The Toxicologist - Society of Toxicology

ical groups in the field of regulatory toxicology while, on the other hand, one of the
most data poor. To this end, they make an excellent model both for the development
of new testing protocols and as a validation tool against which alternative testing
strategies can be evaluated. Specifically, the 16-member panel is being asked to
address the following questions: What is the current status of the use of integrated
testing strategies by regulatory agencies around the world? What is the state of the
science of integrated testing strategies? What are the potential impacts on the public’s
perception and confidence of IATA for pesticides?
1540 THE PROS AND CONS OF USING DATABASES TO
SUPPORT TOXICOLOGICAL DECISION MAKING.
T. Allio. Office of Pediatric Therapeutics, U.S. FDA, Silver Spring, MD. Sponsor: D.
Jacobson-Kram.
This offering will provide a general overview of the use of databases in toxicological
risk assessment and how understanding unique database structure will help safeguard
against pitfalls in your project. Much of the information presented is derived
from personal lessons learned over the years, with case examples in the area of genetic
toxicology. An emphasis is placed on the need to incorporate user feedback
into database development as well as an end user’s ability to accomodate to new
technologies as they develop. A review of several databases available to support decision
making and translational research will be offered. Some tips on how to leverage
the information derived from databases with data from empirical research and
future areas for development will also be highlighted. Items presented in this offering
are representative of the thoughts of the speaker and do not necessarily reflect
the thoughts or policies of the FDA.
1541 NEW RESULTS ON A UNIQUE PSYCHO-
TOXICOGENOMIC DRUG SCREENING ASSAY TO
ASSESS TREATMENT-EMERGENT SUICIDALITY RISK
PRECLINICALLY.
D. Weissmann, L. Vincent, L. Cavarec, C. Plusquellec, C. Leborgne, F.
Allemand and J. Pujol. Biocortech, Paris, France. Sponsor: E. Bush.
In recent years, there has been much focus on treatment-emergent suicidality - also
referred to as drug-induced suicidality - with the FDA recently issuing draft guidance
on how to assess this type of event in future trials. However, there is currently
no way to predict this serious adverse event early in preclinical development. To
possibly fulfill such a need, Biocortech set up an in vitro drug screening assay, exploiting
a biological mechanism known as ‘mRNA receptor editing’ that has been
shown, post mortem, to affect the post-transcription of serotonin 2c receptor
mRNA in a specific way in suicide patients. The assay consists in measuring the
changes of 5HT2cR RNA editing induced by screened drugs in chosen human cells
and in comparing the drug-induced profiles with the ones associated to suicide and
to interferon alpha treatments. On the basis of the results of a first screening of
more than 65 molecules Biocortech entered into a collaboration with 7 pharmaceutical
companies through a partnering with the Drug Safety Executive Council to
perform, under blind conditions, the screening of 48 selected molecules belonging
to several therapeutic classes. The screening was run at three concentrations, with
molecules known to potentially induce suicidality and others for which such events
had never been reported. The rounds of screening have shown that the assay was reproducible,
showing some dose-effect relationships and that screened compounds
could be clustered according to 4 patterns. The new results confirmed the potential
utility of the 5HT2cR mRNA editing-derived drug screening to assess risk of treatment-emergent
suicidality preclinically. According to those results induction of
5HT2cR editing profile mimicking those of suicide or of interferon alpha treatment
by screened drugs could thus potentially constitute a risk factor of treatment
emergent suicidality leading to the lowering of their priority for further development
or to a closer clinical safety surveillance.
1542 DERIVATION OF AN ORAL REFERENCE DOSE AND
DRINKING WATER SCREENING LEVEL FOR
SULFOLANE USING BENCHMARK DOSE MODELING.
C. Thompson 1 , C. Perry 2 , D. Gaylor 3 , A. Tachovsky 2 , B. Burkhalter 2 and L.
Haws 2 . 1 ToxStrategies, Inc., Katy, TX, 2 ToxStrategies, Inc., Austin, TX and 3 Gaylor
and Associates, LLC, Eureka Springs, AR.
Sulfolane is an organic solvent with a wide variety of industrial uses including sour
gas sweetening, removal of hydrogen sulfide during shale and coal processing, the
manufacture of polymers, electronics applications, and may also be found in pharmaceuticals
as a residual contaminant remaining after the manufacturing process.
Though sulfolane is not naturally occurring, it has been detected in groundwater
near facilities where it has been used. Given the potential for human exposure (e.g.,
ingestion in drinking water, dermal contact during bathing and similar activities,
and inhalation of sulfolane mist while showering) and the lack of any state or federal
drinking water standards for sulfolane in the U.S., we employed benchmark
dose (BMD) modeling to develop an oral reference dose (RfD) for sulfolane.
