DOI: 10.1039/C3EM00615H (Critical Review) Environ. Sci.: Processes Impacts, 2014, 16, 672-696
A critical assessment of the photodegradation of pharmaceuticals in aquatic environments: defining our current understanding and identifying knowledge gaps†
Received 19th November 2013 , Accepted 10th March 2014
First published on 19th March 2014
This work presents a critical assessment of the state and quality of knowledge around the aquatic photochemistry of human- and veterinary-use pharmaceuticals from laboratory experiments and field observations. A standardized scoring rubric was used to assess relevant studies within four categories: experimental design, laboratory-based direct and indirect photolysis, and field/solar photolysis. Specific metrics for each category are defined to evaluate various aspects of experimental design (e.g., higher scores are given for more appropriate characterization of light source wavelength distribution). This weight of evidence-style approach allowed for identification of knowledge strengths and gaps covering three areas: first, the general extent of photochemical data for specific pharmaceuticals and classes; second, the overall quality of existing data (i.e., strong versus weak); and finally, trends in the photochemistry research around these specific compounds, e.g. the observation of specific and consistent oversights in experimental design. In general, those drugs that were most studied also had relatively good quality data. The four pharmaceuticals studied experimentally at least ten times in the literature had average total scores (lab and field combined) of ≥29, considered decent quality; carbamazepine (13 studies; average score of 31), diclofenac (12 studies; average score of 31), sulfamethoxazole (11 studies; average score of 34), and propranolol (11 studies; average score of 29). Major oversights and errors in data reporting and/or experimental design included: lack of measurement and reporting of incident light source intensity, lack of appropriate controls, use of organic co-solvents in irradiation solutions, and failure to consider solution pH. Consequently, a number of these experimental parameters were likely a cause of inconsistent measurements of direct photolysis rate constants and quantum yields, two photochemical properties that were highly variable in the literature. Overall, the assessment rubric provides an objective and scientifically-defensible set of metrics for assessing the quality of a study. A major recommendation is the development of a method guideline, based on this rubric, for conducting and reporting on photochemical studies that would produce consistent and reliable data for quantitative comparison across studies. Furthermore, an emphasis should be placed on conducting more dual-fate studies involving controlled photolysis experiments in natural sunlight, and whole system fate studies in either natural or artificial systems. This would provide accurate data describing the actual contribution of photolysis to the overall fate of pharmaceuticals in the environment.
Mark L. Hanson, Charles S. Wong, Ken J. Friesen and Jonathan K. Challis
Mark Hanson defended his Ph.D. in aquatic ecotoxicology at the University of Guelph, Canada in 2002. After completing his postdoctoral studies in France with a focus on ecosystem recovery, he started as an Assistant Professor in the Department of Environment and Geography at the University of Manitoba, Canada in 2004. Since 2010, he has been an Associate Professor, and his research program focuses on the ecological mechanisms of effect and recovery associated with pesticides and others stressors in freshwater ecosystems.
Charles Wong is Canada Research Chair in Ecotoxicology at the University of Winnipeg. His research interests focus on the measurement, fate and effects of chiral and emerging pollutants, for which he has nearly 70 publications in peer-reviewed venues. He currently serves on the North America Board of Directors of the Society of Environmental Toxicology and Chemistry (SETAC), from which he received the 2007 Weston Environmental Solutions Award for the outstanding environmental chemist of the year under age 40. He holds SB and SM degrees from MIT and a Ph.D. from the University of Minnesota, all in civil and environmental engineering.
Ken Friesen is Professor of Chemistry at the University of Winnipeg. His research is on the environmental chemistry of synthetic chemicals, and has been supported by government, industrial and university research grants. He is committed to quality teaching and has held numerous administrative positions including Chair of the Chemistry Department at the University of Winnipeg. He is a member of SETAC and the American Chemical Society. An alumnus of the University of Winnipeg, he holds M.Sc. and Ph.D. degrees from the University of Manitoba.
Jonathan Challis is a M.Sc. candidate with the Department of Chemistry at the University of Manitoba. His research focus involves understanding the occurrence and fate of polar organic pollutants in impacted surface waters using novel passive sampling technology. His published B.Sc. Honours research on the photolytic fate of pharmaceuticals in aquatic systems ultimately served as the basis for the current work. Jonathan has also been extensively involved in work aimed at understanding the use of natural and engineered wetland systems for the removal of contaminants from impacted waters. His work is funded through Canada's Natural Sciences and Engineering Research Council.
Environmental impactHuman- and veterinary-use pharmaceuticals are present in surface waters globally. Understanding the fate of these contaminants is important for characterizing the occurrence in the environment and exposure to non-target organisms. Photolysis of pharmaceuticals is a major degradation process occurring in natural systems, and has been a topic of significant research. This critical review is an evaluation of the state and quality of knowledge regarding this topic using a weight of evidence-style approach. Specifically, the review aims to highlight inconsistencies in experimental design and reporting that contribute to unreliable data found throughout the literature. Major recommendations are made towards the goal of developing accepted testing guidelines for the study of photolytic fate of pharmaceuticals in aquatic environments.
IntroductionHuman- and veterinary-use pharmaceuticals are a diverse class of aquatic contaminants whose physiochemical properties, use patterns, and means of disposal, can result in significant quantities entering surface waters, making them ubiquitous in many aquatic environments.1,2 Once in surface waters, they can produce a broad range of responses in non-target organisms, including at environmentally relevant concentrations.3–5 Significant research into the environmental occurrence, fate, and effects of pharmaceuticals were in part motivated by a number of influential studies and reviews in the late 1990s.1,6–8 This current critique is an extension of these efforts.
