PBPK models in risk assessment—A focus on chloroprene

Mathematical models are increasingly being used to simulate events in the exposure-response continuum, and to support quantitative predictions of risks to human health. Physiologically based pharmacokinetic (PBPK) models address that portion of the continuum from an external chemical exposure to an internal dose at a target site. Essential data needed to develop a PBPK model include values of key physiological parameters (e.g., tissue volumes, blood flow rates) and chemical specific parameters (rate of chemical absorption, distribution, metabolism, and elimination) for the species of interest. PBPK models are commonly used to: (1) predict concentrations of an internal dose over time at a target site following external exposure via different routes and/or durations; (2) predict human internal concentration at a target site based on animal data by accounting for toxicokinetic and physiological differences; and (3) estimate variability in the internal dose within a human population resulting from differences in individual pharmacokinetics. Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, P.M. Hinderliter, Kinetic modeling of beta-chloroprene metabolism. I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans, Toxicol. Sci. 79 (1) (2004) 18–27; M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28–37] developed a PBPK model for chloroprene (2-chloro-1,3-butadiene; CD) that simulates chloroprene disposition in rats, mice, hamsters, or humans following an inhalation exposure. Values for the CD-PBPK model metabolic parameters were obtained from in vitro studies, and model simulations compared to data from in vivo gas uptake studies in rats, hamsters, and mice. The model estimate for total amount of metabolite in lung correlated better with rodent tumor incidence than did the external dose. Based on this PBPK model analytical approach, Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28–37; M.W. Himmelstein, R. Leonard, R. Valentine, Kinetic modeling of β-chloroprene metabolism: default and physiologically-based modeling approaches for cancer dose response, in: IISRP Symposium on Evaluation of Butadiene&Chloroprene Health Effects, September 21, 2005, TBD—reference in this proceedings issue of Chemical–Biological Interactions] propose that observed species differences in the lung tumor dose–response result from differences in CD metabolic rates. The CD-PBPK model has not yet been submitted to EPA for use in developing the IRIS assessment for chloroprene, but is sufficiently developed to be considered. The process that EPA uses to evaluate PBPK models is discussed, as well as potential applications for the CD-PBPK model in an IRIS assessment

The Military Divorce: An Overview

Your Court Review Editors asked Mark Sullivan, nationally known expert on the military divorce, to contribute an article to this journal. Mark recruited colleagues Joe DeWoskin of Kansas City, KS, a retired Army officer, and Kansas District Court Judge Dan Wiley, who presides over domestic relations cases, to assist him. What follows is their round table discussion of the key issues in a military divorce

Comment on `The bronze chime bells of the Marquis of Zeng: Babylonian biophysics in Ancient China' by E. G. McClain

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26558/1/0000097.pd

Influence of heat exchange on foraging behavior of Zonotrichia spp.

The heat exchange of individuals in a foraging mixed population of Zonotrichia leucophrys and Zonotrichia atricapilla in western Oregon is analyzed with respect to the direction of stance and feeding location. Values for heat gain or loss in the field were generated from a model that estimates the equivalent black-body temperature "Te" and from other researchers' laboratory findings for the effect of air temperature, solar radiation, and wind speed on metabolism. Observations were recorded at 1 min intervals throughout the daylight hours with samples at weekly intervals from January to March. A summation of 1,500 observations on direction of stance subjected to a X² test for randomness supports the hypothesis that spatial orientation of individuals is not random. The largest percentage of time for all locations was spent facing south. All wind speeds over 1.0 m.s⁻¹ recorded were from the south yet X² analysis indicated a large difference in stance direction between sites. Also, maximum differences in Te for different stances with respect to the wind direction were only 1°C because of the low values for incoming short wave radiation. More important factors than heat exchange influencing the direction of stance were feeding patterns, social interactions, food availability and the location of the hedge in the area used for cover. Placing a trace line of food perpendicular to the most frequently observed direction of stance caused a significant change in percentage of time spent facing each direction for that location. Individuals were facing the same direction as the majority of their neighbors within a 2 m radius for 68% of the total number of recorded observations for a nonrandom flock orientation. Heat production was affected by the large differences in wind speed among the microhabitats available at the site. Heavy use of an open area for feeding resulted in as much as an 8% increase in daily existence energy (DEE). The intense feeding at this site suggests that possibly the increased caloric intake per unit time at the open site compensates for the greater heat loss and increased susceptibility, to predation. A second possibility relates the circadian feeding pattern to the need for a high rate of caloric intake early in the morning and late in the evening

Multiscale Modeling of Coupled Oscillators with Applications to the Mammalian Circadian Clock.

