Citation:

Droge, S., J. Armitage, J. Arnot, P. Fitzsimmons, AND J. Nichols. Biotransformation Potential of Cationic Surfactants in Fish Assessed with Rainbow Trout Liver S9 Fractions. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 40(11):3123-3136, (2021). https://doi.org/10.1002/etc.5189

Impact/Purpose:

Ionizable organic chemicals are used in a wide array of consumer products and industrial processes. To date, however, it has been difficult to assess their potential for bioaccumulation because they do not partition simply to tissue lipids. Instead, these chemicals tend to partition to polar phospholipids associated with cell membranes. To address this behavior, researchers have adapted existing bioaccumulation models so that they reflect this membrane partitioning behavior. An important input to these models is the rate of biotransformation, as this activity may substantially reduce the extent of bioaccumulation. Presently, however, little is known about the biotransformation of ionizable chemicals in fish. The goal of this study was to measure the in vitro hepatic biotransformation of selected linear chain cationic surfactants in trout liver S9 fractions. These findings were then related to measured cell membrane:water partition coefficients for the same chemicals to assess their significance in the context of bioaccumulation assessment. The results showed that biotransformation is strongly influenced by the length of the linear alkyl chain and the degree of methylation of the cationic amine head group. Based on these results, it is suggested that biotransformation may substantially reduce the potential for bioaccumulation of many cationic surfactants. In some cases, however, this activity may result in production of metabolic products which are themselves bioaccumulative, complicating such assessments. These findings substantially increase current knowledge of cationic surfactants in fish and will be of interest to EPA risk assessors conducting chemical evaluations under amended TSCA. Moreover, the described methods illustrate the value of in vitro bioaccumulation data for screening-level bioaccumulation assessments. Methods of the type can be used to prioritize chemicals for in vivo testing and/or support the identification of lower risk chemical alternatives. As such, this study supports EPA’s stated goals of incorporating new assessment methodologies (NAMs) into chemical risk assessment procedures and reducing the need for live animal testing.

Description:

Biotransformation may substantially reduce the extent to which organic environmental contaminants accumulate in fish. Presently, however, relatively little is known regarding the biotransformation of ionized chemicals, including cationic surfactants, in aquatic organisms. To address this deficiency, a rainbow trout liver S9 substrate depletion assay (RT¿S9) was used to measure in vitro intrinsic clearance rates (CLint; mlmin–1 g liver–1) for 22 cationic surfactants that differ with respect to alkyl chain length and degree of methylation on the charged nitrogen atom. None of the quaternary N,N,N¿trimethylalkylammonium compounds exhibited significant clearance. Rapid clearance was observed for N,N¿dimethylalkylamines, and slower rates of clearance were measured for N¿methylalkylamine analogs. Clearance rates for primary alkylamines were generally close to or below detectable levels. For the N¿methylalkylamines and N,N¿dimethylalkylamines, the highest CLint values were measured for C10–C12 homologs; substantially lower clearance rates were observed for homologs containing shorter or longer carbon chains. Based on its cofactor dependency, biotransformation of C12–N,N¿dimethylamine appears to involve one or more cytochrome P450–dependent reaction pathways, and sulfonation. On a molar basis, N¿demethylation metabolites accounted for up to 25% of the N,N¿dimethylalkylamines removed during the 2¿h assay, and up to 55% of the removed N¿methylalkylamines. These N¿demethylation products possess greater metabolic stability in the RT¿S9 assay than the parent structures from which they derive and may contribute to the overall risk of ionizable alkylamines. The results of these studies provide a set of consistently determined CLint values that may be extrapolated to whole trout to inform in silico bioaccumulation assessments.

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