Improved understanding of pharmaceutical fate is needed to characterize better the risk these compounds pose to both ecosystems and human-health via aquatic exposure. Specifically, defining their environmental fate processes and removal mechanisms is vital, as these influence the magnitude and duration of exposure to a particular pharmaceutical, and hence risk. Considering the growing call and regulatory requirements for the ecological effects of pharmaceuticals to be included in formal risk assessments, it is paramount that high-quality fate data be generated to define and rank accurately the risks these compounds might pose. In turn, characterizing strengths and weaknesses of available data on fate processes for pharmaceuticals, specifically photolysis here, will allow researchers and regulators to direct their resources appropriately to address knowledge gaps. Therefore, we used a weight-of-evidence-style approach to assess the quality of existing data on the photolysis of pharmaceuticals in aquatic environments.
Photolysis is a major mechanism of removal from the aquatic environment for many pharmaceuticals.9,10 Individual compounds can undergo photolysis to varying degrees, depending on their chemical structure. The presence of aromatic rings and conjugated π systems, as well as various functional groups and heteroatoms, facilitate the direct absorption of solar radiation.9 Such structures result in strong absorption in the UV-C wavelength range, with tailing absorption into the UV-B and in some cases UV-A ranges. The potential spectral overlap with natural sunlight (λ > 290 nm11suggests that these pharmaceuticals may degrade at least partially by direct photolysis. As well, pharmaceuticals can also react with photosensitizing species (i.e., indirect photolysis) such as photolytically excited natural organic matter (NOM), nitrate, carbonate, or iron present in the water column.9
The extent of direct photolysis is commonly determined experimentally by obtaining a direct photolysis rate constant under a given irradiation source (sunlight or artificial light). This has been done throughout the literature for a wide range of pharmaceuticals and is relatively simple experimentally.12–19 Furthermore, direct photolysis can be predicted to a large extent by two factors: the rate of light absorption, dependent on the molar absorption properties of a chemical and light intensity in the UV-B and UV-A ranges; and the quantum yield, a measure of how efficiently a compound reacts upon absorption of a photon.20 While quantum yields serve as a much better predictor of direct photolytic fate than just simply rate constants and half-lives, fewer studies tend to measure them as their determination is more complex. Quantum yields are a characteristic property of a compound over a given wavelength range that can be compared across studies and used to predict real environmental fate,20 while a degradation rate constant is completely dependent on the specific light conditions used. In part, this review will touch on the predictive ability of quantum yields and discuss the experimental problems leading to inconsistent quantum yield determination for pharmaceuticals.
Indirect photolysis mechanisms often play a major role in the overall photolytic fate of pharmaceuticals, especially for those drugs that do not appreciably absorb light above 290 nm (e.g., ibuprofen19). Indirect mechanisms are increasingly complex and are much harder to predict, as chemicals can react via multiple pathways through interaction with naturally occurring photo-generated transient species. Many studies have detailed various mechanisms involving triplet excited dissolved organic matter (3DOM), singlet oxygen (1O2), hydroxyl radicals (˙OH), and others.13,21–27 Identifying specific species responsible for indirect photolysis involves detailed kinetic work that may be complicated in some cases by multiple mechanisms and competing effects. These types of issues make predictions regarding indirect photolysis difficult, and thus, pharmaceuticals generally need to be studied, for now, on a case-by-case, compound-by-compound basis. There are, however, methods that can be utilized to isolate possible reactive species and measure bimolecular second-order reaction rate constants for individual pharmaceuticals. These techniques, in some cases borrowed from the radiation chemistry literature, include pulsed radiolysis, spectroscopy, and competition kinetics.28,29
The general classes of pharmaceuticals (e.g., antibiotics, anti-psychotics, non-steroidal anti-inflammatory drugs or NSAIDs, etc.) are an extremely diverse collection of chemical compounds, which can be broken down further into different families of compounds on the basis of some structural similarity and pharmacological function. In many studies evaluated for this review, a subset of compounds from a family of drugs were examined to compare how the extent of photodegradation differs based on structural differences.13,21,23,30 For example, the family of sulfonamide antibiotics contain an identical backbone structure comprised of an aniline ring and a sulfonamide group, differing only in their R-heterocyclic functional groups. Boreen et al. studied a number of five-13 and six-21membered ring sulfonamides and observed differing photochemical reactivity amongst the very similarly structured compounds. Piram et al. also observed differing degrees of photolysis amongst a number of structurally related β-blocker drugs.30 These examples further illustrate the complexity of predicting the environmental photolysis of pharmaceuticals.
Two separate approaches were taken to evaluate and summarize the state of knowledge regarding the aquatic photochemistry of pharmaceuticals. The primary and overarching focus of this critical review employed a weight of evidence-style approach drawing from the work of Van Der Kraak et al.31 in order to assess the quality of data available in the literature as it relates to the photolytic fate of pharmaceuticals in aquatic systems. To this end, we developed a transparent scoring rubric to ascertain the overall quality of the studies under evaluation. Alternatively, a more traditional approach to a review paper was taken whereby relevant studies with similar/contrasting focus and/or findings were summarized and discussed. This took the form of both summary tables of data and discussions throughout the text. The objective of this specific approach, and specifically the use of summary tables, was to create an easily accessible summary of photolytic fate, and to readily identify conflicting conclusions regarding photolysis mechanisms for specific pharmaceuticals. While the two approaches are somewhat separate in practice, the discussion was tied back whenever possible to the weight of evidence-style approach in order to substantiate examples and draw concrete conclusions.
