Bisphenol A Controlled Exposure Study

Bisphenol A (BPA) is utilized primarily in the manufacture of polycarbonate plastic and epoxy
resins, which are widely used in the fabrication of baby bottles and food can linings.
Consequently, human exposures to BPA are widespread. However, there is still uncertainty
about the extent and nature of these exposures. This pharmacokinetic (PK) study is aimed at
refining our understanding of the metabolism and excretion of BPA following two different
routes of administration. This investigation is also intended to help resolve current
controversies in BPA risk assessment. We will administer 100 microgram/kg body weight (bw) of
deuterated BPA (d-BPA) orally and/or dermally (as an ethanol solution or a
carboxymethylcellulose suspension), in up to 50 participants, with comparable numbers of men
to women, and collect blood and urine for measurements of d-BPA and d-BPA conjugates at
selected time points over a six day period post-dosing. The use of d-BPA will allow the
detection of the administered BPA to be distinguished from background BPA. The primary
endpoint of the study is detection of measurable d-BPA and d-BPA conjugates in blood and
urine after administration of a single dose of 100 microgram/kg bw d-BPA applied orally
and/or dermally (as an ethanol solution or a carboxymethylcellulose suspension). Participants
will be given an option to complete either one or both phases of the study, the exposure
visits separated by a period of at least 4 weeks. Dose selection was based on balancing the
need for detectable levels of BPA in blood and urine to meet the objective and the need to
minimize human subject risk. Data from the first 3 participants in the study, who received
oral d-BPA, confirmed dosing during the oral pilot phase was sufficient in capturing
measurable d-BPA in blood and urine and will continue at 100 microgram/kg bw of d-BPA for
oral dosing. Dermal exposure will consist of a pilot phase for this route of administration
comprising 4 participants to assess whether 100 microgram/kg bw of d-BPA applied to the skin
is sufficient to obtain measurable d-BPA in blood and/or urine in order to establish PK
parameters and to evaluate whether the time points are appropriate and necessary. If needed,
the dermal pilot phase will be repeated using an ethanol solution rather than a
carboxymethylcellulose suspension. The design includes sufficient sampling of blood and urine
to define relevant PK parameters, including the rate of BPA absorption, plasma elimination
rate, area under the curve (AUC) and apparent clearance, half-life, the urinary excretion
rate, and the fractional metabolic clearance of the glucuronide and sulfate conjugates.

- INCLUSION CRITERIA:

Participants meeting all of the following criteria will be considered for admission into
this study:

- Male or female 25-45 years of age at the time of enrollment.

- Able to fast overnight (at least 8 hours).

- Able to understand and provide written informed consent in English.

- Able to travel to the NIEHS Clinical Research Unit (CRU) for all required study
visits.

- Male and females of reproductive age agree to use contraception to avoid conceiving a
child and agree not to donate eggs or sperm for six months following their
participation in the study.

EXCLUSION CRITERIA:

- Uncontrolled diabetes:

--Hemoglobin A1C of greater than or equal to 6.5% or a fasting blood glucose of
greater than or equal to 126 mg/dL.

- Known liver dysfunction or disease:

- ALT - higher than the normative value or determined abnormal by the PI.

- AST - higher than the normative value or determined abnormal by the PI.

- ALP - higher than the normative value or determined abnormal by the PI.

- Known kidney dysfunction or disease:

- Estimated Glomerular Filtration Rate (eGFR)- <60 ml/min per the MDRD equation.

- Clinically relevant anemia as defined as hemoglobin concentration <13g/dL for
males and hemoglobin concentration <11g/dL for females.

- Pregnancy: Positive serum quantitative hCG pregnancy test.

- Current lactation.

- BMI less than or equal to 19 and greater than or equal to 35

- Medication use: Given the widespread use of medications, it may not be practical to
instruct subjects to avoid all medication prior to and during the study. Thus,
participant exclusion will be based on use of medications within 48 hours of the
exposure and for the 6 days following the exposure that affect glucuronidation of the
d-BPA dosage: Salicylic acid, acetaminophen, ibuprofen, naproxen, mefenamic acid,
diclofenac, gliclazide carbamazepine, valproic acid, cimetidine, sulfasalazine,
amoxicillin and erythromycin.

- Recent blood donation within the past 8 weeks of the BPA exposure visit (so as not to
exceed donation of 10.5 mL/kg or 550 mL over an 8 week period).