The Toxicologist - Society of Toxicology

ats. The majority of the studies focusing on DEHP toxicity used the oral route of
administration; however, the human sub-population with the highest exposure to
DEHP is infants being treated in neonatal intensive care units, where exposure is
mainly intravenous. Since DEHP is efficiently hydrolyzed in the gut to its active
metabolite MEHP, the route of exposure can have a significant impact on the toxicological
profile of DEHP. We investigated the effects of oral and intravenous (IV)
administration of DEHP in the lungs of a neonatal male rat model. Following a
modification of a study design by Cammack et al. (2003), five-day-old male
Sprague-Dawley rats were dosed either by oral gavage or tail vein injection with 0,
60, 300, or 600 mg DEHP/kg bw/day for 5 or 21 consecutive days. Body weights
were reduced relative to control in pups dosed for 21 days with 600 mg/kg/d
DEHP, independent of the route of administration. Lung weights were not
changed by any treatment. Five and 21 doses of IV, but not oral, 600 mg/kg/d
DEHP caused lung interstitial inflammation and hemorrhage. Multifocal granuloma
centered on capillary emboli were also observed in the alveoli of rats treated
with IV, but not oral, DEHP in a dose-responsive manner, with a LOAEL of 300
mg/kg/d for 5 doses and 60 mg/kg bw/d for 21 doses. No effects were observed in
testis of pups exposed to IV DEHP below 300 mg/kg bw/d for 5 or 21 doses. These
data suggest that IV DEHP is more toxic to the lung than an equivalent oral dose,
and that the lung may be more sensitive to IV DEHP than the testis in the neonatal
rat model. Funded in part by NTP IAG 224-07-0007 between the FDA/NCTR
and the NIEHS/NTP.
618 JUVENILE TOXICITY ASSESSMENT OF
ANIDULAFUNGIN IN RATS.
G. Chmielewski 1 , C. J. Bowman 1 , S. L. Ripp 1 , E. M. Lewis 2 , C. M. Sawaryn 1
and D. M. Cross 3 . 1 Pfizer Inc., Groton, CT, 2 Charles River Laboratories Preclinical
Services, Horsham, PA and 3 Pfizer Inc., Sandwich, United Kingdom.
Anidulafungin (a marketed, non-competitive inhibitor of (1,3)-β-D-glucan synthase)
is being evaluated for pediatric treatment of fungal infections, including
neonates. Juvenile toxicity studies with anidulafungin were conducted to support
neonatal dosing in the clinic as well as to evaluate long-term safety considerations.
The first study was a single dose pilot study administered on Postnatal Day (PND)
7 either intravenously (IV), subcutaneously, or intraperitoneally to Fisher rats to determine
a route of administration with exposure most consistent to intravenous infusion
used in the clinic and adult nonclinical studies (not technically feasible in
young rats). Subcutaneous administration was determined the most appropriate
route and was utilized in a subsequent repeat dose range-finding study from PND
4 to 28 at 0, 10, 30, or 60 mg/kg/day. Pups at ≥30 mg/kg/day had reduced body
weights. In satellite animals, anidulafungin was detected in brain, bone, and heart
following a single dose, while plasma exposure on PND 4 and 28 increased in proportion
with dose. In the pivotal juvenile study, rat pups were treated from PND 4
to 62 (followed by a 5 week recovery period) at 0, 3, 10, or 30 mg/kg/day to evaluate
potential liver toxicity (adult rat target organ) and possible permanent effects on
neurological function due to uncertainties associated with the blood brain barrier
development in neonates. Anidulafungin-related effects included slightly reduced
body weights, increased liver weights, and mild decreases in red blood cell mass
with increased reticulocyte counts. There was no liver pathology and in the post
treatment phase there were no effects on neurological function and no lasting effects
on body weight or hematology. In conclusion, the juvenile rat no-adverse-effect-level
(NOAEL) was 30 mg/kg/day (exposures similar to adult rat NOAEL)
suggesting that juvenile rats are not more sensitive than adult rats to anidulafungin
and that there are no permanent changes to neurological function.
619 ORGAN SYSTEM ASSESSMENTS IN JUVENILE DOG
TOXICOLOGY STUDIES.
K. Robinson, H. Penton, S. Y. Smith and M. Adamo. Toxicology, Charles River
Preclinical Services, Montreal, QC, Canada. Sponsor: M. Vézina.
For some juvenile toxicology studies the dog is considered the most appropriate
species. To meet regulatory guidances/requests from US FDA and EMA there may
be a need to study the development of organ systems, including nervous, cardiovascular,
gastro-intestinal, pulmonary, renal, immune, skeletal (growth) and reproductive,
that develop in the postnatal period. Techniques for assessment of the development
of many of these organ systems are readily available along with historical
control data. However there are limitations in assessing some endpoints in the juvenile
dog. For cardiovascular testing collection of direct or indirect blood pressure
and electrocardiographs (ECG) is feasible. Direct assessment of blood pressure (BP)
however has only been performed in dogs from 4 months of age. Considerations for
this method include the size of the transmitter to implant relative to animal size as
well as the BP catheter and ECG lead length to accommodate for rapid growth.
Jacketed external telemetry has been conducted from 2 months of age with data
collection for at least 24 hours. Pre-weaning ECG and indirect blood pressure using
a tail cuff can also be performed. Variability is reduced when using direct recording.
A full battery of assessments of skeletal growth ranging from measurements of
height and length to imaging (bone densitometry) techniques and histomorphometry
can be applied. For other evaluations, such as of the reproduction, the physiology
of the dog precludes the conduct of meaningful testing. Screens for several systems
such as renal and gastrointestinal are available. In others, such as the nervous
and immune systems, tests such as neurological screens and phenotyping, respectively,
are available. Neurological tests of learning and memory and immune function
testing with T-cell dependent antibody response (TDAR) are under development.
In conclusion, screening for effects on most major organ systems is feasible
being mindful that there are limitations for some assessments due to age, test availability
in toxicology laboratories and historical control data.
620 CHEMICAL INTOLERANCE, ATTENTION
DEFICIT/HYPERACTIVE DISORDER AND AUTISM—
A LINK?
L. P. Heilbrun, R. F. Palmer and C. S. Miller. Family Community Medicine,
University of Texas Health Science Center at San Antonio, San Antonio, TX. Sponsor:
G. Gould.
Background: Chemical intolerance—the inability to tolerate a wide variety of
everyday chemical exposures (fragrances, auto exhaust, cleaning compounds,
etc.)—has been associated in numerous studies with multi-system symptoms including:
asthma, chronic fatigue, cognitive and memory problems, etc. The primary
objective of this study was to investigate the possible association between
chemical intolerance and Attention Deficit/ Hyperactivity Disorder (AD/HD) and
Autism Spectrum Disorder (ASD). Methods: A case-control study was used to test
the hypothesis that mothers of children with AD/HD or ASD would score higher
on the Quick Environmental Exposure and Sensitivity Inventory (QEESI©)—a
validated tool for diagnosing chemical intolerance—than mothers whose children
do not have either ASD or AD/HD. Mothers with (n =183) and without (n= 146)
AD/HD children, and mothers with (n=282) and without (n=72) ASD children
participated in separate online surveys. Results: Compared to control mothers, case
mothers had significantly higher mean scale scores for Chemical Intolerance (p <
.001), Other Intolerances (food, drug, caffeine, alcohol etc.) (p=.01), and
Symptoms (p