The weight-of-evidence approach is increasingly being employed in ecotoxicology, and is often applied to toxicological data to determine evidence for hazard in risk assessments, and to facilitate consistent and reliable data evaluation.32 Overall, there are a number of drivers that prompted this critical review into pharmaceutical photolysis. Firstly, many regulators (e.g., US-, EU-, Japanese-Environmental Protection Agencies, OECD – The Organisation for Economic Co-operation and Development) are working towards the establishment of testing programs and strategies to assess human and wildlife health risks associated with pharmaceuticals in the environment prior to their approval.33 As regulations become more stringent, they will require regulated and consistent testing protocols for their implementation. This is exemplified with the case of endocrine disrupting chemicals (EDCs, e.g., 17α-ethinylestradiol), for which attempts have been made at harmonizing testing strategies and decision-making criteria regarding their fate and effects.33
While post-production release of pharmaceuticals is not currently regulated globally, there is an emerging effort to do so in select jurisdictions. For example, in 1999 the European Commission adopted the “Community Strategy for Endocrine Disruptors” to develop strategies addressing research, communication, and policy, and provide short-, medium-, and long-term recommendations regarding the presence of EDCs in the environment.34 A recent report35 on the implementation of the “Community Strategy for Endocrine Disruptors” summarized a number of these short-, medium-, and long-term actions, including the establishment of a list of priority EDCs, monitoring programs, development of accepted criteria and testing strategies for identification and assessment of EDCs, and legislative actions involving the inclusion of EDCs in the European Union's REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) program (EC 1907/2006).36
Therefore, a critical assessment of the data around fate, in this case photolytic fate, of pharmaceuticals in the environment is needed, with a specific focus on testing criteria and guidelines that will facilitate consistent and reliable research in this area. Additionally, the last review on the photolysis of pharmaceuticals is now a decade old (2003),9 while a more recent (2011) review10 focused on the photodegradation products of pharmaceuticals. Significant research and progress has been made since 2003, with over 120 studies published on the photolysis of pharmaceuticals in the environment since that year – suggesting the need for a detailed critical review.
To this end, we developed a scoring rubric for available peer-reviewed literature based in part on OECD 31637 and US EPA OPPTS 835.221038 guidelines on direct photolysis. Both of these guidelines currently deal expressly with direct photolysis. The rubric developed here encompasses lab/field experimental design and direct/indirect photolysis criteria. Each study was weighted and scored based on how well it met the specific criteria outlined in the rubric. The scores then allow for simple, easily interpreted 2-dimensional plots (y-axis = laboratory studies, x-axis = field studies) to assist in identifying both significant knowledge strengths and gaps in our understanding of photolysis by pharmaceutical class, as well as the quality of the data generated to date. Relevant studies were highlighted, and their contributions to photochemical knowledge as well as their limitations are summarized using the rubric. The rubric approach ultimately helps to outline parameters to enable the drawing of comprehensive conclusions regarding the photolytic fate of pharmaceuticals. In various contexts, this critical review evaluated laboratory versus field photolysis investigations, direct and indirect photolysis, rate constants and quantum yields, photodegradation products, the quality of experimental design, and the reporting of data and information, all as they pertain to the aquatic photochemistry of pharmaceuticals.
Literature used in the reviewA total of 120 papers were critically evaluated and scored, representing a large majority of the relevant literature available on this topic.12–19,21–26,30,39–143 Papers for inclusion were obtained via searches of the Web of Knowledge and SciFinder databases between June and September 1, 2013. The following search terms were used in various combinations: photolysis, photodegradation, pharmaceuticals, drugs, polar organic pollutants, environment(al), aquatic, surface waters, wetlands, experiment(s). In summary, studies included used either natural sunlight or artificial light emitting wavelengths greater than ≈290 nm (environmentally relevant) as an irradiation source (i.e., simulating natural sunlight). Studies done in non-aqueous solution or under non-environmentally relevant wavelengths (<290 nm, e.g., for advanced oxidation treatment) were not included in this review.
Of these papers, 83% were published in the last ten years (2004–2013) and 42% in the last four (2010–2013), suggesting a significant increase in both the interest and knowledge regarding the photochemical fate of pharmaceuticals in aquatic environments. From this list of evaluated works and scores, the volume and quality of knowledge, respectively, for a given pharmaceutical drug can be ascertained by considering the number of times a given drug was studied and the overall scores those studies obtained. This type of information highlights data gaps regarding specific pharmaceuticals and/or the quality of data generated for a given compound. Generally speaking, there were seven major classes of pharmaceuticals that were among the most studied in terms of their photolytic fate in aquatic environments. These were (1) antibiotics (59/50 – # publications studying the respective compound class/# of different compounds studied in the class); (2) non-steroidal anti-inflammatory drugs or NSAIDs (22/7); (3) anti-psychotics (22/15); (4) β-blockers (19/10); (5) cholesterol-lowering drugs (12/6); (6) hormones (11/7); and, (7) analgesics (8/6). The studies included in this review represented a total of 116 different pharmaceutical compounds. Table S1A–G (ESI†) provides a list of all the studies evaluated and scored using the rubric, and the scores obtained by each study, organized alphabetically by pharmaceutical class. Individual scoring sheets for specific studies are available from the corresponding author upon request.
Weight-of-evidence-style scoringThe full scoring rubric is provided in Table S2.† The rubric is divided into four sections: (1) experimental design; as well as important parameters or metrics involved in laboratory-based study of (2) direct photolysis, (3) indirect photolysis, and (4) field/solar photolysis. Each scoring metric was chosen to encompass as much information as possible about the quality of the study that could be examined objectively and rapidly. Additionally, wherever possible, criteria were designed as ‘yes’ or ‘no’ questions in order to make the system as simple as possible. The last criterion in the rubric “Other processes considered as they relate to photolysis” was the one area that allowed some discretion in scoring. This criterion gave additional points for aspects of a study that either did not fit into any of the developed criteria or were not photolysis-specific, but related and important in some way to the overall fate of the drug.