Many biological systems function based on two essential motifs: network interactions between cells and integration across timescales. Both of these are ubiquitous in coupled biological oscillators, such as in heart and brain tissues, which require communication and coordination between cellular oscillators across timescales in order to generate tissue-level rhythms. Mathematical modeling can provide invaluable insight in order to explain this complexity. In this dissertation, we develop a detailed model of the suprachiasmatic nucleus (SCN), the central circadian (daily) pacemaker in mammals, and numerical methods for simulating it. This new multiscale model resolves the intracellular molecular events that generate circadian rhythms as well as the cellular electrical activity important for relaying timing information to the rest of the brain. The model not only reproduces experimental findings, but also makes several new predictions about the role of intercellular signaling in the SCN, some of which we experimentally validate. First, the model explains how intercellular signaling in the SCN increases robustness of tissue-level rhythms. Second, it proposes a new mechanism by which the SCN can differentially regulate intra-SCN synchrony and SCN output signals through a single neurotransmitter signaling on disparate timescales. Third, it shows how the response polarity of cells to this neurotransmitter changes depending on the particular daylength an animal has been entrained to. By modulating the response and the intrinsic period of subsets of SCN neurons, phase-locked populations of cells are used to encode the daylength of the entraining signal. Finally, the model predicts that a kinase can be used to modulate the firing rate of cells to control SCN output. On the whole, the model answers many open questions about signaling within the SCN and control of SCN output to the rest of the brain. It presents a holistic picture of the SCN as a robustly oscillating network with its synchrony and output signals modulated on two different timescales in response to the entraining light signal. The computational framework developed herein with parallelization using GPUs provides an important tool for circadian research, and a model computational system for the many multiscale projects currently studying brain function.PhDApplied and Interdisciplinary MathematicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/113644/1/dewoskin_1.pd

From Survival to Success: The Journey of Corporate Transformation at Haier

http://deepblue.lib.umich.edu/bitstream/2027.42/39594/3/wp207.pd

Network Dynamics Mediate Circadian Clock Plasticity

A circadian clock governs most aspects of mammalian behavior. Although its properties are in part genetically determined, altered light-dark environment can change circadian period length through a mechanism requiring de novo DNA methylation. We show here that this mechanism is mediated not via cell-autonomous clock properties, but rather through altered networking within the suprachiasmatic nuclei (SCN), the circadian “master clock,” which is DNA methylated in region-specific manner. DNA methylation is necessary to temporally reorganize circadian phasing among SCN neurons, which in turn changes the period length of the network as a whole. Interruption of neural communication by inhibiting neuronal firing or by physical cutting suppresses both SCN reorganization and period changes. Mathematical modeling suggests, and experiments confirm, that this SCN reorganization depends upon GABAergic signaling. Our results therefore show that basic circadian clock properties are governed by dynamic interactions among SCN neurons, with neuroadaptations in network function driven by the environment

Environmental Impact on Vascular Development Predicted by High-Throughput Screening

Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease

An Assessment of the Interindividual Variability of Internal Dosimetry during Multi-Route Exposure to Drinking Water Contaminants

The objective of this study was to evaluate inter-individual variability in absorbed and internal doses after multi-route exposure to drinking water contaminants (DWC) in addition to the corresponding variability in equivalent volumes of ingested water, expressed as liter-equivalents (LEQ). A multi-route PBPK model described previously was used for computing the internal dose metrics in adults, neonates, children, the elderly and pregnant women following a multi-route exposure scenario to chloroform and to tri- and tetra-chloroethylene (TCE and PERC). This scenario included water ingestion as well as inhalation and dermal contact during a 30-min bathroom exposure. Monte Carlo simulations were performed and distributions of internal dose metrics were obtained. The ratio of each of the dose metrics for inhalation, dermal and multi-route exposures to the corresponding dose metrics for the ingestion of drinking water alone allowed computation of LEQ values. Mean BW-adjusted LEQ values based on absorbed doses were greater in neonates regardless of the contaminant considered (0.129–0.134 L/kg BW), but higher absolute LEQ values were obtained in average adults (3.6–4.1 L), elderly (3.7–4.2 L) and PW (4.1–5.6 L). LEQ values based on the parent compound’s AUC were much greater than based on the absorbed dose, while the opposite was true based on metabolite-based dose metrics for chloroform and TCE, but not PERC. The consideration of the 95th percentile values of BW-adjusted LEQ did not significantly change the results suggesting a generally low intra-subpopulation variability during multi-route exposure. Overall, this study pointed out the dependency of the LEQ on the dose metrics, with consideration of both the subpopulation and DWC