((adverse)LOEC) values for tamoxifen citrate of 5.12 microg/L and 5.6 microg/L, respectively.

Estrogenic activity of tropical fish food can alter baseline vitellogenin concentrations in male fathead minnow (Pimephales promelas)

“…Other researchers have also reported large individual variation in the VTG concentration of control fish [38] and in the VTG response following oestrogen exposure [39]. This variation in plasma VTG concentration between fish seems unlikely to be due to the physiological status of the fish, as all fish within one tank were of the same age and kept under identical conditions.…”

Early Life-Stage Toxicity of Eight Pharmaceuticals to the Fathead Minnow, Pimephales promelas

“…Winter et al (2008) reported a 28-day growth NOEC and LOEC for the b 1 -adrenergic receptor antagonist atenolol to be 3.2 and 10 mg/L, respectively. However, decreases in growth during this 28-day study may be transient and not representative of impacts during an entire fish full life cycle (Williams et al 2007).…”

Population‐level consequences for wild fish exposed to sublethal concentrations of chemicals – a critical review

“…Similarly, the anticancer drug tamoxifen citrate interferes with oestrogen signalling, yet a full life cycle (~9 month) exposure at concentrations higher than those typically found in the environment (0.18 μ g L −1 ) did not affect reproduction of fathead minnow (Williams et al . ). Often chemical exposures conducted in the shorter term find effects at concentrations higher than those found in the environment with the suggestion that such exposure regimes are predictive of the effects of longer exposures to lower (environmentally relevant) concentrations.…”