The Toxicologist - Society of Toxicology

luted OFR and CRL. Culture media extracts also were prepared from lenses exposed
to solutions and rinsed with saline prior to extraction. No colony growth was
observed in cells treated with extracts of OFR- and CRL-treated lenses. There was
no toxicity in any untreated lenses. Direct contact test conducted in L929 cells
under the same conditions reveled a slight zone of cell lysis only under the lenses
soaked in OFR and CRL. Importantly, exposing cells directly to solutions or unrinsed
lenses produces different results due to contributions of surfactants and
buffering agents similar to acute ocular exposure. In summary, as a part of product
development, we propose this strategy to identify solution with less potential for
toxicity resulting from exposure to either complete formulation or released ingredients
from lenses.
1322 TRANSLATIONAL IMAGING OF AN INJECTABLE POLY-
L-LACTIC ACID DERMAL FILLER.
N. J. Barlow 1 , D. Wilson 1 , R. Rimsky 1 , L. Wachsmuth 1 , T. Coulthard 2 and X.
Ying 1 . 1 Disposition, Safety and Animal Research, sanofi-aventis U.S., Inc.,
Bridgewater, NJ and 2 VisualSonics, Inc., Toronto, ON, Canada.
Sculptra® Aesthetic is a dermal filler composed of injectable poly-L-lactic acid
(PLLA) that is approved for the treatment of mild to deep nasolabial fold wrinkles.
The purpose of this translational imaging study was to determine the visibility of
the PLLA by various clinical imaging technologies, including computed tomography
(CT), radiography (X-ray), magnetic resonance imaging (MRI), and ultrasound
imaging. Rats received Sculptra® Aesthetic by subcutaneous injection at two
distinct sites on Days 1 and 90. Rats were imaged on Day 91 and skin from the two
injection sites and an untreated site was collected for a correlative microscopic examination.
The PLLA was well visualized by ultrasound 24 hours after injection;
but, was poorly visualized by ultrasound 90 days after injection and the observations
may not have been due to the PLLA because there was a lack of microscopic
correlation with the ultrasound findings. Sculptra® Aesthetic was well visualized
with MRI 24 hours after injection in T1, T2 and/or T2*-weighted images.
However, after 90 days the appearance of the injection site did not differ from the
untreated reference site using MRI. Sculptra® Aesthetic was not visualized with
CT and radiography at either time point. Microscopically, Sculptra® Aesthetic was
observed 24 hours after injection in the subcutaneous tissue and was associated
with acute inflammation; these findings correlated with the observations visualized
by ultrasound and MRI imaging. The PLLA was also observed microscopically in
the subcutaneous tissue 90 days after injection and was associated with granulomatous
inflammation. The respective inflammation at 24 hours and 90 days was an
expected acute and chronic foreign body reaction to the PLLA. In summary, the
PLLA-based dermal filler Sculptra® Aesthetic was visualized in rat skin 24 hours
following subcutaneous injection using ultrasound and MRI; however, it was not
definitively observed with the various imaging modalities after 90 days.
1323 EVALUATION OF EXTRACTABLES/LEACHABLES FROM
IMPLANTED MEDICAL DEVICES.
L. A. Haighton 1, 2 , H. Fikree 2 , L. Sarkissian 2 and J. W. Card 2 . 1 Cantox Health
Sciences International, Mississauga, ON, Canada and 2 Ashuren Health Sciences,
Mississauga, ON, Canada.
Safety evaluation of implanted medical devices has traditionally focused on biocompatibility
issues (tissue reactivity, inflammation, immunogenicity, cytotoxicity);
however, consideration of potential leachables is now a necessary component. Even
though leachables typically arise in only trace amounts, the assessment of leachables
can add greatly to the cost of developing medical devices with the expected financial
repercussions to the patient. An approach is proposed that combines existing
knowledge of risk assessment methods and extractables/leachables (E/L) assessment
practices from inhalation devices to derive thresholds to support the safety of implanted
medical devices with limited need for additional toxicology testing. This
approach takes into consideration the differences in exposure routes and the fact
that E/L have varying degrees of diffusion and hydrophilicity which factor into the
potential exposure duration. Highly hydrophilic residuals are likely to be leached
(and exhausted) early from medical devices and would have a short residence time;
conversely, very hydrophobic compounds may be leached more gradually from the
medical device, resulting in a longer exposure period. Thus, the principle concepts
in deriving thresholds specific for E/L from an implanted medical device are: (i) the
justification for the use of thresholds in risk assessment; (ii) the importance of exposure
duration in determining risk and the science supporting that exposure to
low doses over an extended period of time is more potent than higher-dose exposure
for a shorter duration; (iii) the potential for organ toxicity which is dependent
upon the amount of leachable systemically available (bioavailability differences between
inhalation and implantation); and, (iv) target patient population. The value
of this approach is demonstrated by applying the derived thresholds to representative
E/L with varying exposure profiles.
1324 AGE-RELATED DIFFERENCES IN CHOLINESTERASE
(CHE) INHIBITION IN IMMATURE AND ADULT RATS
AFTER ACUTE OR REPEATED EXPOSURES TO
CHLORPYRIFOS (CPF) OR CPF-OXON (CPFO).
