TY - CHAP

T1 - Identification and initial toxicity assessment of Thalidomide and its phototransformation products

AU - Mahmoud, Waleed M. M.

AU - Toolaram, Anju Priya

AU - Menz, Jakob

AU - Leder, Christoph

AU - Schneider, Mandy

AU - Kümmerer, Klaus

N1 - Conference code: 14

PY - 2013

Y1 - 2013

N2 - Thalidomide (TD) became known as a sedative drug used for sleeping pills and morning sickness of pregnant women in the 1950s. In the 1960s, TD was withdrawn because of its teratogenicity. Recently, TD became a promising drug for the treatment of a number of cancers and inflammatory diseases. Consequently, a potential increased influx of TD into the aquatic environment has to be expected. Furthermore, incomplete degradation in surface water or effluent and drinking water treatment photolysis can occur. This makes it imperative to assess the fate and toxic effects of TD and its transformation products. In this study, the behavior of TD was monitored during irradiation with a medium-pressure Hg-lamp. The primary elimination of TD was monitored and structures of PTPs were assessed by LC-UV-FL-MS/MS. The estimation of the relevant properties of TD and its photoproducts (PTPs) and hydrolysis products (HTPs) was performed using in silico QSAR models. Mutagenicity of 47mg/L TD after 2, 4, 8, 16, 32, 64 and 128 min of irradiation was assessed in the Ames microplate format (MPF) aqua assay (Xenometrix, AG). In addition, toxicity towards environmental bacteria was investigated in a modified luminescent bacteria test using Vibrio fischeri. New PTPs were formed during irradiation. They were more polar than TD. All the PTPs peaks increased with irradiation time until 32 min and then began to decrease. One PTPs peak was formed at 16 min then increased until 128 min. Two of the PTPs were isomers of TD with the same molecular mass. TD and its PTPs did not exhibit mutagenic activities in the Salmonella typhimurium strains TA 98, and TA 100 with and without metabolic activation. In contrast, QSAR analysis of PTPs and HTPs provided evidence for mutagenicity and carcinogenicity by investigating additional endpoints in silico compared with the experimental Ames tests. In the luminescent bacteria test, a steady increase of toxicity during the treatment procedure was observed. The acute toxicity started to increase significantly after 16 min of irradiation compared to the parent compound. After 128min of irradiation, a maximum of 96% acute luminescence inhibition of the reaction mixtures was measured [dilution 1:2 (v/v)]. The diluted reaction mixtures [dilution 1:50 (v/v)] showed no significant inhibition. The analysis of luminescence inhibition and growth inhibition showed a significant toxification starting from 32 min of irradiation. QSAR analysis with these endpoints provided evidence for positive alerts for acute toxicity on environmental bacteria in several identified PTPs and HTPs.In conclusion, the UV irradiation eliminated TD itself but lead to the formation of several PTPs. Some of the PTPs are more toxic to the investigated bacteria than the parent compound but do not show mutagenic activity in the Ames test. Nevertheless the results show the toxic potential of the photo PTPs and deserve further attention.

AB - Thalidomide (TD) became known as a sedative drug used for sleeping pills and morning sickness of pregnant women in the 1950s. In the 1960s, TD was withdrawn because of its teratogenicity. Recently, TD became a promising drug for the treatment of a number of cancers and inflammatory diseases. Consequently, a potential increased influx of TD into the aquatic environment has to be expected. Furthermore, incomplete degradation in surface water or effluent and drinking water treatment photolysis can occur. This makes it imperative to assess the fate and toxic effects of TD and its transformation products. In this study, the behavior of TD was monitored during irradiation with a medium-pressure Hg-lamp. The primary elimination of TD was monitored and structures of PTPs were assessed by LC-UV-FL-MS/MS. The estimation of the relevant properties of TD and its photoproducts (PTPs) and hydrolysis products (HTPs) was performed using in silico QSAR models. Mutagenicity of 47mg/L TD after 2, 4, 8, 16, 32, 64 and 128 min of irradiation was assessed in the Ames microplate format (MPF) aqua assay (Xenometrix, AG). In addition, toxicity towards environmental bacteria was investigated in a modified luminescent bacteria test using Vibrio fischeri. New PTPs were formed during irradiation. They were more polar than TD. All the PTPs peaks increased with irradiation time until 32 min and then began to decrease. One PTPs peak was formed at 16 min then increased until 128 min. Two of the PTPs were isomers of TD with the same molecular mass. TD and its PTPs did not exhibit mutagenic activities in the Salmonella typhimurium strains TA 98, and TA 100 with and without metabolic activation. In contrast, QSAR analysis of PTPs and HTPs provided evidence for mutagenicity and carcinogenicity by investigating additional endpoints in silico compared with the experimental Ames tests. In the luminescent bacteria test, a steady increase of toxicity during the treatment procedure was observed. The acute toxicity started to increase significantly after 16 min of irradiation compared to the parent compound. After 128min of irradiation, a maximum of 96% acute luminescence inhibition of the reaction mixtures was measured [dilution 1:2 (v/v)]. The diluted reaction mixtures [dilution 1:50 (v/v)] showed no significant inhibition. The analysis of luminescence inhibition and growth inhibition showed a significant toxification starting from 32 min of irradiation. QSAR analysis with these endpoints provided evidence for positive alerts for acute toxicity on environmental bacteria in several identified PTPs and HTPs.In conclusion, the UV irradiation eliminated TD itself but lead to the formation of several PTPs. Some of the PTPs are more toxic to the investigated bacteria than the parent compound but do not show mutagenic activity in the Ames test. Nevertheless the results show the toxic potential of the photo PTPs and deserve further attention.

KW - Chemistry

UR - http://www.icce2013.org/docs/BookOfAbstracts.pdf

M3 - Published abstract in conference proceedings

SP - 366

BT - 14th EuCheMS International Conference on Chemistry and the Environment

PB - European Association for Chemical and Molecular Sciences / Division of Organic Chemistry

T2 - 14th International Conference on Chemistry and the Environment - EuCheMS 2013

Y2 - 25 June 2013 through 28 June 2013

ER -