The Toxicologist - Society of Toxicology

y partial purification of urine (from 15 male subjects with NHL and 30 male controls)
with a solid phase extraction method and analysis by ultra-performance liquid
chromatography/tandem mass spectrometry to assay 40 estrogen related compounds.
The results show that there are significantly higher levels of depurinating
estrogen-DNA adducts in the NHL cases than in the controls. In addition, the ratios
of the sum of depurinating estrogen-DNA adducts to the sum of their corresponding
estrogen metabolites and conjugates, which reflects the extent of imbalance
of estrogen metabolism in the body, were significantly higher in the cases than
in the controls. We conclude that formation of E1(E2)-3,4-Q, which arise from imbalance
in estrogen metabolism, plays a very important role in the etiology of
NHL. The ratios can be utilized as novel biomarkers to predict the risk and provide
targeted strategies of NHL prevention in clinic settings.
881 CURRENT USES AND UNDERSTANDING OF THE
TISSUE CROSS REACTIVITY ASSAY.
J. L. Bussiere 1 ,J. Cavagnaro 5 , E. Galbreath 3 ,T. Machlachlan 6 , N. Dybdal 4 and
M. Leach 2 . 1 Toxicology, Amgen, Inc., Thousand Oaks, CA, 2 Drug Safety Research and
Development, Pfizer, Andover, MA, 3 Toxicology, Lilly Research Laboratories,
Indianapolis, IN, 4 Safety Assessment, Genentech, Inc., South San Francisco, CA,
5 AccessBio, Boyce, VA and 6 Pharmacology and Toxicology, Genzyme, Framingham, MA.
Tissue cross-reactivity (TCR) studies are screening assays conducted with monoclonal
antibodies and related antibody-like biopharmaceuticals primarily to identify
off-target binding, and secondarily to identify sites of on-target binding that
were not previously identified. As presently utilized by the biopharmaceutical industry
and regulatory agencies, TCR studies usually involve the ex vivo immunohistochemical
(IHC) staining of a panel of frozen tissues from humans and animals.
However, other methods of conducting TCR studies are possible. While ex vivo
TCR studies have become routine in the development of antibody therapeutics,
their value for the purpose of making safety assessment decisions by both industry
and regulatory agencies has been questioned as experience with the assay has increased.
Recently, an industry white paper was published to review the use of tissue
cross-reactivity studies in the development of antibody-based biopharmaceuticals:
history, experience, methodology, and future directions. In addition, a multinational
pharmaceutical and biotechnology company survey was conducted to gain a
better understanding of the use and value of the TCR assay in the development of
biotherapeutic molecules. The information from this survey can be used to help understand
the appropriate use and interpretation of this assay in a nonclinical drug
development program. Our panel of experts will address the following issues of importance
including how we got to where we are today; the technical aspects of the
TCR assay and issues with interpretation; case studies and summary from white
paper on use of TCR; industry survey results on use of the TCR assay; and, the new
technologies for identifying off-target binding of monoclonal antibodies.
882 RISK AND RISK MANAGEMENT OF POTENTIALLY
TOXIC COMPOUNDS FORMED BY COOKING FOOD.
S. J. Hermansky 1 , W. Li 8 , S. Saunders 2 , N. Rachman 4 , S. Olin 5 , T. Troxell 3 ,
M. Bolger 6 and A. Tritscher 7 . 1 ConAgra Foods, Omaha, NE, 2 High Country
Toxicology Group, Beech Mountain, NC, 3 Exponent, Washington, DC, 4 Grocery
Manufacturer’s Association, Washington, DC, 5 ILSI Research Foundation,
Washington, DC, 6 U.S. FDA Center for Food Safety and Nutrition, Washington,
DC, 7 World Health Organization, Geneva, Switzerland and 8 Frito Lay, Plano, TX.
The discovery of acrylamide in food in 2002 by Swedish researchers initiated an international
effort to assess exposure and manage risk to the public. Millions of dollars
and countless hours of resources have been dedicated to this effort around the
world. The concept that cooking changes the chemistry of food is not new but the
presence of acrylamide across a wide variety of foods brought a new perspective to
food safety for the international regulatory community. This issue continues to develop
as different research groups focus on multiple heat-formed chemicals and various
aspects of toxicology of these naturally occurring compounds. From the recent
completion of the European Union HEATOX (Heat-Generated Food Toxicants:
Identification, Characterization, and Risk Minimization) project to the development
of increasingly sensitive and refined analytical methods that are able to detect
ever lower concentrations of compounds in foods, it is becoming increasingly clear
that acrylamide only represents one compound of many. This revelation presents
challenges to both the scientific and regulatory communities. Just as importantly,
resources are more frequently stretched thin as scientific debates are played out in
the mass media and the credibility of the scientific and regulatory process is challenged.