It is important to note that for the purposes of this work, the scoring rubric was designed specifically for environmentally relevant, experimental photolysis studies and thus the rubric criteria were chosen accordingly. It is important that the rubric be somewhat focused, otherwise evaluations simply become too time consuming and difficult to conduct. As a result, studies that did not fit well with our rubric criteria were generally not evaluated (e.g., photolysis modeling-type studies). However, this rubric is highly adaptable to fit different types of studies, and it is strongly encouraged that it be modified accordingly so that this technique can be used in other contexts and applications. While not explicitly scored, conducting studies either under or in the spirit of good laboratory practice (GLP) as well as open dissemination are highly encouraged.
A majority of the metrics making up the Experimental section of the rubric were adapted from the OECD Guidelines for the Testing of Chemicals no. 316: Phototransformation of Chemicals in Water – Direct Photolysis37 and the US EPA Fate, Transport, and Transformation Test Guideline OPPTS 835.2210: Direct Photolysis Rate in Water By Sunlight.38 Specific recommendations from the guidelines were either used as ‘yes’ (=1) or ‘no’ (=0) criteria (e.g., triplicate irradiations, dark control) or adapted to work as weighted criteria (e.g., wavelength distribution of light source, sample vessel, measured light flux) on a number scale, 0–4 (Table S2†). Other rubric criteria were designed from, and based on, experimental precedents set in the literature, with common trends across studies being incorporated into certain criteria. For example, detailed photo-product studies generally apply high-resolution mass spectrometry (and to a lesser extent, nuclear magnetic resonance), monitor formation/loss of photodegradation products, and propose mechanisms/pathways for the breakdown of parent pharmaceuticals to photo-products. Thus, these aspects of a study represented top scores (3–4) for the photo-product criterion.
The direct and indirect photolysis sections focused on the quality and thoroughness of the kinetic data, and for the most part were derived from experimental aspects common throughout kinetic photolysis literature. The criterion ‘R2-value of first-order plots’ (i.e., the degree of linearity) evaluates the uncertainty in the kinetic data, giving an indication as to the appropriateness of fitting (pseudo) first-order kinetics to the data. Furthermore, reporting errors in rate constants and quantum yields is important to lend transparency to the study in terms of precision of the experimental technique and the spread in the data. Determination of rate constants and quantum yields, consideration of pH and pKa, measurement of photosensitizing species, and the absorbance spectra of both compound and matrix are important metrics addressed across a large number of published photolytic fate studies, and thus, are important to consider when evaluating the quality of a study. The above mentioned rubric sections apply to both laboratory and sunlight photolysis experiments. However, extra considerations are necessary to account for different experimental methods used in the field versus the laboratory, hence the field/solar photolysis criteria (Table S2 in ESI†). While we recognize that other definitions of appropriate criteria are possible, our rubric approach allowed for data evaluation in a quantitative and consistent manner, and can be easily modified as needed.
Briefly, a study would be described by the pharmaceutical compound(s) studied and a set of pre-defined keywords, chosen based on the type and nature of the experiments conducted (see Table S3† for two examples of evaluated studies). These seven keywords were: lab irradiations, sunlight irradiations, field experiment, direct photolysis, indirect photolysis, photo-products, and quenching/competition mechanism experiments. The rubric was then filled out, including an explanation for why each criterion was scored as it was. The scores from each rubric section were totalled, and a brief description of the general findings was given.
One of the purposes of this rubric was to assess and identify which experimental and kinetic aspects of a photolysis study were necessary to produce both environmentally relevant and reliable data (i.e., information that can be used to understand and/or predict photolytic fate processes of pharmaceuticals) and give a score accordingly. For example, wavelengths below ≈ 290 nm and/or the use of organic solvents in the irradiation solutions – which may quench photosensitizing/intermediate species, altering the photolysis mechanism – were considered fundamental flaws in terms of environmental relevance of a study. Consequently, a study with these fundamental flaws in the experimental design would receive a lower score. This rubric also served to highlight any significant insufficiency in the basic reporting of information. This was especially evident for specific experimental criteria including number of replicates, dark controls, organic solvent carrier, solution pH, and temperature. If specific criteria were not explicitly reported in a study, it was assumed that these were not met, thus resulting in lower scores. In general, higher scores should equate to stronger, higher quality data and thus, predict environmental fate more accurately. However, as many of the studies scored were conducted in the laboratory, comparison to environmental fate data was in many cases not possible given a lack of field photolysis data for many pharmaceuticals. Where possible, comparisons to this end are made and discussed in the relevant sections of this review.
ResultsA hypothetical ‘maximum score’ was 73, based on the highest score in every criterion of the rubric. Studies were considered high quality if they obtained an overall score (lab and/or field) >40; mid-quality, 25–40; and low-quality, <25. While these rankings of high-, mid-, and low-quality studies, and the respective scoring range are somewhat arbitrary and specific to this rubric only, they are largely based on the average overall score for all laboratory and field studies (32), essentially following a normal distribution around the average. Scores ranged from 12–53, having a mode of 19 (obtained by 31 studies). To ensure the scoring exercise was consistent and reliable, 5% (six studies) of the total evaluated studies were chosen at random and re-scored. An average standard deviation of 1.1 (SD range = 0–2.1) was obtained between the initial and re-scored scores.
