The Toxicologist - Society of Toxicology

on respiratory changes immediate and delayed in onset. Independent on the mode
of induction, response was characterized by increased influx of neutrophilic granulocytes
(PMN) and delayed respiratory response. BN rats induced by the high C x
short t protocol elaborated the most pronounced influx of PMNs and delayedonset
responses. No route-of-induction related differences in elicitation thresholds
were found. This data suggest that the vigor of asthma-like responses appears to
support the well established dose-of-induction paradigm. The more pronounced
elicitation response following topical induction is consistent with the appreciably
higher dose that can be delivered to the skin as compared to the respiratory tract.
Likewise, inhalation induction becomes more efficient using a high C, short t exposure
regimen which is consistent with the common view held that intermittent
peak exposures are important contributing factors in the ontogenesis of this occupational
disease.
905 PEPTIDE REACTIVITY OF CHEMICAL RESPIRATORY
ALLERGENS.
J. F. Lalko 1, 2 . 1 The University of Manchester, Manchester, United Kingdom and
2 Research Institute for Fragrance Materials Inc., Woodcliff Lake, NJ. Sponsor: I.
Kimber.
A common characteristic of all chemical allergens, both respiratory and skin, is the
ability to form stable associations with proteins. The covalent modification of nucleophilic
amino acids by electrophilic chemical allergens is a key step in the sensitization
process; with the resulting non-self, hapten-protein complex being sufficient
to provoke an immune response. In recent years this mechanistic
understanding has been exploited to develop in vitro screening assays to identify
potential skin sensitizers. Typically, these Peptide Reactivity Assays (PRAs) are conducted
by incubating the test chemical in the presence of a model peptide and characterizing
the reaction by measuring the depletion of the nucleophile and/or the
formation of adducts (via HPLC UV and/or MS detectors of various configurations).
These developments have focused primarily on the identification of skin
sensitizers; however, there is interest in applying similar approaches to the identification
of chemical respiratory allergens. The available information, though limited,
shows that both chemical respiratory and skin allergens result in positive responses
for reactivity in PRAs. From a risk assessment and management perspective, it is advantageous
to separate chemicals based on their potential to act as either skin or respiratory
allergens. Some investigators have pointed to selective modification of specific
amino acids or proteins (i.e. comparing cysteine to lysine; or cell vs. serum
associated protein binding) as contributing to the ability of an allergen to result in
one or the other form of sensitization. Overall, experience to date indicates that
chemical reactivity measurements can provide useful information and have the potential
to form a key component of future integrated testing strategies to characterize
potential respiratory allergens. Such opportunities will be surveyed against a
background of the immunobiology of allergic sensitization and current state-of-theart
approaches to the measurement of peptide/protein reactivity.
906 GENE EXPRESSION CHANGES AND THE
IDENTIFICATION OF CHEMICAL RESPIRATORY
ALLERGENS.
D. R. Boverhof. The Dow Chemical Company, Midland, MI.
There is a need for experimental approaches for the identification and characterization
of chemicals with the potential to induce respiratory allergy. Currently there is
uncertainty with regards to the mechanisms involved in the development of respiratory
allergy and their distinctions from contact allergy. Toxicogenomic technologies
allow for global profiling of gene expression in response to xenobiotic exposure
and represent powerful tools that have the potential offer important insights into
the molecular mechanisms involved in the development of allergy. Toxicogenomic
analyses also have the advantage of profiling the entire transcriptome such that
novel markers and new insights into the mechanisms of respiratory allergy can be
identified. Published studies have already indicated that chemical allergens provoke
a number of changes in gene expression in various tissues including lymph
nodes, skin and pulmonary tissue and these changes have offered preliminary insights
into the molecular pathways that may lead to the development of respiratory
allergy. However, as with all toxicological investigations, full interpretation and application
of the data will require the appropriate consideration of temporal-, dose-,
and tissue-dependent responses and a systematic evaluation including a robust experimental
design with genomic endpoints anchored to traditional immunotoxicology
endpoints. Ultimately, the increased molecular understanding may be leveraged
to develop novel biomarkers to classify agents with potential to induce
respiratory allergy as part of the hazard characterization process. This presentation
194 SOT 2011 ANNUAL MEETING
will describe the opportunities that exist for the identification and discrimination
of respiratory and contact allergens based on mapping of exposure induced changes
in gene expression.
