PNNL-13501 - Pacific Northwest National Laboratory

Mechanistic Modeling of Early Genotoxic Events for Chemicals and Radiation
Study Control Number: PN00064/1471
Robert D. Stewart
Mechanistic models are needed to improve our understanding of, and ability to predict and mitigate, the human health
effects of exposure to hazardous agents found at many DOE facilities, such as tritium, beryllium, and organic solvents.
Our project will advance the state of the art in mechanistic modeling of early biophysical events involved in the
development of cancer.
Project Description
This project has two main goals: 1) develop a scalable
and extensible modeling framework to bridge the gap
between dosimetry and early events involved in the
pathogenesis of cancer, and 2) perform the initial work
needed to demonstrate the feasibility of using detailed
molecular and cellular models to predict dose-response
effects at the organ and tissue levels.
A calculational framework to integrate molecular and
cellular dose-response models into three-dimensional
tissue constructs has been developed. As a high-impact
way to illustrate how such modeling tools might be used
to study the effects of complicated workplace or
environmental exposures, we used our modeling tools to
examine ways that the temporal and spatial delivery of
radiation to a tumor could be manipulated to improve
treatment outcome.
Introduction
Genotoxic chemical agents and ionizing radiation create a
multitude of different types of DNA damages. Regardless
of the process or agent that initially creates the DNA
damage, the same basic physiochemical and biochemical
processes either correctly repair the damage or convert the
damage into a lethal or nonlethal point mutation or
chromosome aberration. Because of cellular adaptations
in damage repair and effects associated with, for example,
the mitotic cell cycle, the expected number of point
mutations and chromosome aberrations created in a cell is
a complicated and generally nonlinear function of a cell’s
exposure history.
Two fundamental questions that must be answered in
order to quantitate the health risks associated with human
exposure to man-made physical and chemical agents are:
“How many and what kinds of abnormal genetic
294 FY 2000 Laboratory Directed Research and Development Annual Report
alterations are created in a cell per unit dose of the
agent?” and “How many of these randomly created
genetic alterations does it take to transform a normal cell
into one capable of producing a cancer?” The central aim
of this project is to help answer these questions by
advancing the state of the art in mechanistic modeling of
DNA damage formation, repair, and misrepair processes.
Moreover, this project aims to better link these
fundamental processes to cell transformation and killing
effects in vitro and in vivo.
Results and Accomplishments
A major focus of the project this year has been to develop
the scalable and extensible software tools needed to
integrate molecular and cellular models into more realistic
three-dimensional organ, tissue, and tumor models. We
have also further refined our model calibration and testing
strategy.
From Molecules to Man: Three-Dimensional Tissue
Modeling
In our modeling approach, an organ, tissue, or tumor is
first subdivided into a large number of smaller,
rectangular tissue regions. Then, we use a molecular and
cellular dose-response model to simulate the life history
of a large number of cells (and their progeny) in each
tissue region. Biophysical response quantities of interest
such as the yield of lethal and nonlethal genetic
alterations in critical subpopulations (stem cells) or in
certain regions of the tissue can then be computed from
the life histories of the individual cells. The main
advantage of this ab initio approach is that the degree of
realism in the tissue model is ultimately only limited by
our computing capabilities, our understanding of intra-
and intercellular biophysical processes, and the
availability of appropriate experimental datasets for use as
model inputs and in model testing.