An example score plot is shown in Fig. 1, with mock laboratory (y-axis) and field (x-axis) study scores plotted for three compounds, to orientate the reader as to how these score plots should be interpreted. The quality of data generated by a given study can be understood through the scores of given pharmaceuticals, based on where they fall on the plots. Generally speaking, compounds clustering closer to the upper right corner of these plots suggest high quality of laboratory and field data, while the lower left corner implies low quality data. The purpose of this exercise is to represent graphically the quality of laboratory and/or field data for specific pharmaceuticals within a family, via the rubric scores. The scoring of studies in this case is a surrogate for the quality of data, so a low score implies low quality data while a high score implies high quality data. A select set of our compiled results from our scoring exercise are depicted in Fig. 2, grouped by five major drug families: sulfonamides, fluoroquinolones, β-blockers, non-steroidal anti-inflammatory drugs (NSAIDs), and analgesics.
|Fig. 1 Model score plot of ‘mock’ lab and field scores for three example compounds. The four sections on the plot show the general areas of the graph that represent low- (<25) and high-quality (>40) data. Areas on the graph in between these regions represent mid-quality data (25–40). The numbers at each data point indicate the number of publications for that specific compound (above/below data point – number of laboratory-based studies; left/right of data point – number of field studies). Error bars represent the standard error of the mean.|
|Fig. 2 Scoring plots of laboratory and field studies for selected compounds from five families of pharmaceuticals: (A) sulfonamides, (B) fluoroquinolones, (C) β-blockers, and (D) non-steroidal anti-inflammatory drugs (NSAIDs) and general analgesics. The numbers at each data point indicate the number of publications for that specific pharmaceutical (above/below data point – number of laboratory-based studies; left/right of data point – number of field studies). Error bars represent the standard error of the mean.|
The photochemical fate of the β-blocker family has been studied extensively in the literature. Atenolol (open diamond; Fig. 2C) is a good example of how these plots can help identify data gaps for individual compounds. It has been studied nine times in the laboratory producing relatively strong data (average score >30, with a small standard error), but has only been studied under natural sunlight once, with a score of 25. Moreover, we note that acebutolol, alprenolol, bisoprolol, and pindolol – comprising close to half of the β-blockers that have been studied photochemically in the peer-reviewed literature – all overlap each other in the lower left hand corner of the plot (Fig. 2C) with a score of 19, suggesting relatively low quality of data for these compounds. Thus, conducting future investigations for atenolol under field conditions, and for the other β-blockers in general, are two recommendations from our scoring exercise.
The sulfonamide antibiotics are another family of drugs commonly studied in the literature. Sulfamethoxazole (open square, Fig. 2A) has been studied eight times in the lab and six times in the field, with an average score near or above 30 in both cases. The relatively small error bars for sulfamethoxazole indicate that all fourteen studies share similar scores (i.e., similar quality of data), which in this case should be considered a strong data set overall. Alternatively, for sulfadiazine (closed small square, Fig. 2A) and sulfadimethoxine (down-facing small triangle, Fig. 2A) we note large horizontal error bars (N = 2 field studies), indicating that one study scored significantly greater than the other for these two compounds. In such a case, a potential application of this scoring technique could be to differentiate the reliability of data from the scores of two (or more) respective studies. Furthermore, when there are discrepancies between data sets, this approach can aid in determining which data should be used and applied, e.g., within risk assessments,32 development of regulatory guidelines, and/or environmental fate modeling exercises. Of course, aside from just comparing scores, the data itself must also be critically examined (e.g., assessing the consistency within the science of photochemistry) to make a final decision as to the validity of one study over another.
There are other gaps that can be identified by using the rubric, besides lack of knowledge around specific compounds or classes of pharmaceuticals. For example, it reveals aspects often missed or overlooked in photochemical studies due to lack of reporting and/or oversights in experimental design, as noted previously by Fatta-Kassinos et al.10 and Hu et al.144 Some of the major and common oversights amongst the papers included:
• A lack of information regarding the irradiation source, wavelength range, light intensity/flux, and the radiometer/actinometer measurement technique – 44% of studies either did not report anything regarding light intensity measurement or reported a light intensity but not the measurement technique used (i.e., actinometer);
• Whether multiple irradiations were conducted – 63% of studies either did not report if replicate irradiations were done or reported single replicates;
• The use of dark controls – a number of studies made no mention of a control sample – 33% of studies did not report the use of dark controls;
• The presence of a solvent carrier in the aqueous irradiation solutions, which may quench photosensitizer species – 54% of studies either did not explicitly report the presence or absence of solvent in irradiation solutions or reported the use of solvents known to quench photosensitizing species (e.g., methanol for hydroxyl radicals);
• Consideration or reporting of pH in the irradiation solutions – 22% of studies did not report the pH of the irradiation solutions.
These criteria were considered fundamental to a strong photochemical investigation, yet they are frequently underreported in the literature, making interpretation and comparisons amongst studies difficult. For example, if a study simply fails to report the pH of the irradiation solution, comparison is difficult given that the protonation state can have a significant effect on the photochemical kinetics of many pharmaceuticals.13,15,21–23,65
Discussion: current progress and specific challengesAs noted, a significant amount of work has been done since the late 1990s to investigate the photochemical fate of pharmaceuticals in water, culminating in a large collection of data. Progress has been made in understanding and elucidating the photolytic mechanisms that limit the persistence of many pharmaceutical contaminants in aquatic environments. Herein, we summarize current knowledge and challenges regarding kinetics and mechanisms of photolysis, quantum yield determination, and photodegradation products, based on data and trends observed during the scoring exercise. Specifically, this discussion will focus on many of the rubric metrics that were frequently overlooked throughout the literature. The general direct and indirect photolytic processes dominating the fate of seven well-studied pharmaceuticals representing the six most-studied classes (ciprofloxacin – antibiotic; sulfamethoxazole – antibiotic; ibuprofen – NSAID; carbamazepine – anti-psychotic; atenolol – β-blocker; clofibric acid – cholesterol lowering agent; and 17α-ethinylestradiol – synthetic hormone) are summarized in Table 1. The following discussions will be focused on the experimental techniques used and inconsistencies in the resultant data produced.