We will discuss the challenges and opportunities presented by risk management
of compounds formed in food during cooking.
883 EMERGING SCIENCE FOR ENVIRONMENTAL HEALTH
DECISIONS: TOOLS, STRATEGIES, AND EVIDENCE.
W. H. Farland. Colorado State University, Fort Collins, CO.
The last year was very productive for the National Research Council’s (NRC)
Standing Committee on Emerging Science for Environmental Health Decisions,
sponsored by the National Institutes of Environmental Health Science. A number
of timely, topical sessions were held that included SOT members that were of special
relevance to toxicology, risk assessment, and public health. These topics were
designed to extend discussion contained in two 2007 NRC reports — Toxicity
Testing in the 21st Century: A Vision and a Strategy and Application of
Toxicogenomics Technologies to Predictive Toxicology and Risk Assessment. These
sessions brought together government, industry, environmental groups, and the academic
community to discuss emerging scientific concepts and advances and their
potential implications for environmental health decisions. Specifically, these sessions
have explored emerging tools and technologies for epigenetics, computational
toxicology, stem cell models, and exposome research and their potential roles in
identifying, quantifying, and mitigating environmental impacts on human health.
In follow up to these dynamic sessions we will highlight many aspects of this important
topic. Our panel of experts will address what was learned linking specifically
to the common threads among the sessions, such as bioinformatics and expanding
input information for systems approaches to toxicology. In closing, we’ll
synthesize how to best integrate data across these emerging and evolving areas of research
and explore potential next steps for using such data and insights in environmental
health decisions and policy.
884 METABOLIC BASIS OF RESPIRATORY TRACT
CHEMICAL TOXICITY.
L. S. Van Winkle 1 and X. Ding 2 . 1 Center for Health and the
Environment/Veterinary Medicine: Anatomy, Physiology and Cell Physiology,
University of California Davis, Davis, CA and 2 Division of Environmental Health
Sciences, Laboratory of Molecular Toxicology, Wadsworth Center, New York State
Department of Health, Albany, NY.
The respiratory tract, including both the lung and the nasal tissue, has substantial
metabolic activity, which can influence the distribution and action of drugs and
xenobiotics, either inhaled or ingested. The metabolic enzymes that are active in the
respiratory tract include cytochrome P450 monooxygenases, esterases, oxidoreductases,
and dehydrogenases. Their distribution and activity can vary greatly with
anatomic location, by species, sex and history of prior exposure. Respiratory tract
metabolic activity can either enhance, or inhibit, local and systemic chemical toxicity.
While this basic principle has been understood and investigated for many years,
recent new approaches have allowed more in-depth investigation of the mechanisms
of toxicity in the respiratory tract following exposure to bioactivated toxicants.
Significant advances have been made, with the use of novel animal models,
new detection methods, application of site-specific approaches to colocalize toxicity
and metabolism, recombinant human enzymes, and modeling, which enhance our
understanding of the contributions of xenobiotic metabolism in the respiratory
tract to toxicity in humans. Several examples highlighting recent progress in this
area will be presented.
885 ROLE OF CYP2A AND CYP2F ENZYMES IN
RESPIRATORY TRACT CHEMICAL TOXICITY –
INSIGHTS FROM P450 KNOCKOUT AND
HUMANIZED MOUSE MODELS.
X. Ding 1, 2 . 1 Laboratory of Molecular Toxicology, Wadsworth Center, New York State
Department of Health, Albany, NY and 2 School of Public Health, State University of
New York at Albany, Albany, NY.
Microsomal P450 enzymes metabolize numerous xenobiotic compounds.
Transgenic and knockout mouse models are valuable for determining P450s’ roles
in various environmental diseases. Cyp2a5 and Cyp2f2 are among a cluster of
Cyp2a, 2b, 2f, 2g, 2s genes on mouse chromosome 7, many of which are expressed
preferentially or abundantly in the respiratory tract. A Cyp2a5-null mouse and a
Cyp2f2-null mouse have been produced and characterized recently in this laboratory.
Initial application of these two mouse models to studies on xenobiotic metabolism
has led to interesting findings on the roles of the respective P450 enzymes in
the in vivo metabolism and respiratory tract toxicity of several important environmental
chemicals. For examples, CYP2A5 was found to play a major role in the
metabolic activation of NNK, a tobacco-specific nitrosamine, in both lung and
nasal olfactory mucosa (OM); it also contributes to the metabolic activation of
naphthalene and 3-methylindole in the OM, but not in the lung . On the other
hand, CYP2F2 plays the major role in naphthalene metabolic activation in the
SOT 2011 ANNUAL MEETING 189