Photolysis Kinetics Of Five Antiviral Drugs In Aqueous Environment And Their Toxicity Prediction Evaluation

The water environment accounts for 71%of the earth’s surface area and is in the dynamic balance of continuous circulation on the earth.The change of chemical composition and content in the water environment has a great impact on the surrounding ecological environment.Most organic pollutants undergo a series of natural degradation processes after entering the water environment.Light conversion caused by solar radiation is one of the most important attenuation pathways of pharmaceuticals and personal care products（PPCPs）in the water environment.Antiviral drugs are part of widely used PPCPs.According to the global pharmaceutical sales data,their sale volume ranks in the top 10.The massive use and discharge of antiviral drugs pose a potential threat to aquatic organisms and humans.Thus,it is critical to understand the photochemical degradation behavior of antiviral drugs in aqueous environment and provide a data basis for environmental persistence and toxicity assessment.In this study,the photolysis kinetics of five antiviral drugs（emtricitabine,zidovudine,abacavir,stavudine and lamivudine）in pure water,fresh water and seawater and the effects of different environmental conditions were studied using simulated solar experiment,and the direct photolysis products and pathways of emtricitabine and abacavir were analyzed.The toxicity of parent chemicals and photolysis products of five antiviral drugs was evaluated by computational toxicology tools.The results are given as follows:Emtricitabine and zidovudine mainly undergo direct photolysis（about 58-80%and 87.7-99.7%respectively）,abacavir mainly undergoes indirect photolysis（about74.6-83.3%）,while stavudine and lamivudine only undergo direct photolysis.The second-order reaction rates of emtricitabine,zidovudine,abacavir,lamivudine and stavudine with ~1O₂are（2.43±0.40）×10~8M^-1s^-1,（8.91±0.29）×10~8M^-1s^-1,（4.93±0.22）×10~8M^-1s^-1,（0.99±0.06）×10~8M^-1s^-1,（1.86±0.09）×10~8M^-1s^-1respectively.The second-order reaction rates of emtricitabine,zidovudine,abacavir,lamivudine and stavudine with·OH are（3.56±0.32）×10¹⁰M^-1s^-1,（2.36±0.04）×10¹¹M^-1s^-1,（8.93±0.34）×10¹⁰M^-1s^-1,(1.54±0.02×10¹¹M^-1s^-1,（2.47±0.08）×10¹⁰M^-1s^-1respectively.The photolysis rates of emtricitabine and zidovudine in fresh water are lower than that in pure water,but higher than in seawater while abacavir is on the opposite.The photolysis rate of abacavir in seawater is six times than that in pure water.Stavudine and lamivudine are photostable in pure water,while the photolysis rate in fresh water is higher than that in seawater.It is worth noting that in addition to direct and indirect photolysis abacavir could also undergo self-sensitization photolysis.For the influence of environmental factors,this paper mainly focuses on the effects of DOM（dissolved organic matters）,some anions and NH₄⁺.DOM can promote the photolysis of abacavir,stavudine and lamivudine,but inhibit the photolysis of emtricitabine and zidovudine.NO₃^-can significantly promote the photolysis of these five antiviral drugs.NO₂^-has no obvious effects on the photolysis of emtricitabine and zidovudine but can significantly inhibit abacavir and promote the reaction rate of stavudine and lamivudine.SO₄^2-has no obvious effects on the photolysis of emtricitabine and zidovudine,but can increase the reaction rates of abacavir,stavudine and lamivudine.NH₄⁺can accelerate the photolysis process of abacavir and inhibit the photolysis of stavudine,emtricitabine and zidovudine,but no effects on lamivudine were observed.HCO₃^-and CO₃^-can inhibit the photolysis of four drugs（except stavudine）to varying degrees.Halogen ions can inhibit the photolysis of emtricitabine and zidovudine,but promote the photolysis of abacavir,stavudine and lamivudine.The toxicity assessment has been performed using three toxicity prediction tools（ECOSAR,Discovery Studio 3.0（DS）and Toxicity Estimation Software Tool（T.E.S.T.））.The half-lethal concentration(LC₅₀)and maximum non-effective concentration（Chv）of abacavir are predicted to be in the range of 10-100 mg/L and0.1-1 mg/L respectively,and the Chv of zidovudine is in the range of 1-10 mg/L.According to the EU chemical acute toxicity standard and China chemical chronic toxicity standard,abacavir is considered to be harmful(based on LC₅₀)and toxic（based on Chv）,zidovudine is considered to be harmful（based on Chv）,while emtricitabine,stavudine and lamivudine have low acute and chronic toxicity.For developmental toxicity endpoint,emtricitabine and lamivudine are simulated to be positive by DS but negative by T.E.S.T.;abacavir is predicted to be negative by DS and positive by T.E.S.T.;stavudine is predicted to be positive by both DS and T.E.S.T..For mutagenicity endpoint,abacavir is shown to be negative by DS and positive by T.E.S.T.;emtricitabine,lamivudine and stavudine are predicted to be negative by both DS and T.E.S.T..In addition,all antiviral drugs except abacavir are shown to have carcinogenic effects on male and female mouse.Finally,the toxicity of most photolysis products showed a decreasing trend compared with parent compounds.