Estimation of tetrabromobisphenol A (TBBPA) percutaneous uptake in humans using the parallelogram method

Abstract

Tetrabromobisphenol A (TBBPA) is currently the world’s highest production volume brominated flame retardant. Humans are frequently exposed to TBBPA by the dermal route. In the present study, a parallelogram approach was used to make predictions of internal dose in exposed humans. Human and rat skin samples received 100 nmol of TBBPA/cm2 skin and absorption and penetrance were determined using a flow-through in vitro system. TBBPA-derived [14C]-radioactivity was determined at 6 hour intervals in the media and at 24 hours post-dosing in the skin. The human skin and media contained an average of 3.4% and 0.2% of the total dose at the terminal time point, respectively, while the rat skin and media contained 9.3% and 3.5%, respectively. In the intact rat, 14% of a dermally-administered dose of ~100 nmol/cm2 remained in the skin at the dosing site, with an additional 8% reaching systemic circulation by 24 hours post-dosing. Relative absorption and penetrance was less (10% total) at 24 hours following dermal administration of a ten-fold higher dose (~1,000 nmol/cm2) to rats. However, by 72 hours, 70% of this dose was either absorbed into the dosing-site skin or had reached systemic circulation. It is clear from these results that TBBPA can be absorbed by the skin and dermal contact with TBBPA may represent a small but important route of exposure. Together, these in vitro data in human and rat skin and in vivo data from rats may be used to predict TBBPA absorption in humans following dermal exposure. Based on this parallelogram calculation, up to 6% of dermally applied TBBPA may be bioavailable to humans exposed to TBBPA.

The biological fate of decabromodiphenyl ethane following oral, dermal or intravenous administration

“…Dermal uptake and penetrance were greater than expected when compared to previous dermal disposition studies performed in this laboratory (Knudsen et al, 2015, Knudsen et al, submitted 2016). When maximal flux was calculated, DBDPE flux fell between that of 2-ethylhexyl tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP) and greatly exceeded the estimated flux for decabromodiphenyl ether (Abdallah et al, 2015a).…”

“…Dermal studies were conducted as described previously (Knudsen et al, 2015). A single dermal dose of [ 14 C]-DBDPE (5 μL, 2.7 nmol/cm 2 ) dissolved in toluene was applied to dorsal scapular skin and samples were collected for 24 h. Toluene was used as a vehicle due to limited solubility of the test chemical in more traditional solvents such as ethanol or acetone in this laboratory.…”

“…In addition, in vitro studies were conducted using split-thickness skin (i.e., epidermis and upper portion of the dermis) from human donors and female SD rats exposed to DBDPE. For these studies, the term ‘absorbed’ is used to describe the portion of the applied dose found within the skin, ‘penetrated’ is used to describe chemical that has completely diffused through the skin into the underlying media, analogous to the amount reaching systemic circulation following in vivo exposure (Demierre et al, 2012, Knudsen et al, 2015). The sum of excreted and retained [ 14 C]-radioactivity in tissues outside the dosed skin was used to determine the total penetrated fraction in vivo.…”

Estimation of human percutaneous bioavailability for two novel brominated flame retardants, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP)

“…In vitro studies were conducted as described previously by Knudsen et al (53). Briefly, full-thickness human skin was obtained from the National Disease Research Interchange (Philadelphia, PA, USA) from 4 Caucasian individuals aged 78-87 years old (2 male and 2 female, dorsal/scapular skin, excised ≤ 12 h post-mortem, shipped at −80 °C).…”

“…Similarly, although dose retained within skin (‘absorbed’) may ultimately be removed by normal desquamation and never reach the bloodstream, amounts recovered in the ‘absorbed’ fraction were included in the estimations of bioavailability in an effort to provide conservative estimates for uptake. In descriptions of in vitro experiments, ‘penetrated’ is used to describe chemical that has completely diffused through the skin into the underlying fluid (termed ‘receptor fluid or perfusion media’), analogous to the amount reaching systemic circulation following in vivo exposure (52, 53). The sum of excreted and retained [ 14 C]-radioactivity in tissues outside the dosed skin was used to determine the total penetrated fraction in vivo .…”