Model predictions of moderate iodide deficiency assuming a maternal dietary iodide intake of 150 μg/d.

<p>Costeira et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref063" target="_blank">63</a>] measured iodide in breast milk and maternal and infant urine (median and 25 and 75% interquartiles) and later reported maternal serum thyroid hormones [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref064" target="_blank">64</a>]. <b>(A)</b> Maternal urinary iodide concentrations. <b>(B)</b> Breast milk iodide concentrations. <b>(C)</b> Nursing infant urinary iodide concentrations. <b>(D)</b> Maternal serum thyroid hormone concentrations.</p

Model calibration (Fig 5A) and model evaluation (Fig 5B) of infant serum thyroid hormones.

<p><b>(A)</b> Model calibrated predictions of nursing infant serum thyroid hormones, assuming a maternal dietary iodide intake of 250 μg/d and using reference intervals (2.5, 50, and 97.5%) for infant serum T4, fT4, and T3 concentrations [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref023" target="_blank">23</a>]. Infant serum thyroid hormone concentration predictions for a maternal intake of 400 μg/d were identical to a maternal intake of 250 μg/d of iodide. <b>(B)</b> Measured and simulated infant serum T4, fT4, and T3 concentrations assuming a maternal intake of 250 or 400 μg/d of iodide. Verberg et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref060" target="_blank">60</a>] reported reference intervals (2.5, 50, and 97.5%) for fT4 only in infants from Germany on 7, 14, 21, 28 and 90 days of age (▲). Elmlinger et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref059" target="_blank">59</a>] reported reference intervals (2.5, 50, and 97.5%) for 8–15 days of age for infants from Germany and are shown as 15 days of age (■). Franklin et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref061" target="_blank">61</a>] from New Zealand reported mean ±SD infant serum T4, fT4, and T3 concentrations on days 5 (n = 40), 10 (n = 35), and 15 (n = 33) (■). Williams et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref062" target="_blank">62</a>] from the United Kingdom reported mean ±SD infant serum T4, fT4, and T3 concentrations on days 7 (n = 163), 14 (n = 6), and 28 (n = 9).</p

Local sensitivity analysis (SA) for serum fT4 in euthyroid and moderate iodide deficient lactating mother and nursing infant.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.s001" target="_blank">S1</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.s003" target="_blank">S3</a> Tables for model parameter definitions. SA >0.1 and <0.5 ▽, SA>0.5 and <1.1 ▲.</p

Model evaluation for iodide assuming maternal dietary iodide intake of 250 and 400 μg/d.

<p><b>(A)</b> Measured concentrations (μg/L) of iodide in maternal urine (■) from individual lactating women [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref024" target="_blank">24</a>] in the United States (250 μg/d, lower line and 400 μg/d, upper line). <b>(B)</b> Measured concentrations (μg/L) of urinary iodide from individual nursing infants (■) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref058" target="_blank">58</a>] over 90 days postpartum and another 43 nursing infants [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref018" target="_blank">18</a>] shown as an average age of 63 days (■).</p

Model predictions of moderate iodide deficiency assuming a dietary iodide intake of 50 μg/d.

<p>Mulrine et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref069" target="_blank">69</a>] measured iodide in breast milk and maternal and infant urine of an iodide deficient population from New Zealand (mean ±SD). <b>(A)</b> Maternal urine. <b>(B)</b> Breast milk. <b>(C)</b> Infant urine.</p

Measured maternal serum T4, fT4, and T3 concentrations (nmol/L) in 16 lactating women (■) residing in the United States [24].

<p>Solid lines represent model calibrated predictions for serum thyroid hormones assuming a maternal iodide intake of 250 μg/d. Simulations performed for maternal dietary intake of 400 μg/d resulted in very slight increases of serum thyroid hormones.</p

Model calibration predictions are for maternal intake of 250 μg/d iodide, divided equally among three meals per day and an infant nursing eight times during the day.

<p><b>(A)</b> Measured concentrations (μg/L) of iodide in breast milk (●) from individual lactating women [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref016" target="_blank">16</a>] in Boston, MA USA and reported mean and median values from lactating women (Day 60, ■) representing a wide range of postpartum days [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref035" target="_blank">35</a>]. A larger maternal dose of 400 μg/d of iodide is shown representing possible ingestion of supplemental iodine (e.g., vitamins). The daily peak and trough shape of the breast milk concentrations represent the mother’s schedule for daily dietary intake of iodide over a 12 hr period. <b>(B)</b> Measured concentrations (μg/L) of maternal urinary iodide (■) from individual lactating women [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref016" target="_blank">16</a>] in the Boston, MA USA. Model calibrated prediction of urinary iodide concentration for maternal dietary iodide intake of 250 μg/d with accompanying prediction for 400 μg/d maternal dietary iodide. <b>(C)</b> Measured concentrations (μg/L) of iodide in infant urine (■) from individual nursing infants [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149300#pone.0149300.ref016" target="_blank">16</a>] in Boston, MA, USA. Model calibrated prediction of nursing infant urinary iodide concentration for maternal intake of 250 μg/d of iodide and accompanying prediction for 400 μg/d maternal dietary iodide.</p

Use of novel inhalation kinetic studies to refine physiologically-based pharmacokinetic models for ethanol in non-pregnant and pregnant rats

<div><p></p><p>Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these <i>in vivo</i> studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios.</p></div