907 A MODIFIED LOCAL LYMPH NODE ASSAY FOR
HAZARD IDENTIFICATION OF CHEMICAL
RESPIRATORY ALLERGENS.
T. Yoshida. Health Science, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
The LLNA was developed as a method for the characterization of contact allergens
using mice and several attempts had been continued for reducing animal and RI
usage in GHS. However, it is well established that chemical respiratory allergens
also test positive in this assay and exploiting this as an alternative strategy for hazard
identification will be addressed. Evaluation of cytokine gene expression relating
Th1/2 in the lymphocytes of regional lymph nodes is useful to identify respiratory
allergy. Chemicals are applied to ears in original LLNA but this challenging pathway
is differing from actual respiratory exposure. In this presentation, the methods
with the application of chemicals to nasal cavities or inhalation and measuring proliferation
of lymphocytes and evaluation of cytokine profiles in each regional lymph
nodes; cervical or lung hilar based on same concepts to LLNA will be introduced.
908 SAFER PRODUCTS FOR A SUSTAINABLE WORLD:
LINKING CHEMICAL DESIGN AND TOXICOLOGY.
H. Zenick 1 and P. Beattie 2 . 1 National Health Environmental Effects Research Lab.,
U.S. EPA, Research Triangle Park, NC and 2 SciVera, Inc. and Arcalis Scientific, LLC,
West Bloomfield, MI.
There is no more greatly studied characteristic of molecules than their ability to exhibit
biological activity and major industries, including pharmaceuticals and pesticides,
are based on this science. Billions of dollars are spent to evaluate the risk of
chemicals in the environment and billions more are to discover new chemicals that
have beneficial biological effects. One of the goals of green chemistry first introduced
by Paul Anastas and John Warner in 1998, is to reduce or eliminate the use
and generation of hazardous substances throughout the design, manufacture, and
use of chemical products. The principles of green chemistry and engineering are
now being widely embraced beyond the traditional chemical and pharmaceutical
industries, into formulators and manufacturers of consumer products. Information
on the potential hazards of the substances that are incorporated into final products
is needed in order to assess and design safer products and processes. Recent advances
in understanding the mechanisms of toxicity, the development of in vitro
high-throughput screening (HTS) assays as well as other predictive and in silico
methods allow for rapid assessment and screening of many more chemicals than
had been possible in the past using traditional whole animal models. With the reform
of the Toxic Substances Control Act (TSCA) and other state and global regulations
requiring toxicity information and assessment of safer alternatives on thousands
of chemicals, it is imperative that these predictive toxicology methods be
incorporated into the assessment paradigm. As new industrial chemicals are designed
with green chemistry and engineering principles, these toxicology screening
methods can be used to efficiently evaluate substances, minimizing potential adverse
health effects both in the workplace and to the final consumer.
909 GREEN CHEMISTRY DONE RIGHT: A PARTNERSHIP
BETWEEN CHEMICAL DESIGN AND TOXICOLOGY.
P. Anastas. Office of Research and Development, U.S. E.P.A., Washington, DC.
Sponsor: H. Zenick.
Given the tens of thousands of chemicals in use in the US and the world in dramatically
increasing volumes, there is a great need to proactively design molecules,
processes and products to minimize environmental and health impacts. There is a
pressing need to learn how to design molecules that are inherently less toxic.
Manufacturing processes need to be designed to use the least toxic substances for
the job and to minimize downstream waste. The design or formulation of endproducts
should take into account environmental and health impacts through their
entire lifecycle. The field of green chemistry encompasses these ideas. This talk will
introduce the major principles of green chemistry with a focus on the role of toxicology
in advancing these tenets using tool such as high throughput screening and
computational and informational technologies