Table 1Summary of direct and indirect photolysis mechanisms for a select group of seven well-studied pharmaceuticals (at least five literature studies per compound) representing the six most-studied drug classes (antibiotics, NSAIDs, anti-psychotics, β-blockers, cholesterol-lowering agents, and hormones). A summary of the general findings from all studies for a given compound is given, followed by any recommendations as to potential data gaps or inconsistencies across studiesb
Direct photolysis quantum yields
|Compound (CAS)||Study typea||Photolysis mechanism||Ref.|
|Ciprofloxacin (85721-33-1)||L||Direct photolysis identified as major mechanism – rapid degradation (t1/2 = 1.2 min). Slightly reduced degradation rates in synthetic waste water and river water||Babic et al.12|
|L||Photolysis in water spiked with CaCO3 (direct versus indirect mechanisms not separated) was significant without fine particulate organic matter (FPOM) – rapid degradation (t1/2 = 2.9 h). FPOM reduced aqueous concentration significantly (sorption), slowing photolytic degradation||Belden et al.48|
|L||Direct photolysis identified as major mechanism – rapid degradation (t1/2 = 23 min). Also suggested that self-sensitized photo-oxidation via ˙OH and 1O2 is an important mechanism. Indirect photolysis species (humic acids, nitrate, iron) did not increase or decrease degradation rates compared to direct photolysis||Ge et al.23|
|L||Direct photolysis identified as major mechanism – rapid degradation (t1/2 = 13 min). Variable but small indirect effects. Faster and slower rates compared to direct photolysis depending on the concentrations of nitrate, cDOM, and carbonate||Lam et al.26|
|L||Only direct photolysis was considered, at 5 different pH values. Most reactive at pH 8.6. Rapid degradation (t1/2 ≈ 20 min). The extent of photolysis ranged, depending on pH||Torniainen et al.120|
|L||Only direct photolysis was considered, at 3 different pH values. Most reactive at pH 7. Rapid degradation (t1/2 ≈ 9 min). The extent of photolysis ranged, depending on pH||Vasconcelos et al.124|
|L||Only direct photolysis was considered at 11 pH values between 2–12. Most reactive at pH 8. Rapid degradation (t1/2 = 23 min). The extent of photolysis ranged, depending on pH||Wei et al.131|
|L, F||Photolysis in sterilized mesocosm water (direct versus indirect mechanism not separated) was significant in lab (t1/2 = 1.9 h) and field mesocosms (t1/2 = 1.1 h) (low levels of particulate organic carbon) – rapid degradation. Presence of amended DOC slowed degradation in lab. Lab mesocosm water spiked with POC reduced soluble ciprofloxacin at a rate more rapid then photolysis||Cardoza et al.53|
|S||Photolysis experiments only conducted in raw, unfiltered river water samples (no direct photolysis). Complete decomposition (≈0% remaining) of ciprofloxacin was observed after 20 minutes. Rapid degradation||Sturini et al.116|
|S||Direct and indirect photolysis. Slow degradation. Complete decomposition (≈0% remaining) took >150 days in pure water and ≈125 days in river water. Based on general consensus in the presented literature, these results appear to be an obvious outlier, thus omitted from the summary. The low score this study received (25) further supports the omission from the summary statement||Turiel et al.123|
|Summary||—||Consensus amongst all studies that direct photolysis is the major mechanisms responsible for photodegradation of ciprofloxacin. Photolysis rates in general are rapid for this compound. Degradation is most rapid at slightly basic pH||—|
|Recommendation||—||Data for this compound is generally consistent across studies. The two sunlight studies are of lower quality based on the rubric scores. Should be studied more under natural sunlight and in the field for comparisons to laboratory derived data||—|
|Sulfamethoxazole (723-46-6)||L||Only direct photolysis was assessed. Degradation was rapid. The neutral form at pH 3.2 was most reactive (t1/2 = 0.031 h)||Bonvin et al.49|
|L||Direct and indirect photolysis were important processes. Direct photolysis degradation was quick (t1/2 ≈ 4 h, approximated from graph). In wetland water containing significant levels of DOC, nitrate, and carbonate, degradation increased (t1/2 ≈ 2 h, approximated from graph). ˙CO3− and 3DOM were important photosensitizing species||Jasper and Sedlak75|
|L||Direct photolysis identified as major mechanism. Rapid degradation (t1/2 = 1.5 h). Indirect experiments in synthetic field water (varying concentrations of DOM, nitrate, carbonate) resulted in slower degradation (t1/2 = 2.8–6 h, depending on concentration of photosensitizers). Indicated that ˙OH radicals mediated degradation however this effect was smaller than the light screening||Lam et al.84|
|L||Direct photolysis was identified as the major photolysis mechanism. Degradation was rapid (t1/2 = 12.6 min). Greatest reactivity observed at acidic pH. Indirect photolysis experiments in the presence of fulvic acids and suspended particles decreased degradation rates||Niu et al.100|
|L||Direct photolysis was found to be the major mechanism. Degradation was rapid (t1/2 ≈ 1 h, exact half life values were not reported). Indirect photolysis experiments in the presence of humic material or nitrate resulted in much slower degradation||Trovo et al.122|
|L, S||Direct and indirect photolysis was found to be important photolysis mechanisms. Direct photolysis was slow (t1/2 = 2.4 days in sunlight – calculated using measured quantum yield). In the presence of nitrate or humic acids photolysis half lives were 4.3 and 3.1 times faster compared to direct photolysis||Andreozzi et al.41|
|L, S||Direct photolysis was identified as the primary mechanism. Degradation was quick, and most rapid in its neutral state (t1/2 = 3.2 h in sunlight). Indirect photolysis may be important in some waters. 1O2 and ˙OH-radicals may only play a role in nitrate and humic rich waters where the concentration of these species would be high||Boreen et al.13|
