The Toxicologist - Society of Toxicology

PCB and OH-PCB. To evaluate the health effect on the next generation, it is necessary
to estimate the contamination level of PCBs and OH-PCBs according to the
congeners.
622 ENDOCRINE EFFECTS OF A NOVEL HIV-NNRTI IN
SEXUALLY IMMATURE FEMALE CYNOMOLGUS
MONKEYS.
F. van Velsen 4 , J. Sternberg 1 , B. Niggemann 1 , S. Friderichs-Gromoll 1 , G.
Weinbauer 1 , I. Vanwelkenhuysen 2 , L. Grooten 2 , S. Lachau-Durand 4 , S. De
Jonghe 2 , L. De Schaepdrijver 2 , T. Coogan 3 , L. Lammens 2 , A. Raoof 4 and W.
Coussement 2 . 1 Covance Laboratories GmbH, Muenster, Germany, 2 GPCD, Janssen
Pharmaceutica, Beerse, Belgium, 3 PCD, Centocor, Radnor, PA and 4 PCD, Tibotec,
Beerse, Belgium.
The compound has shown endocrine effects on adrenal glands and ovaries in rats
and dogs indicative of adrenal CYP21 inhibition and early onset of ovulation
(dogs). Non-human primates share with man a significant adrenal androgenic pathway.
Inhibition of CYP21 may exert masculinization in prepubertal individuals as
has been described for congenital adrenal hypertrophy due to CYP21 deficiency.
The chosen model shares with women an identical physiology in terms of onset of
puberty and ovulation. The endocrine effects were further evaluated in 1-2 year old
female cynomolgus (Macaca fascicularis) treated for 8 weeks with 0, 200 and 500
mg/kg/day. The results on baseline and ACTH-stimulated hormone levels and
standard toxicity parameters indicate that the NNRTI inhibits CYP21 also in the
cynomolgus monkey. In addition, the compounds appeares to inhibit 17α-hydroxylase
and 17,20 lyase (CYP17), key enzymes for the adrenal androgenic pathway.
The enzyme inhibitions appeared to be partial and transient. The inhibition of
CYP17 and the partial and transient inhibition of CYP21 alleviate the concern of
masculinization of prepubertal children. The absence of any indication of early
onset of puberty in the immature cynomolgus monkey model being a more relevant
model for man neutralizes the concern due to the results of the dog studies. The
lower dose tested in the cynomolgus monkeys was not without adrenal endocrine
effects whereas the exposure to the compound was not significantly higher than
that in adult patients treated with the clinical efficacious daily dose of 25 mg. Longterm
clinical safety studies with higher doses than 25 mg qd have never resulted in
any clinically relevant endocrine effect. Therefore, it is concluded that the immature
cynomolgus monkey model is oversensitive to the adrenal endocrine effects of
the NNRTI.
623 IMPAIRED REPRODUCTION IN ADULT MALE, BUT
NOT FEMALE, RATS FOLLOWING JUVENILE
TREATMENT WITH THE AROMATASE INHIBITOR,
EXEMESTANE.
G. Cappon 1 , M. E. Hurtt 1 , R. E. Chapin 1 and L. Burns-Naas 2 . 1 DSRD, Pfizer,
Groton, CT and 2 DSRD, Pfizer, LaJolla, CA.
Aromatase inhibitors are currently being investigated in combination with growth
hormone for the ability to improve final height in children. Exemestane is an irreversible
steroidal aromatase inhibitor, structurally related to androstenedione.
Because of its mechanism of action, the drug was investigated for the potential to
affect mature reproductive systems when administered to immature rats. Male and
female rat pups were treated with exemestane (0, 30, 100, 300 mg/kg) once daily
from PND 7-50 (male) or 7-41 (female). Maturation of the reproductive system
was evaluated by monitoring the onset of vaginal patency or preputial separation.
After maturation, treated rats were mated with untreated rats to evaluate the potential
impact on reproductive function. After mating (males) or on GD14 (females)
rats were euthanized and reproductive organs evaluated microscopically.
