Kinetic Time Courses of Bisphenol-S in Volunteers

Kinetic Time Courses of Bisphenol-S in Female Volunteers Orally and Dermally Exposed to Bisphenol-S

The time course of bisphenol S in plasma and urine will be monitored in female adults exposed to a single oral and dermal dose of bisphenol-S. Six female will be recruited. Blood and urine will be collected at specified times post-treatment. Bisphenol concentrations will be measured in those samples.

Study Overview

• Status: Unknown
• Conditions: PHARMACOKINETICS
• Intervention / Treatment: Other: Bisphenol-S

Detailed Description

As a first step, volunteers will be exposed orally acutely to 0.1 mg / kg of body weight (bw) orally (corresponding to 7 mg for an individual of 70 kg). According to the recent assessment by the US Environmental Protection Agency (U.S. EPA), this dose is considered to be associated with no adverse effect for a subchronic exposure scenario in rats (EPA, 2014). The deuterated form of bisphenol S (BPS d8, Toronto Research Chemical) will be used to avoid potential interference with BPS in the diet. The dose that will be administered to volunteers (0.1 mg / kg bw) orally, in deuterated form, is identical to that previously used in a study in volunteers exposed to Bisphenol A (0.1 mg / kg of BPA-d6 administered oral in volunteers) (Thayer et al., 2015).

The BPS reference dose (RfD) was established based on a 45-day parental toxicity study in orally exposed male rats with No-Observed Adverse Effect Level (NOAEL) 10 mg / kg bw (Lowest-Observed-Adverse-Effect-Level (LOAEL) of 60 mg / kg bw / day for parental toxicity, and a NOAEL and LOAEL value of 60 and 300 mg / kg bw / day for reproductive toxicity) (EPA 2014) (page 4-282). The dose administered in volunteers will be 100 times lower than the NOAEL and consider an inter-species uncertainty factor of 10 and interindividual of 10. The six volunteers will then be exposed orally acutely to the previously determined dose (0.1 mg / kg bw).

For the administration, the product will be dissolved in ethanol (100 mg / ml equivalent to 10 mg / 100 μl) and the solution will be deposited on a cookie (deposit of about 70 μl of solution on a cookie for an individual of 70 kg) and the ethanol is allowed to evaporate before giving each volunteer, with the subsequent consumption of 100 ml of water.

In a second component, volunteers will be exposed dermally acute at a dose of 1 mg / kg bw. It is important to note that there is currently no recommended reference dose for dermal exposure. Studies on the toxicokinetics of bisphenol A (BPA) in the animal and human model estimated that the absorption fraction was 8.6 ± 2.1% in human skin explants (n = 7) (Demierre et al. , 2012). The expected dermal administration dose assumes that dermal absorption is <10% based on the Demierre study and therefore may be higher than the oral dose. Preliminary experience on a volunteer will be done before doing all the planned volunteers.

About 48 hours before dermal exposure to BPS, it is recommended to remove the hair on the forearm while taking care not to irritate the skin too much. The solution will then be applied to an area of 40 cm2 of the forearm and delimited by the indelible marker. The BPS will be added in suspension in an aqueous solution containing 1% of carboxymethylcellulose and administered in the form of drops (70 µl for an individual of 70 kg). The treated area will be left uncoated and unwashed for a period of 4 hours. After 4 hours, the application area will be washed with water and soap. This type of application is therefore similar to an exposure of the general population via the skin (manipulation of cash receipts).

The kinetics of bisphenol S (BPS) and its metabolite (glucurono-conjugated BPS (BPSG) in blood will be documented by collecting blood by venous puncture at time: -30 min (control sample) and at fixed times during a 48-h period post-treatment: at 15 min, 30 min, 45 min, 1 h, 1 h 15, 1 h 30, 1 h 45, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 24 h and 48 h post-treatment (n = 17 samples per individual). A catheter will be inserted during the day of exposure, to allow serial blood sampling. A total of 20 ml will be collected per time point, which represent a total of 340 ml, which is inferior to a blood donation.

To document urinary time cours, complete urine voids will be collectedin distinct bottles at fixed time periods: -10 h-0 h (control) and 0-2 h, 2-4 h, 4-6 h, 6-8 h, 8-10 h, 10-12 h, 12-14 h, 14-24 h, 24-48 h and 48-72 h post-administration (n = 11 collections per individual and all void between two time points will be pooled).

• Study Type: Interventional
• Enrollment (Anticipated): 6
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Michèle Bouchard, PhD; Phone Number: 1640 5143436111; Email: michele.bouchard@umontreal.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3C3J7
      • Recruiting
      • Université de Montréal
      • Contact: Michèle Bouchard, PhD; Phone Number: 1640 5143436111; Email: michele.bouchard@umontreal.ca
      • Contact: Jonathan Côté, MSc; Phone Number: 2374 5143436111; Email: jonathan.cote.3@umontreal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female

Exclusion Criteria:

• People with liver or kidney problems or cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bisphenol-S kinetics - oral exposure; Six female volunteers will be exposed orally acute at the reference dose level(0.1 mg / kg bw). For the administration, the product will be dissolved in ethanol (100 mg / ml equivalent to 10 mg / 100 μl) and the solution will be deposited on a cookie (deposit of about 70 μl of solution on a cookie for an individual of 70 kg) and the ethanol is allowed to evaporate before giving each volunteer, with the subsequent consumption of 100 ml of water.	Other: Bisphenol-S; Oral and dermal exposure in volunteers
Experimental: Bisphenol-S kinetics - dermal exposure; volunteers will be exposed dermally acute at a dose of 1 mg / kg bw. The solution will be applied to an area of 40 cm2 of the forearm and delimited by the indelible marker. The BPS will be added in suspension in an aqueous solution containing 1% of carboxymethylcellulose and administered in the form of drops (70 .mu.l for an individual of 70 kg). The treated area will be left uncoated and unwashed for a period of 4 hours. After 4 hours, the application area will be washed with water and soap. This type of application is therefore similar to an exposure of the general population via the skin (manipulation of cash receipts).	Other: Bisphenol-S; Oral and dermal exposure in volunteers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicokinetics of bisphenol-S	Time course in blood and urine	0-72 h post-treatment

Collaborators and Investigators

• Sponsor: Université de Montréal
• Investigators: Principal Investigator: Michèle Bouchard, PhD, Université de Montréal

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: November 7, 2017
• First Submitted That Met QC Criteria: November 7, 2017
• First Posted (Actual): November 13, 2017

Study Record Updates

• Last Update Posted (Actual): May 9, 2018
• Last Update Submitted That Met QC Criteria: May 3, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Bisphenol S, toxicokinetics
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Estrogens, Non-Steroidal; Estrogens; Antioxidants; Free Radical Scavengers; Bisphenol A
• Other Study ID Numbers: EST-17-174

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No