Analysis of ToxCast results for alkylphenols demonstrate effects from multiple modes of action and inform on their hazard assessment
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Owner/Developer: Society of Environmnetal Toxicology and Chemistry (SETAC)
United States of America
10 November 2014
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ToxCast is a project of the US EPA to evaluate the biological activity of chemicals and to assist with prioritization of future testing.¬†Both 4-tert-octylphenol (OP) and 4-nonylphenol (branched) (NP) were evaluated in ToxCast Phase II and in an endocrine-related subset of the ToxCast Phase II assays. OP and NP were active in 21% and 20% of these in vitro assays, respectively, which is a relatively active signature based on the highest reported activity of 31% among the entire suite of chemicals tested. The relatively high incidence of "hits" for NP and OP is due in part to multiple in vitro assays evaluating estrogen receptor (ER) activity; NP and OP are known to have weak estrogen activity (average 3,000 - 5,000-fold weaker than estradiol in ToxCast Phase II). AC50 responses for NP and OP in ER assays were detected at concentrations ranging from 0.2-13.6 ¬µM. Androgen receptor (AR) binding was noted at higher concentrations with AC50 values ranging from 7-15 ¬µM. Additional responses, apart from indications of endocrine activity, were noted for both NP and OP at a similar dose range (AC50: 2.47-15 ¬µM). Responses within this dose range included: mitochondrial toxicity, P450 monooxygenase activity, retinoid X receptor signaling, antioxidant responses, and induction of transcription factors related to metal homeostasis. Several of these molecular activities are considered sentinel responses for non organ specific activity; however, the mitochondrial toxicity from NP and OP exposures are of particular interest for several reasons. The AC50 values for NP and OP mitochondrial toxicity occurred at a relatively low dose range (2-3 ¬µM), and were within an order of magnitude of the AC50 for rotenone, a known mitochondrial toxicant. Mitochondrial depolarization has been previously reported for NP in the literature and is in agreement with ToxCast assay outputs; however, this mode of action has received little attention, despite the severity of potential outcomes. Notably, regressions comparing mitochondrial toxicity and acute aquatic toxicity indicate a good correlation, particularly for compounds with mitochondrial toxicity below 10 ¬µM. The ToxCast dataset for NP and OP indicates that multiple biological activities are operational within the same concentration ranges, and mitochondrial toxicity may explain, and even drive, the high acute aquatic in vivo toxicity of NP and OP.
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