Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms

Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation between in vitro exposures, in vivo physiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process

Amplitude Changes during Ventricular Fibrillation: A Mechanistic Insight

Introduction: Clinically in ventricular fibrillation (VF), ECG amplitude, and frequency decrease as ischemia progresses and predict defibrillation success. In vitro ECG amplitude declines without ischemia, independent of VF frequencies. This study examines the contribution of cellular electrical activity and global organization to ECG amplitude changes during VF. Methods and Results: Rabbit hearts were Langendorff-perfused (40 mL/min, Tyrode’s solution) and loaded with RH237. During VF, ECG, and epicardial optical action potentials were recorded (photodiode array; 256 sites, 15 mm × 15 mm). After 60 s of VF, perfusion was either maintained, global ischemia produced by low-flow (6 mL/min), or solution [K+]o raised to 8 mM. Peak-to-peak amplitude was determined for all signals. During VF, in control, ECG amplitude decreased to a steady-state (∼57% baseline), whereas in low-flow steady-state was not reached with the amplitude continuing to fall to 33% of baseline by 600 s. Optically, LV amplitude declined more than RV, reaching significance in control (LV vs. RV; 33 ± 5 vs. 63 ± 8%, p < 0.01). During VF in 8 mM [K+]o, amplitude changes were more complex; ECG amplitude increased with time (105 ± 13%), whilst LV amplitude decreased (60 ± 15%, p < 0.001). Microelectrode studies showed amplitude reduction in control and 8 mM [K+]o (to ∼79 and ∼93% baseline, respectively). Evaluation of electrical coordination by cross-correlation of optical signals showed as VF progressed coordination reduced in control (baseline 0.36 ± 0.02 to 0.28 ± 0.003, p < 0.01), maintained in low-flow (0.41 ± 0.03 to 0.37 ± 0.005, p = NS) and increased in 8 mM [K+]o (0.36 ± 0.02 to 0.53 ± 0.08, p < 0.05). Conclusion: ECG amplitude decline in VF is due to a combination of decreased systolic activation at the cellular level and increased desynchronization of inter-cellular electrical activity

Key Scientific Issues in the Health Risk Assessment of Trichloroethylene

Trichloroethylene (TCE) is a common environmental contaminant at hazardous waste sites and in ambient and indoor air. Assessing the human health risks of TCE is challenging because of its inherently complex metabolism and toxicity and the widely varying perspectives on a number of critical scientific issues. Because of this complexity, the U.S. Environmental Protection Agency (EPA) drew upon scientific input and expertise from a wide range of groups and individuals in developing its 2001 draft health risk assessment of TCE. This scientific outreach, which was aimed at engaging a diversity of perspectives rather than developing consensus, culminated in 2000 with 16 state-of-the-science articles published together as an Environmental Health Perspectives supplement. Since that time, a substantial amount of new scientific research has been published that is relevant to assessing TCE health risks. Moreover, a number of difficult or controversial scientific issues remain unresolved and are the subject of a scientific consultation with the National Academy of Sciences coordinated by the White House Office of Science and Technology Policy and co-sponsored by a number of federal agencies, including the U.S. EPA. The articles included in this mini-monograph provide a scientific update on the most prominent of these issues: the pharmacokinetics of TCE and its metabolites, mode(s) of action and effects of TCE metabolites, the role of peroxisome proliferator–activated receptor in TCE toxicity, and TCE cancer epidemiology

Key Issues in the Modes of Action and Effects of Trichloroethylene Metabolites for Liver and Kidney Tumorigenesis

Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs), and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA), and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl)-l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans

Constraints on Cosmic Strings due to Black Holes Formed from Collapsed Cosmic String Loops

The cosmological features of primordial black holes formed from collapsed cosmic string loops are studied. Observational restrictions on a population of primordial black holes are used to restrict $f$, the fraction of cosmic string loops which collapse to form black holes, and $\mu$, the cosmic string mass-per-unit-length. Using a realistic model of cosmic strings, we find the strongest restriction on the parameters $f$ and $\mu$ is due to the energy density in $100 MeV$ photons radiated by the black holes. We also find that inert black hole remnants cannot serve as the dark matter. If earlier, crude estimates of $f$ are reliable, our results severely restrict $\mu$, and therefore limit the viability of the cosmic string large-scale structure scenario.Comment: (Plain Tex, uses tables.tex -- wrapped lines corrected), 11 pages, FERMILAB-Pub-93/137-

Limits on Black Hole Formation from Cosmic String Loops

In theories with cosmic strings, a small fraction of string loops may collapse to form black holes. In this Letter, various constraints on such models involving black holes are considered. Hawking radiation from black holes, gamma and cosmic ray flux limits and constraints from the possible formation of stable black hole remnants are reanalyzed. The constraints which emerge from these considerations are remarkably close to those derived from the normalization of the cosmic string model to the cosmic microwave background anisotropies.Comment: 14 pages, no figures, Latex (RevTex), Submitted to PR

Tele-branding in TVIII: the network as brand and the programme as brand

In the era of TVIII, characterized by deregulation, multimedia conglomeration, expansion and increased competition, branding has emerged as a central industrial practice. Focusing on the case of HBO, a particularly successful brand in TVIII, this article argues that branding can be understood not simply as a feature of television networks, but also as a characteristic of television programmes. It begins by examining how the network as brand is constructed and conveyed to the consumer through the use of logos, slogans and programmes. The role of programmes in the construction of brand identity is then complicated by examining the sale of programmes abroad, where programmes can be seen to contribute to the brand identity of more than one network. The article then goes on to examine programme merchandising, an increasingly central strategy in TVIII. Through an analysis of different merchandising strategies the article argues that programmes have come to act as brands in their own right, and demonstrates that the academic study of branding not only reveals the development of new industrial practices, but also offers a way of understanding the television programme and its consumption by viewers in a period when the texts of television are increasingly extended across a range of media platforms