Approaching a closer surrogate for the biologically effective dose with subcellular partitioning-based toxicokinetic models

A general concept in risk assessment is that a threshold of exposure exists above which adverse effects are initiated. Toxicity is related to the target-site concentration or the biologically active dose. Although it is often a huge challenge to measure the specific dose metric of metal toxicity, significant progress has been obtained to approach closer to the target-site concentration. Such developments are reviewed in the present study. In addition, a general framework to simulate the subcellular metal partitioning, which is supposed to account for the internal metal sequestration, is developed and applied to various metals. The framework allows for delineating mechanisms of internal metal sequestration. Moreover, the specificity in these mechanisms, which varies among metals, species, and exposure conditions, might explain the complicated relationship between the internal concentration and metal toxicity. Attention should be paid to the data requirements as the high number of unknown parameters might be accompanied by potential uncertainties. In addition, future efforts should focus on linking the concentration of metals in sensitive fractions and toxicological effects. </p

Female reproductive cycle stages (AB, C1, C2, D1 and D2, according to Geffard et al. [25]) and sampling periods for biological response measurements in males and females during the food starvation experiment.

<p>Female reproductive cycle stages (AB, C1, C2, D1 and D2, according to Geffard et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125154#pone.0125154.ref025" target="_blank">25</a>]) and sampling periods for biological response measurements in males and females during the food starvation experiment.</p

Energy reserve levels during each stage of the reproductive cycle in females and males (mean ± SD, n = 6).

<p>A: Glycogen (mg/g wet weight), B: Lipids (mg/g wet weight), C: Total proteins (mg BSA/g wet weight), D: Available energy (mg/mg wet weight). Histograms with the same letters are not statistically different (Kruskal-Wallis test: <i>p</i><0.05).</p

Amylase (A, μg maltose/mg BSA/min) and trypsin (B, μg p-Na/mg BSA/min) activity levels in <i>Gammarus fossarum</i> exposed to 3 levels of food starvation (control: fed 7 days a week; 2/7: fed 2 days a week; 1/7: fed 1 day a week) after 11 and 43 days (means ± SD, n = 6).

<p>For each date and gender, bars with the same letter were not significantly different (p < 0.05). The hash (#) symbol points to significant changes between the two sampling times for each diet condition (p < 0.05).</p

Available energy (mJ/mg wet weight) in <i>Gammarus fossarum</i> females and males exposed to three levels of diet stress (control, fed 7 days per week; fed 2 days per week; and fed 1 day per week) after 11 and 23 days (mean ± SD, n = 6).

<p>Stars indicate significant differences between the starved organisms and the fed control organisms (Mann-Whitney test: <i>p</i><0.05). The hash (#) symbol indicates a significant difference between the two sampling time points for each diet condition tested (Mann-Whitney test: <i>p</i><0.05).</p

Digestive enzymes activities in <i>Gammarus fossarum</i> females (♀) and males (♂) exposed to three levels of diet stress (control, fed 7 days per week; fed 2 days per week; and fed 1 day per week) after 11 and 23 days (mean ± SD, n = 6).

<p>A: Amylase (mg maltose/mg BSA/min), B: Trypsin (µg p-Na/mg BSA/min). Stars indicate significant differences between the starved organisms and the fed control organisms (Mann-Whitney test: <i>p</i><0.05). The hash (#) symbol indicates a significant difference between the two sampling time points for each diet condition tested (Mann-Whitney test: <i>p</i><0.05).</p

Available energy (mJ/mg wet weight) in <i>Gammarus fossarum</i> exposed to 3 levels of food starvation (controls: fed 7 days a week; 2/7: fed 2 days a week; 1/7: fed 1 day a week) after 11 and 43 days (means ± SD, n = 6).

<p>For each date and gender, bars with the same letter were not significantly different (p < 0.05). The hash (#) symbol points significant changes between the two sampling times in each diet condition (p < 0.05).</p

Digestive enzyme activities during each stage of the reproductive cycle in females and males (mean ± SD, n = 6).

<p>A: Amylase (mg maltose/mg BSA/min), B: Cellulase (mg maltose/mg BSA/min), C: Trypsin (µg p-Na/mg BSA/min). Histograms with the same letters are not statistically different (Kruskal-Wallis test: <i>p</i><0.05).</p

Mean embryo numbers in <i>Gammarus fossarum</i> females exposed to 3 levels of diet starvation (control: fed 7 days a week; 2/7: fed 2 days a week; 1/7: fed 1 day a week) after 43 days (means ± SD, n = 6).

<p>Bars with the same letter were not significantly different (p < 0.05).</p

Intensities of internal standard metabolites (normalized to the maximal response) analyzed by LC(RPLC)-(ESI+)- or LC(HILIC)-(ESI-)- HRMS after extraction of 50 mg of brain with 2.5 mL of different proportions of MeOH/H₂O /heptane.

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