Simulating Microdosimetry in a Virtual Hepatic Lobule

The liver plays a key role in removing harmful chemicals from the body and is therefore often the first tissue to suffer potentially adverse consequences. To protect public health it is necessary to quantitatively estimate the risk of long-term low dose exposure to environmental pollutants. Animal testing is the primary tool for extrapolating human risk but it is fraught with uncertainty, necessitating novel alternative approaches. Our goal is to integrate in vitro liver experiments with agent-based cellular models to simulate a spatially extended hepatic lobule. Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule. We analyzed the effects of vascular topology and metabolism on the cell-level distribution following oral exposure to chemicals. The spatial distribution of metabolically inactive chemicals was similar across different vascular networks and a baseline well-mixed compartment. When chemicals were rapidly metabolized, concentration heterogeneity of the parent compound increased across the vascular network. As a result, our spatially extended lobule generated greater variability in dose-dependent cellular responses, in this case apoptosis, than were observed in the classical well-mixed liver or in a parallel tubes model. The mass-balanced graphical approach to modeling the hepatic lobule is computationally efficient for simulating long-term exposure, modular for incorporating complex cellular interactions, and flexible for dealing with evolving tissues.Author Summary: Virtual tissues are emerging as a powerful tool for computational biology. By encoding known biology into a simulation of tissue function, gaps in knowledge can be identified. As a simulation of tissue function, in silico experiments can be performed inexpensively and rapidly. There are over 6000 chemicals produced in large quantities that may be present in our environment, many of which have not been thoroughly examined for human toxicity. Traditional toxicity testing is expensive, lengthy, and relies heavily upon the use of animals. For this reason in vitro toxicity testing techniques are being developed. However, techniques are needed to relate in vitro results to in vivo conditions. The liver is often the first tissue to show signs of toxicity and therefore a predictive liver toxicity simulator would be a powerful tool to reduce the financial and animal cost of toxicity testing. As a first step, we have developed a model for relating environmental exposure to cell-level concentrations; a model for virtual tissue microdosimetry. We identify regimes in which this approach is equivalent to previous techniques, as well as regimes where large cell-to-cell variability exists. This variability should have consequences both for normal liver function and the onset of injury.