The Toxicologist - Society of Toxicology

2690 APPLICATION-SPECIFIC CONSIDERATIONS IN
EVALUATION OF PHYSIOLOGICALLY-BASED
PHARMACOKINETIC (PBPK) MODELS.
L. M. Sweeney. TERA, Cincinnati, OH.
“One size fits all” statements regarding model confidence (i.e., the model is simply
“acceptable” or “unacceptable”) fail to capture the subtleties inherent in the many
ways physiologically based pharmacokinetic (PBPK) models can be used in risk assessment.
For example, a model that is acceptable in one context, such as route-toroute
extrapolation, many not be adequate for other purposes, such as interspecies
extrapolation. Predictions of a given dose metric that may be bounded (e.g., by
physiological considerations) could be considered to be reliably estimated by a
model for which other dose metrics are not characterized with sufficient confidence.
Application-specific considerations should be incorporated in PBPK model evaluation
to ensure that these useful tools are appropriately applied in risk assessment.
2691 CHARACTERIZATION OF POPULATION
DISTRIBUTIONS IN PBPK MODEL PARAMETERS.
H. J. Clewell. The Hamner Institutes for Health Sciences, Research Triangle Park, NC.
Population analysis is being applied in PBPK modeling, through rigorous Bayesian
statistical analysis and simulation of population variability by Monte-Carlo sampling
of parameters. Bayesian analysis in particular provides estimates of population
variability and uncertainty in various parameters, but the outcome depends to some
extent on the assumed initial (prior) distributions, and can only represent what is
known from the study population analyzed, rather than the population as a whole.
This talk discusses appropriate choices of parameter distributions such that the full
population variability and uncertainty can be captured as well as considerations on
how probabilistic modeling results can be integrated into current risk assessment
practice.
2692 ALTERNATE APPROACHES AND ISSUES IN
INTEGRATING PHARMACOKINETIC WITH
BENCHMARK-DOSE (BMD) MODELING.
P. M. Schlosser. NCEA, U.S. EPA, Washington, DC.
Physiologically-based and traditional pharmacokinetic (PK) models may be integrated
with benchmark-dose (BMD) dose-response modeling by using PK-modelpredicted
internal doses as inputs to BMD analysis, which estimates a point-of-departure
(POD) dose equivalent to a no-observed adverse effect level. A human
PBPK model would then used to estimate the human-equivalent exposure.
However, each time the PK model is revised, which may happen several times during
an extensive regulatory review process, the BMD analysis must be revised accordingly;
if the analysis is for multiple animal species/genders/target tissues/endpoints,
the effort involved can become substantial vs. simply conducting the BMD
analysis once using applied exposure levels. Also, if tumors arise in multiple tissues,
a single dose metric must be used to correctly estimate total tumor risk with current
standard statistical methods. These and other issues to be discussed make the approach
for integration of PK and BMD modeling less than straightforward.
Different approaches are therefore likely to be preferred for different assessments,
depending on the details and level of complexity of the analysis. (Disclaimer: The
views expressed in this abstract are those of the author and do not represent the policy
of the U.S. Environmental Protection Agency.)
2693 EXPLICIT PHARMACOKINETIC MODELING: TOOLS
FOR DOCUMENTATION, VERIFICATION, AND
PORTABILITY.
J. F. Wambaugh 1 , R. Tornero-Velez 2 , E. McLanahan 3 , Y. Tan 2 , W. Setzer 1 and I.
Shah 1 . 1 National Center for Computational Toxicology, U.S. EPA, Research Triangle
Park, NC, 2 National Exposure Research Laboratory, U.S. EPA, Research Triangle
Park, NC and 3 National Center for Environmental Assessment, U.S. EPA, Research
Triangle Park, NC .
Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple
exposure pathways require the use of complex mathematical models, such as
physiologically-based pharmacokinetic (PBPK) models. The process of translating
the abstract mathematics of a PBPK model description into a computational implementation
is typically a tedious process fraught with the potential for error.
Sometimes key information, such as parameters or even whole equations, is unintentionally
omitted from published results. Furthermore, complex models are often
576 SOT 2011 ANNUAL MEETING
interpreted by a wide community of scientists and policy makers; it is important
that the language used to communicate the model be explicit and coherent. Fields
allied with toxicology, such as systems biology, have created markup languages (i.e.
