Monograph on the Potential Human Reproductive and ... - OEHHA

320 CHAPIN ET AL.
Table 81
Summary of High Utility Developmental Toxicity Studies (Single Dose Level)
Dose and dosing period
Model (route) (mg/kg bw/day) Significant developmental findings Reference
Rat
Sprague–Dawley (oral by 0.04, PND 23–30 and animals m ERa expression in females vs. males in medial Ceccarelli et al.
pipette) evaluated at PND 37 or 90 pre-optic area (also seen with positive control)k (2007)
Testosterone in males at PND 37 but not PND 90
Sprague–Dawley males 0.040, PND 23–30 k Investigation of new object, k intromission Della Seta et al.
(oral by pipette) latency, kserum testosterone (2006)
F344/N dams (gavage) 0.1, GD 3–PND 20 k Correct avoidance responses and m failure of Negishi et al.
avoidance in active avoidance testing; no m in (2004a)
locomotion following trans-2phenylcyclopropylamine
hydrochloride
challenge in males
Sprague–Dawley males 100, PND 23–53 m Age of preputial separation; m kidney and Tan et al. (2003)
(gavage) thyroid weights; k liver weight; k cortical
thickness of the kidney; m hydronephrosis; m
multinucleated giant cells in seminiferous
tubules; kno. undergoing spermatogenesis
Mouse
CD-1 dam (oral) 0.050, GD 16–18 m Anogenital distance adjusted for body weight Gupta (2000)
on PND60; m prostate weights on PND 3, 21,
and 60; k relative (to body weight) epididymis
weight in the bisphenol A group on PND 60; m
androgen receptor binding on PND 21 and 60
CD-1 dam (oral from 0.010, GD 11–18 k Place preference associated with d- Laviola et al.
syringe) amphetamine in females (2005)
CD-1 dam (oral by pipette) 0.010, GD 14–18; offspring In mice exposed only during gestational Palanza et al.
mated and dosed with 0 or development or in adulthood during (2002)
0.010 on GD 14–18 pregnancy: k time nursing and in nest and m
time nest building, resting alone, grooming, and
out of nest In mice exposed during both
gestational development and in adulthood
during pregnancy: m time resting alone
CD-1 dam (oral by pipette) 0.010, GD 14–18 m No. of prostate ducts and proliferating cell Timms et al.
nuclear antigen staining in dorsolateral (2005)
prostate; m prostate duct volume in dorsolateral
and ventral prostate
m, k Statistically significant increase, decrease compared to controls; 2no statistically significant effects compared to controls.
bisphenol A was given at multiple dose levels. These
studies included oral and subcutaneous administration
routes; due to pharmacokinetic considerations, studies
using the oral route are of greater utility in estimating
human risk.
3.4 Summary of Developmental Toxicity Data
The studies summarized here are those considered by
the Panel to be the most important and relevant for the
assessment of the effects of Bisphenol A on the human
population. Evaluation of the scientific literature was
made on the scientific quality of the study and also on its
relevance to the assessment of the level the concern about
potential effects of BPA on human health. The judgment
was based on the criteria the Panel adopted which
focused on the potential for providing information for
the evaluation process. Several excellent studies have
been placed in the ‘‘adequate-but-limited-utility’’ category
with regard to the evaluation process. The Panel did
not consider the source of funding of any of the studies
in any of their deliberations.
It is highly unlikely that humans would ever experience
the very high internal levels of bisphenol A that are
produced after an injection of bisphenol A. While it
would be possible to measure levels of parent compound
and metabolite after injections, no parenteral exposure
studies in this data set have done so. Section 1 and
(Wilson et al., 2006) indicate that ca. 99% of human
exposure comes from dietary sources, and bisphenol A is
subject to efficient first-pass metabolic conversion in the
gut and liver to the inactive glucuronide conjugate in
humans and rats (Pottenger et al., 2000; Völkel et al., 2002;
Inoue et al., 2003b). In contrast, bisphenol A injected
subcutaneous or i.p. circulates as much higher proportion
of the unconjugated parent compound (Pottenger
et al., 2000). Because oral exposure is so relevant to the
human situation, and the uncertainties associated with
the altered internal metabolite profile and the abundant
data from oral studies, the Panel puts greater weight on
studies using the oral route of exposure for formulating
levels of concern about human exposures.
The hypothesis has been advanced that the Charles
River SD rat is insensitive to estrogens and other EDCs
and therefore it should not be used for developmental
studies of potential endocrine disruptors, and the studies
of the effects of BPA that used this strain should be
discounted. In order to address this important issue the
Birth Defects Research (Part B) 83:157–395, 2008