There is increasing pressure to develop
alternative ecotoxicological
risk assessment approaches that do not rely on expensive, time-consuming,
and ethically questionable live animal testing. This study aimed to
develop a comprehensive early life stage toxicity pathway model for
the exposure of fish to estrogenic chemicals that is rooted in mechanistic
toxicology. Embryo-larval fathead minnows (FHM; Pimephales
promelas) were exposed to graded concentrations of 17α-ethinylestradiol
(water control, 0.01% DMSO, 4, 20, and 100 ng/L) for 32 days. Fish
were assessed for transcriptomic and proteomic responses at 4 days
post-hatch (dph), and for histological and apical end points at 28
dph. Molecular analyses revealed core responses that were indicative
of observed apical outcomes, including biological processes resulting
in overproduction of vitellogenin and impairment of visual development.
Histological observations indicated accumulation of proteinaceous
fluid in liver and kidney tissues, energy depletion, and delayed or
suppressed gonad development. Additionally, fish in the 100 ng/L treatment
group were smaller than controls. Integration of omics data improved
the interpretation of perturbations in early life stage FHM, providing
evidence of conservation of toxicity pathways across levels of biological
organization. Overall, the mechanism-based embryo-larval FHM model
showed promise as a replacement for standard adult live animal tests.
Standardized laboratory tests with a limited number of model species are a key component of chemical risk assessments. These surrogate species cannot represent the entire diversity of native species, but there are practical and ethical objections against testing chemicals in a large variety of species. In previous research, we have developed a multispecies toxicokinetic model to extrapolate chemical bioconcentration across species by combining single-species physiologically based toxicokinetic (PBTK) models. This "top-down" approach was limited, however, by the availability of fully parameterized single-species models. Here, we present a "bottom-up" multispecies PBTK model based on available data from 69 freshwater fishes found in Canada. Monte Carlo-like simulations were performed using statistical distributions of model parameters derived from these data to predict steady-state bioconcentration factors (BCFs) for a set of wellstudied chemicals. The distributions of predicted BCFs for 1,4-dichlorobenzene and dichlorodiphenyltrichloroethane largely overlapped those of empirical data, although a tendency existed toward overestimation of measured values. When expressed as means, predicted BCFs for 26 of 34 chemicals (82%) deviated by less than 10-fold from measured data, indicating an accuracy similar to that of previously published single-species models. This new model potentially enables more environmentally relevant predictions of bioconcentration in support of chemical risk assessments.
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