Pharmaceutical Compounds in our Water Supply: Causes, Consequences and Solutions Hanoz Santoke Weihua Song William Cooper University of California, Irvine

Outline Introduction – pharmaceuticals in water, fluoroquinolones, advanced oxidation Methods and Materials – LINAC and mass spectroscopy Results and Discussion – transient spectra, rate constants, and degradation mechanisms Conclusions

Pharmaceuticals in Natural Bodies of Water Dozens of pharmaceutical and personal care products detected in various rivers, streams and lakes Fluoroquinolone levels up to 0.12  g/L in various streams in the US (Kolpin 2002) Effluent from a Patancheru, India drug manufacturing facility contained many pharmaceuticals in the mg/L range, with six of the top eleven active pharmaceutical ingredients detected being fluoroquinolones (Larsson 2007)

Pharmaceuticals in our Drinking Water Pharmaceutical compounds, including antibiotics, anti- convulsants, mood stabilizers and sex hormones, have been detected at ppb levels in the drinking water supplies of at least 41 million Americans (Associated Press investigation, 2008) No federal or state standards exist for pharmaceuticals in drinking water (tap or bottled)

Drinking Water Test Results Source: Associated Press, 2008

Pathways to the Environment Human and animal excretion –High drug use in the United States: 3.7 billion prescription and 3.3 billion non-prescription purchases per year –Most drugs are incompletely metabolized in the body (Kummerer 2004)

Pathways to the Environment - continued Dumped “down the drain” by consumers and medical facilities (Halling-Sorensen 1998) Manufacturing facilities (Larsson 2007)

Environmental Consequences Pharmaceutical compounds, including fluoroquinolones, are toxic to plants such as Lemna Gibba, which is commonly used as a test species for assessing aquatic toxicants (Brain 2004)

Environmental Consequences - continued Fluoroquinolones have been found to be toxic to various aquatic organisms, and their selective toxicity may impact ecosystem structure (Robinson 2005) A mixture of pharmaceuticals at environmental concentrations has been shown to inhibit the growth of human embryonic cells by as much as 30% (Pomati 2006)

Current Treatment Technologies Biodegradation Nanofiltration Activated carbon adsorption Ozonation Reverse Osmosis Only reverse osmosis can effectively remove pharmaceuticals, but at very high cost

Advanced Oxidation/Reduction Processes Hydroxyl radicals – oxidizing agent Hydrated electrons – reducing agent Generated by radiating ozone or hydrogen peroxide Studies have shown that AOPs are very promising (cheaper and more efficient) in removing pharmaceutical compounds from water (Huber 2003)

What are Fluoroquinolones? Quinolones are a set of broad-spectrum antibiotics Fluoroquinolones are quinolones with a fluorine atom attached to the central ring 9 fluoroquinolones are currently FDA-approved for humans Levofloxacin (“Levaquin”) best-selling, $1.5 billion in 2006 Adverse effects include nerve or tendon damage, and heart problems Many types of bacteria have built up resistance

Target Compounds

Objectives Determine absolute bimolecular reaction rate constants for the reactions of hydroxyl radicals and hydrated electrons with several common fluoroquinolones Study degradation pathways to identify the byproducts formed in the process. This information may be used to design an advanced oxidation process to remove these compounds from wastewater.

Degradation Studies Cesium-137 radiation source to prepare samples with various doses of radiation HPLC to measure concentrations of radiated samples Liquid chromatography - mass spectroscopy to identify molecular weights of byproducts and elucidate degradation mechanism

Degradation by Cesium Radiation Concentration of danofloxacin as a function of radiation dose

LC-MS Data Defluorination of marbofloxacin: mass chromatograms for molecular weight 360, [M-H] ‒ =359, at various radiation doses.

Degradation Pathways

Degradation Pathways Legend

Transient Spectra

Transient Spectra Observations strong absorbance in the 350 to 400 nm range max of each intermediate was red-shifted by around 100 nm compared to that of the parent compound, characteristic of OH addition to the aromatic ring to form the corresponding hydroxycyclohexadienyl radical Flumequine has the transient spectra most comparable to the model compound

Linear Accelerator Linear Accelerator at Notre Dame Radiation Laboratory to calculate absolute bimolecular reaction rate constants

A few equations Radiolysis of water H 2 O  e- aq (0.27) + H (0.06) + OH (0.28) + H 2 (0.05) + H 2 O 2 (0.07) + H 3 O + (0.27) Isolation of OH e- aq + N 2 O + H 2 O  N 2 + HO - + OH H + N 2 O  OH + N 2 Isolation of e- aq (CH 3 ) 2 CHOH + OH  (CH 3 ) 2 COH + H 2 O (CH 3 ) 2 CHOH + H  (CH 3 ) 2 COH + H 2

Calculation of Rate Constants: Hydroxyl Radical Danofloxacin + hydroxyl radical Pseudo-first order rate constant as a function of concentration.

Calculation of Rate Constants: Hydrated Electron Danofloxacin + hydrated electron Pseudo-first order rate constant as a function of concentration.

Summary of Results Compound · OH max (nm) k ( · OH) (M -1 s -1 )k (e - aq ) (M -1 s -1 )  -irradiation Half life (kGy) Orbifloxacin370(6.94 ±.08) x 10 9 (2.25 ±.02) x Flumequine360(8.26 ±.28) x 10 9 (1.83 ±.01) x Marbofloxacin400(9.03 ±.39) x 10 9 (2.41 ±.02) x Danofloxacin440(6.15 ±.11) x 10 9 (1.68 ±.02) x Enrofloxacin400(7.95 ±.23) x 10 9 (1.89 ±.02) x Model compound 350(7.65 ±.20) x 10 9 (1.49 ±.01) x

Degradation Pathways Legend

Rate Constant Trends Piperazine ring provides steric hindrance, which decreases · OH rate constant Electron-donating oxygen atom increases · OH rate constant Cyclopropane functional group appears to reduce rate constants

Conclusions Pharmaceutical residue in our drinking water is a major environmental and human health issue Advanced Oxidation/Reduction Processes hold great promise for the removal of pharmaceutical compounds This work helps us understand the reactions of fluoroquinolones with hydroxyl radicals, which will be useful in designing a pilot-scale AO/RP system

If you gave me several million years, there would be nothing that did not grow in beauty if it were surrounded by water. - Jan Erik Vold, What All The World Knows, 1970 Thank you! Questions?