Systems Biology Markup Language) to standardize the syntax of mathematics and
documentation, allowing models to be disseminated as supplemental material in articles
or through on-line databases. We propose a formal declarative description of
PBPK models, PhLexicOn, to assure published models are thoroughly documented
and can be readily translated into popular simulation software. Completeness of a
model is not sufficient, it must make sense in terms of the relationships among tissue
volumes, blood flows and other fundamental biology. Plausibility is assessed
though an ontology that defines the appropriate constituents of physiologicallybased
systems. Tools are in development to: efficiently verify semantic validity
based on the ontology, and automate translation into executable simulations to
evaluate consistency with published results. PhLexicOn is a framework for documenting,
verifying, and translating legacy and state-of-the-art models for re-usability
and efficient dosimetry estimation of chemicals for use in human health risk assessments.
This abstract does not necessarily reflect U.S. EPA policy.
2694 ROLE OF BIOMARKERS IN ASSESSING TOBACCO
HARM REDUCTION: A TOXICOLOGICAL
PERSPECTIVE.
C. Timchalk and R. Corley. Pacific Northwest National Laboratory, Richland, WA.
In 2009, the Family Smoking Prevention and Tobacco Act was passed by Congress,
signed into law, and the U.S. FDA was tasked with regulating tobacco. The U.S.
FDA’s stated goals are to use the best available science to guide the development and
implementation of effective public health strategies to reduce the burden of illness
and death caused by tobacco products. A potential component of this effort is the
implementation of a risk/harm reduction strategy, in which the removal or reduction
of harmful ingredients within tobacco products is one possible approach. In
this regard, a joint World Health Organization (WHO) and International Agency
for Cancer Research (IARC) working group proposed a strategy for lowering toxicant
yields in tobacco products based on animal and human toxicity data for individual
constituents. This risk based approach requires the prioritization of main
stream smoke (MSS) constituents according to their individual risk of developing
cancer. In this context, we will explore current and new strategies that have the potential
to identify priority constituents for reduction. This will include strategies
that utilized conventional approaches to MSS risk assessment which calculate risks
according to exposure and hazard. A potential alternative approach for evaluation
of MSS constituents exploits a strategy developed by the International Program on
Chemical Safety (IPCS) to improve individual chemical risk assessment utilizes a
weight-of-evidence approach within a mode-of-action (MOA) framework. Finally,
a Quantitative Risk Assessment (QRA) strategy will be considered which combines
advanced computational and experimental lung dosimetry, smoking patterns and
behavior data, human variability, and available toxicity/cancer potency factors to
develop compound-specific comparative estimates of risk for MSS constituents.
The primary focus will be placed on both the strengths and weaknesses of the various
approaches in the context of a MSS harm reduction strategy.
2695 LEGISLATIVE AND REGULATORY OVERVIEW.
M. Zeller. Pinney Associates, Bethesda, MD. Sponsor: C. Timchalk.
Tobacco harm reduction policy is a complex and emotionally charged issue. For
many decades, the public health community found it difficult to independently
evaluate express and implied risk and harm reduction marketing tactics of the tobacco
industry. The challenge was exacerbated by the absence of tobacco product
regulation. The classic example of the impact of no regulation was the marketing of
“light” and “low tar” cigarettes that implied lower risk to smokers. As a consequence,
we have witnessed generations of smokers who otherwise may have been
motivated to quit that instead compensated for the lower tar and nicotine by increasing
consumption, thereby negating any real or perceived reductions in risk.
Recent passage of the Family Smoking Prevention and Tobacco Control Act
(FSPTCA) changes everything. Under the new law, the U.S. Food and Drug
Administration now has a set of regulatory tools to control toxicant delivery, exposure
and risk reduction claims, and many other aspects of tobacco product manufacturing
and marketing. Similar opportunities for effective, science-based tobacco
product regulation are possible under the Framework Convention for Tobacco
Control. This presentation will provide an overview of the history of how the tobacco
industry made health-related claims in the unregulated marketplace. Key
provisions of the FSPTCA will be described, including those which empower FDA