Exemestane was well-tolerated at all dose levels and there were no effects on age at
onset of vaginal patency or preputial separation. There was no drug-related effect
on female reproductive function. Treatment of juvenile male rats with exemestane
caused an increase in cohabitation time prior to copulation and decreased copulation
rates; however, pregnancy rates and litter size was not affected in rats that successfully
mated. Decreased weight of the testis (10-15%) and epididymis (20-30%)
were noted at al dose levels and the number of Sertoli cells was decreased in all dose
groups. These data show that an aromatase inhibitor can reduce Sertoli cell proliferation
during maturation and at clinically-relevant concentrations. The sensitive
window for this effect is limited to the period of Sertoli cell proliferation, which is
completed in rats by around PND 15 and prior to puberty in humans. Treatment
beginning at a later time relative to the window for Sertoli cell proliferation or for a
longer duration is not expected to have any additional adverse effect since the effect
is not degenerative.
134 SOT 2011 ANNUAL MEETING
624 MOST BPA-FREE PLASTICS RELEASE CHEMICALS
HAVING ESTROGENIC ACTIVITY (EA): BPA-FREE
DOES NOT MEAN EA-FREE.
G. Bittner 1, 2, 3 , C. Z. Yang 1 , S. Yaniger 2 and D. Klein 2 . 1 CertiChem, Inc., Ausin,
TX, 2 PlastiPure, Inc., Austin, TX and 3 University of Texas, Austin, TX. Sponsor:
R. Tice.
Scientists have recently expressed serious concerns about possible adverse health effects
of bisphenol-A (BPA) that has estrogenic activity (EA) that causes many adverse
health effects at low (pM-nM) doses, especially in fetal and juvenile mammals.
We used a roboticized MCF-7 cell proliferation assay to quantify release of
chemicals having EA in saline or ethanol extracts of many types of commercially
available plastic materials. To properly detect release of chemicals having EA, we
show that plastic products should be extracted with more-polar and less-polar solvents—and
exposed to common-use stresses such as microwaving, UV radiation,
and/or boiling. If only one extraction solvent is used and no common-use stresses
are applied, then most plastic products are mischaracterized as EA-free. In contrast,
when extracted with two solvent types and exposed to common use stresses, almost
all ( over 90%) commercially available plastic products, including those advertised
as BPA-free, release chemicals having EA. As one example, all products tested made
from Eastman’s Tritan resins released chemicals having easily detectable EA—often
at levels greater than that released by BPA-based polycarbonate bottles.
Products that do not release chemicals having EA can be cost-effectively made with
currently available technologies by using chemicals with no detectable EA in all
steps of the manufacturing process. Such EA-free products are producible at minimal
additional cost. It is now realistically possible to eliminate the potential health
risk posed by the leaching of chemicals having EA from plastics into food products.
Supported by NIH SBIR44ES014806.
625 MANGANESE LEVELS IN CARPET DUST ARE
ASSOCIATED WITH PROXIMITY TO AGRICULTURAL
USE OF MANEB AND MANCOZEB.
R. Gunier 1 , D. R. Smith 2 , A. Bradman 1 and B. Eskenazi 1 . 1 University of
California, Berkeley, CA and 2 University of California, Santa Cruz, CA.
Rationale: Although manganese (Mn) is an essential nutrient, at high exposure levels
Mn is a potent neurotoxicant. The fungicides maneb and mancozeb are ~21%
Mn by weight and more than 140,000 kg of these pesticides are applied each year
in the Salinas Valley, California. However, it is not clear whether these pesticides
contribute to environmental Mn exposure to children. The objective of this study
was to evaluate the relationship between Mn levels in carpet dust and residential
proximity to reported agricultural uses of maneb and mancozeb. Procedures: We
collected carpet dust samples from over 300 residences enrolled in the Center for
the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study.
Carpet dust samples were sieved to < 150 μm, digested in 7.5 N nitric acid and analyzed
using inductively coupled plasma optical emission spectroscopy. The latitude
and longitude of each residence was determined using GPS. We used a geographic
information system to summarize pesticide use for several distances around each
residence (500, 1000, 1500 and 2000 m) and time periods prior to dust collection
(7, 30, 90 and 180 days). We calculated Pearson correlation coefficients between
Mn levels in carpet dust and the pounds of maneb and mancozeb applied for these
combinations of distance and time. Results: We found detectable levels of Mn in all
homes with a median concentration of 173 μg/g (range=8.4-414 μg/g; n=75 residences
analyzed thus far). The strongest correlation (ρ=0.48) with Mn levels in carpet
dust (μg Mn/g dust) was observed for the pounds of maneb and mancozeb applied
within 1,500 m of the home during the 30 days prior to sample collection.
Mn concentrations were also significantly higher in homes where farmworkers lived
than in those without farmworkers (p