HABILITATIONSSCHRIFT

 


Tierärztliche Hochschule Hannover / Bibliothek – University of Veterinary Medicine Hannover – Foundation / Library

 

Nils Helge Schebb

 

Investigation of human exposure, metabolism and biological effects of the antibacterial triclocarban

 

NBN-Prüfziffer

urn:nbn:de:gbv:95-h2706

publication

Hannover, Tierärztliche Hochschule, Habilitationsschrift, 2010

text

http://elib.tiho-hannover.de/dissertations/h_schebb14.pdf

summary

The antibacterial soap additive triclocarban (TCC) is widely used in personal care products. TCC shows a high environmental persistence in the aquatic environment and possesses the potential to act as an endocrine disruptor in mammals. In the present work we developed analytical methods for the detection of TCC and its metabolites and applied them to determinate human exposure and bioconcentration in fish. Moreover, metabolism and off-target effects on human enzymes were investigated to assess potential effects of TCC on human health. Using a new sensitive and rapid online solid phase extraction-LC-MS/MS method and a newly developed immunoassay, levels of TCC in urine and blood were quantified following exposure by showering of human subjects with a commercial bar soap containing 0.6% TCC. Starting from a temporary topical dose of 70 ± 15 mg TCC from soap, a low but significant dose of about 6 µg/kg body weight was absorbed by the subjects. TCC blood levels reached a concentration of up to 500 nM. Elimination of TCC required more than 72 hours; however no accumulation was observed after repeated exposure by showering.

 

The tested Medaka fish bioconcentrate TCC from the surrounding water by about 700-fold, which is lower than expected based on the chemical properties of the highly lipophilic halogenated hydrocarbon. After transferring the fish into fresh water, the compound was rapidly eliminated with a t1/2 of 1 h.

 

In humans and fish TCC was excreted in form of its metabolites, and it is concluded that higher organisms possessing an efficient phase I and phase II metabolism do not accumulate TCC, as earlier described for snails and algae. Oxidative conversion by cytochrom-P450 monooxygenases led to the hydroxylated metabolites 2’-OH, 3’-OH, 6-OH-TCC and 3,4-dichloro-4’-hydroxy-carbanilide (DHC), which are rapidly conjugated by various UDP-glucuronosyltransferases. Renal excretion of TCC almost exclusively occurs in form of its direct N-glucuronides. UGT1A9 was the only UGT isoform that catalyzed this direct conjugation.

 

The ortho and para hydroxylated phase I metabolites of TCC can be further oxidized to electrophilic reactive quione imines, which covalently bind glutathione (GSH) and proteins. However, the formation of protein adducts was found to be very low in keratinocytes showing significant CYP activity. Upon co-treatment with an Ah- receptor agonist a substantial - but still low - level of protein adducts was detected in the skin cells. The inducible isoform CYP1A1 was found to catalyze the metabolic activation of TCC via dehalogenation and hydroxylation to DHC and oxidation to the para-quione imine. It is concluded that co-exposure of Ah-receptor agonists such as polycyclic aromatic hydrocarbons and TCC may lead to the formation of reactive metabolites in skin, which raises the possibility of skin sensitization.

 

By using a newly developed LC-MS based high-content screening method it was shown that TCC is an inhibitor of the soluble epoxide hydrolase in the nanomolar concentration range. However, a topical administration of TCC to rats at a dose that is similar to the concentration of TCC to which humans are exposed during showering with TCC containing soap did not alter plasma biomarkers of sEH activity. Nevertheless, there is only a small margin between the absorbed doses in animal studies causing a systemic sEH inhibition and downstream biological effects and exposure levels. Moreover, local dermal effects of TCC containing cosmetics are likely, if one takes into account the high sEH inhibitory potency of the compound together with its high concentration in cosmetics.

 

The findings indicate that a careful risk-benefit analysis of TCC in personal care products should be undertaken. In particular, long term exposure studies in man, which include biomonitoring of TCC and sEH activity in blood and skin should be carried out to evaluate if the exposure level reached when using PCPs containing up to 1.5% TCC might pose a health risk. With the analytical methods method described herein, we provide excellent analytical tools for these studies.

 

keywords

Antibakterieller Wirkstoff, lösliche Epoxidhydrlase, Metabolismus, antibacterial, soluble epxoxide hydrolase, metabolism

kb

953