Several studies involving oral exposures were identified and determined to be useful
for development of toxicity benchmarks. Applying BMD modeling to several toxicological
endpoints in these studies, RfD values ranging 0.012–0.037 mg/kg/day
were calculated. The lower end of the range (0.01 mg/kg/day) was ultimately selected
as the RfD in keeping with typical U.S. EPA practices. A drinking water
screening level was subsequently developed based on this RfD using ingestion pathway
equations and assumptions consistent with U.S. EPA’s Regional Screening
Levels (RSLs). This resulted in a drinking water screening level of 365 ppb. As a
screening level, this value incorporates conservative assumptions to ensure an ample
margin of safety and, as such, this value cannot be viewed as a bright line for adverse
health effects, but rather provides the public with a reasonable degree of confidence
that concentrations at or below 365 ppb are unlikely to impact their health.
In contrast, concentrations above 365 ppb would need to be evaluated more closely
to determine the likelihood for adverse health effects.
1543 ASSESSMENT OF POPULATION HEALTH RISKS FROM
ENVIRONMENTAL POLLUTION BY EMISSIONS OF A
CHEMICAL WEAPONS DESTRUCTION FACILITY.
M. Kombarova 1 , I. Lomteva 2 , A. Radilov 1 , E. Tsibul’skaya 1 , N. Goncharov 1
and N. Khlebnikova 1 . 1 RIHOPHE, Saint Petersburg, Russian Federation and
2 Institute for Applied Ecology and Hygiene, Saint Petersburg, Russian Federation.
Sponsor: R. Gupta.
The program of chemical weapons destruction, implemented in the Russian
Federation as a signatory state of the Chemical Weapons Convention, envisions as
one of its primary priorities safety provision of the population in regions potentially
subject to an impact of Chemical Weapons Destruction Facilities (CWDFs). To assess
the population health risks in protective activities zone of the CWDF in the
Maradykovsky settlement (Kirov Region, Russian Federation), we developed and
applied a computer program realizing the procedure, accepted in the Russian
Federation and presented in the “Manual on Assessment of Human Health Risk
from Environmental Chemicals” (R 2.1.10.1920-04, Moscow, 2004). The risk assessment
procedure is based on two approaches: (1) direct risk assessment by the results
of environmental monitoring and (2) risk assessment by emission dispersion
modelling. Analysis of the design and engineering documentation and atmospheric
emission inventory of the Maradykovsky CWDF allowed identification of priority
air emission chemical pollutants: nitrogen, sulfur, and carbon oxides; alkali metal
phosphates and sulfates; manganese compounds; C12-C19 alkanes, gasoline, fueloil
ash; particulate matter; Russian VX (RVX), isobutyl methylphosphonic acid, 2-
(diethylamino)ethyl isobutyl sulfide. The exposure scenario was found to be chronic
inhalation, with the respiratory, sight, and digestive organs as the principal targets
in the human body. Risk assessment on the basis of atmospheric air monitoring data
revealed enhanced noncarcinogenic risks of exposure of respiratory organs to particulate
matter (by a factor of 1.7) and to a complex of chemical pollutants, including
nitrogen and sulfur dioxides and particulate matter (by a factor of 1.5).
Computer dispersion modeling of emissions of the Maradykovsky CWDF predicts
acceptable chronic non-carcinogenic and carcinogenic risk levels.
1544 INITIAL TOXICOLOGIC CHARACTERIZATION OF
TRIAMINOGUANIDINIUM-1-METHYL-5-
NITRIMINOTETRAZOLATE (TAG-MNT) IN FEMALE
RATS AND IN VITRO ASSAYS.
L. R. Williams, C. J. Cao, E. LaFiandra, L. C. Crouse, M. A. Bazar, W. S. Eck
and M. S. Johnson. Directorate of Toxicology Health Effects Research Program
(MCHB-TS-THE), U.S. Army Public Health Command (Provisional), Aberdeen
Proving Ground, MD.
Sustainable use of training ranges requires the development of compounds that
have a minimal impact to the environment when used in a weapon system.
Triaminoguanidinium-1-methyl-5-nitriminotetrazolate (TAG-MNT) is a military
compound of interest for application in weapon systems. To ensure the health of
potentially exposed personnel and the environment, several initial toxicity investigations
were conducted and the results compared with another widely used energetic
(hexahydro-1,3,5-trinitro-1,3,5-triazine; RDX). In a novel microplate Ames
SOT 2011 ANNUAL MEETING 331