M. S. Marty 1 , A. K. Andrus 1 , M. P. Bell 1 , J. K. Passage 1 , A. W. Perala 1 , K. A.
Brzak 1 , S. N. Fishman 1 , M. J. Bartels 1 and D. R. Juberg 2 . 1 The Dow Chemical
Company, Midland, MI and 2 Dow AgroSciences, Indianapolis, IN.
To examine age-related differences in ChE inhibition, PND 11 rats (8/sex/dose)
and adult female rats (8/dose) were exposed acutely or repeatedly to CPF or CPFO
by gavage in corn oil. Samples were collected at time-of-peak ChE inhibition and
analyzed via modified Ellman method. Blood levels of CPF, CPFO, and/or trichlorpyridinol
were determined. Acute CPF studies: ChE activity was measured after a
single dose of 0, 0.05, 0.1, 0.5, 2, 5 (pups only) or 10 (adults only) mg/kg CPF.
Both pups and adults had comparable decreases in brain ChE at the highest CPF
dose (5 mg/kg in pups; 10 mg/kg in adults) and significant RBC ChE inhibition at
≥2 mg/kg, although pups had higher plasma CPF levels at each dose level. In both
age groups, ChE inhibition NOEL brain = 2 mg/kg and NOEL RBC = 0.5 mg/kg CPF
with acute exposure. Repeated CPF studies: ChE was measured in PND 21 pups
and adult females after 11 daily exposures to 0, 0.05, 0.1, 0.5, 1, 3.5 mg/kg/day
CPF. At 3.5 mg/kg/day, pups had similar ChE inhibition to adults across all tissues,
despite having higher plasma CPF levels. At 0.5 mg/kg/day, RBC ChE was inhibited
in adults and pups. In both age groups, ChE inhibition NOEL brain = 0.5 mg/kg
and NOEL RBC = 0.1 mg/kg/day CPF with repeated exposure. CPFO studies: ChE
activity was measured after single or repeated CPFO doses (acute: 0, 0.005 (pups
only), 0.01, 0.05, 0.1, 0.5, or 1 (adults only) mg/kg; repeated: 0, 0.01 or 0.5
mg/kg/day). Brain ChE was not inhibited in pups or adults at any CPFO dose in
either exposure scenario. In both age groups, ChE inhibition NOEL RBC = 0.1
mg/kg and 0.01 mg/kg/day CPFO with acute and repeated exposures, respectively.
Across studies, plasma ChE inhibition was similar to that seen in RBCs. These data
indicate that young pups are not more sensitive to ChE inhibition by CPF or
CPFO over the lower portion of the dose-response curves.
1325 REPEATED DEVELOPMENTAL CHLORPYRIFOS
EXPOSURE INCREASES ENDOCANNABINOID LEVELS
IN THE BRAIN OF JUVENILE RATS.
R. L. Carr, A. B. Ward and M. K. Ross. Center for Environmental Health Sciences,
Mississippi State University, Mississippi State, MS.
The endogenous cannabinoids 2-arachidonylglycerol (2-AG) and anandamide
(AEA) play vital roles during nervous system development including regulating axonal
guidance and synaptogenesis. The degradation of 2-AG and AEA is mediated
by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively.
We have previously reported that developmental repeated exposure to 5
mg/kg chlorpyrifos (CPS) results in inhibition of these enzymes in rat forebrain
with FAAH activity being more sensitive than cholinesterase (ChE) activity. This
greater sensitivity of FAAH than ChE is also present following exposure to lower
dosages of CPS (18% ChE as compared to 40% FAAH inhibition at 4 hrs following
1 mg/kg CPS). However, it is not clear if the inhibition of FAAH results in any
changes in the level of the endocannabinoids especially at low dosages. To determine
this, 10 day old rat pups were exposed daily for 7 days to either corn oil or increasing
dosages of CPS (1, 2.5, or 5 mg/kg) by oral gavage. At 12 hrs post exposure
to the three dosages, forebrain 2-AG levels were significantly increase by 27%, 44%,
and 96% while forebrain AEA levels were significantly increased by 86%, 148%,
and 253%. This significant accumulation of 2-AG and AEA could result in activation
of endocannabinoid transmission during brain maturation. This could have
implications for the appropriate development of the endocannabinoid system leading
to permanent alterations in neuronal brain circuits and behavioral responses.
1326 PON1 STATUS MODULATES CEREBELLAR GENE
EXPRESSION CHANGES ASSOCIATED WITH
DEVELOPMENTAL EXPOSURE TO CHLORPYRIFOS
OXON.
T. B. Cole 1, 2 , R. P. Beyer 2 , T. K. Bammler 2 , S. S. Park 1 , F. M. Farin 2 , L. G.
Costa 2 and C. E. Furlong 1 . 1 Genome Sciences and Medicine, Division of Medical
Genetics, University of Washington, Seattle, WA and 2 Environmental and
Occupational Health Sciences, University of Washington, Seattle, WA.
Chlorpyrifos (CPF) affects brain development and function via multiple mechanisms.
Individuals carrying the Q192 allele of paraoxonase (PON1) are more sensitive
than those carrying the R192 allele to the effects of CPF and chlorpyrifos oxon
SOT 2011 ANNUAL MEETING 283