|L, S||Only direct photolysis was assessed. Degradation was rapid under lab-light and sunlight, with half lives around 1 h (t1/2 values not given). Photolysis was pH dependent and most reactive in acidic solution||Moore et al.98|
|L, S||Direct photolysis was identified as primary mechanism in pure water (t1/2 = 1.7 h) and lake water (t1/2 = 1.6 h). In STP effluent indirect photolysis was significant (t1/2 = 1 h), attributed to ˙OH radicals and 3DOM. Also, deoxygenation led to more rapid direct photolysis indicating that direct photolysis proceeds through a triplet excited state||Ryan et al.111|
|S, F||Photolysis in natural river water (direct versus indirect mechanism not separated). No photodegradation observed, however samples were only irradiated for 6 h||Kunkel et al.80|
|S, F||Photolysis experiments done in natural mesocosm water (direct versus indirect mechanism not separated). No kinetic data given, but photolysis was concluded to be an important removal mechanism from mesocosms||Lam et al.85|
|Summary||—||Direct photolysis seems to be the primary mechanism for many studies. Indirect photolysis is variable between studies. Some report light screening effects while others observe small increases in degradation due to 1O2, ˙OH-radicals, or 3DOM. Indirect photolysis seems to be largely dependent on the type of water used in the experiments and the concentrations of photosensitizing species. In general photolysis of sulfamethoxazole is rapid to quick. The neutral form is most reactive||—|
|Recommendation||—||Data for this compound is consistent. Sulfamethoxazole is very well studied in the lab and field. No recommendations||—|
|Ibuprofen (15687-27-1)||L||Direct photolysis was of minor importance (t1/2 = 277 h). Rates increased significantly in the presence of fulvic acids (t1/2 = 36, 25, 9 h depending on type of fulvic acid). ˙OH radicals (terrestrial-DOM) and 3DOM (algal/bacterial-DOM) were important photosensitizing species||Jacobs et al.73|
|L||Direct photolysis was of minor importance. Slow degradation (t1/2 = 205 h). In river water, degradation rate increased significantly (t1/2 = 15 h). Indirect photolysis identified as major mechanism – photosensitizing species not identified||Lin et al.18|
|L||No significant degradation was observed for direct photolysis experiments (t1/2 = 1437–11931 h depending on light source). Indirect experiments in the presence of humic material significantly increased half lives (t1/2 = 556–921 h, depending on light source). Indirect photolysis was identified as the primary mechanism||Peuravuori et al.104|
|L||Direct photolysis was of minor importance. Slow degradation (half life not reported, but from plots t1/2 ≫ 24 h). Indirect photolysis of some importance (rates not given), with ˙OH being the primary photosensitizing species||Vione et al.126|
|L, S||In lab experiments, direct photolysis was identified as the primary mechanism. Moderate degradation (t1/2 = 4 h). Degradation rates slowed slightly in seawater and river water. For sunlight experiments done in river water degradation was slow (t1/2 = 324 h)||Matamoros et al.96|
|L, S||No significant degradation was observed under natural sunlight, thus laboratory lamp (5× stronger than sunlight) was used. Direct photolysis showed moderate degradation (t1/2 = 11.6 h). Degradation rates increased significantly in river water (t1/2 = 2.6 h). Indirect photolysis was identified as the primary mechanism. ˙OH radicals played a role in degradation, likely along with other reactive oxygen species||Packer et al.19|
|S||Only direct photolysis was considered. Slow degradation (t1/2 = 9900 h in May to 600 h in August)||Yamamoto et al.139|
|S, F||Direct photolysis identified as major mechanism. Slow degradation (t1/2 = 6.3 days). Experiments in river water did not increase or decrease degradation rates compared to direct photolysis. In situ field rates (natural river system) were slightly faster (t1/2 = 4.6 days)||Fono et al.68|
|S, F||Photolysis in natural river water (direct versus indirect mechanism not separated). No photodegradation observed, however samples were only irradiated for 6 h||Kunkel et al.80|
|Summary||—||A majority of the studies observe indirect photolysis to play a major role in photodegradation of ibuprofen. There are some studies that found direct photolysis to be important. ˙OH radicals seem to be the main photosensitizer responsible for this degradation. In general, photolysis of ibuprofen is slow||—|
|Recommendation||—||With few exceptions, data for this compound is consistent. Ibuprofen has been studied multiple times in the lab and field. No recommendations||—|
|Carbamazepine (298-46-4)||L||Only direct photolysis experiments conducted. Photolysis was for the most part slow but varied significantly with pH and dissolved oxygen (t1/2 = 0.5–95 h). Reactivity was greatest at acidic pH and low dissolved oxygen levels||Calisto et al.14|
|L||Photolysis experiments were done in natural river water (direct versus indirect mechanism not separated). Degradation was slow (t1/2 ≈ 5 days, from zero-order plots). Kinetic data not reported||Calza et al.52|
|L||Direct and indirect photolysis was important. Indirect photolysis experiments in artificial river water (humic acids, iron, nitrate, Cl−) showed slightly decreased degradation compared to the direct photolysis rates. Iron and Cl− in solution caused degradation rates to increase significantly. Half lives were not reported||Chiron et al.59|
|L||Direct photolysis was of minor importance. Degradation in pure water was slow (t1/2 = 19 h). Indirect photolysis experiments with NOM enhanced photolysis of carbamazepine significantly (t1/2 = 6.8 h)||Doll et al.64|
|L||Direct photolysis processes were insignificant. Indirect photolysis in wetland water resulted in moderate degradation (t1/2 ≈ 8.5 h, estimated from plot). 3DOM was found to contribute slightly to removal, but degradation was primarily through reaction with ˙OH radicals at pH 8.5. At pH 10.5 degradation rate decreased by 70% because of low reactivity with ˙CO3− radicals||Jasper and Sedlak75|
|L||Direct photolysis was of minor importance. Degradation in pure water was slow (t1/2 = 115 h). Indirect photolysis increased degradation rates significantly (t1/2 = 6–55 h, depending on the concentrations of DOM, nitrate, and carbonate). ˙OH radicals suggested as the species likely responsible for degradation||Lam et al.84|
|L||Photolysis overall was very slow (t1/2 ranging from 33 days in pure water to 21 days in humic rich water)||Peuravuori et al.104|
|L, S||Direct and indirect photolysis rates were slow. Direct photolysis was slow (t1/2 ≈ 100 days in sunlight – calculated using measured quantum yield). In the presence of nitrate, photolysis was 2.3 times faster compared to direct photolysis. Humic acids acted as a light screen, slowing degradation down four-fold||Andreozzi et al.42|
|L, S||Direct and indirect photolysis contributed to degradation. Direct photolysis was slow (t1/2 ≈ 38.5 h; lab-light). Indirect photolysis experiments in seawater and two different natural river waters significantly increased degradation rates (t1/2 ≈ 14.4, 12.8, 8.25 h, respectively; lab-light). In natural sunlight degradation in one of the river waters was slow (t1/2 ≈ 67.4 h)||Matamoros et al.96|
|S||Direct photolysis degradation was slow (t1/2 = 121.6 h). Indirect photolysis experiments increased degradation significantly (t1/2 = 69, 24.5, 11.2 h – half lives decreasing with increasing concentrations of nitrate). Humic acid acted as a light screen, slowing degradation down significantly compared to direct photolysis (t1/2 = 233.7 h). In natural river water the half life was increased further to 907 sunlight hours||Andreozzi et al.41|
|S||Only direct photolysis was considered. Slow degradation (t1/2 = 2100 h in May to 84 h in August)||Yamamoto et al.139|
|S, F||Photolysis experiments were done in natural river water (direct versus indirect mechanism not separated). No photodegradation observed, however samples were only irradiated for 6 h||Kunkel et al.80|
|S, F||Photolysis experiments done in natural mesocosm water (direct versus indirect mechanism not separated). Degradation was slow (t1/2 ≈ 10 days). Photolysis was concluded to be an important removal mechanism from mesocosms||Lam et al.85|
|Summary||—||Overall, photodegradation is slow. Carbamazepine seems to be relatively persistent towards direct photolysis. Indirect photolysis in most cases increased degradation rates. Humic material reported to enhance or slow degradation, varying from study to study. Likely to do with type and concentration of humic material. ˙OH radicals seem to the primary photosensitizer responsible for degrading carbamazepine||—|
|Recommendation||—||Data for this compound is consistent. Carbamazepine is very well studied in the lab and field. No recommendations||—|
|Atenolol (29122-68-7)||L||Only direct photolysis was considered. Degradation was slow at pH 7.4 (t1/2 = 45.2 h) to moderate at pH 4 (t1/2 = 6.87 h)||Andrisano et al.43|
|L||Direct photolysis was not a significant degradation process. Indirect photolysis in the presence of fulvic acids was moderate in air saturated solutions (t1/2 = 10.8 h) to rapid in nitrogen purged solutions (t1/2 = 5.9 min). Degradation increased with increasing pH = 6–10. Presence of metal cations slowed degradation. 3DOM was identified as the species responsible for the indirect photolysis||Chen et al.22|
|L||Direct photolysis processes were insignificant. Indirect photolysis in wetland water resulted in moderate degradation (t1/2 ≈ 9 h, estimated from plot). Degradation was primarily through reaction with ˙OH radicals at pH 8.5, accounting for 80% of removal. At pH 10.5 degradation rate was mostly unchanged because of high reactivity with ˙CO3− radicals||Jasper and Sedlak75|
|L||Only indirect photolysis was tested. Degradation in the presence of nitrate was moderate (t1/2 = 11.4 h) and increased to rapid at higher nitrate concentrations (t1/2 = 1.6 h). Reactivity was slightly greater at pH 4.8 versus pH 10.4. Humic substances slowed degradation acting as a light filter. Nitrate induced ˙OH radicals were identified as the primary degradation mechanism||Ji et al.76|
|L||Only direct photolysis experiments were conducted. Direct photolysis was slow (t1/2 = 350 h)||Liu et al.92|
|L||Direct photolysis was of minor importance. Degradation was slow (t1/2 = 670 h). In three different types of natural river water degradation was slow but increased significantly compared to direct photolysis (t1/2 = 35–127 h). A small portion of this degradation was attributed to biodegradation||Liu et al.91|
|L||Direct photolysis in pure water and indirect photolysis in sewage effluent were not observed. Stable towards photolysis||Piram et al.30|
|L||Direct and indirect photolysis experiments. Direct photolysis was slow (t1/2 = 8.2 days) and accounted for ≈7% of total degradation. Presence of NOM significantly increased degradation. Primary reactive species was 3DOM accounting for 85% of degradation. Hydroxyl radicals accounted for ≈7%||Wang et al.129|
|L||Direct photolysis experiments did not result in any degradation. The presence of DOM caused photodegradation. Rates increased with concentration of DOM. Half lives were at least >20 h (estimated from plots) and depended on the type of DOM. When nitrate was present, DOM slowed down degradation (t1/2 = 6.8–8.9 h, depending on DOM type) compared to nitrate itself (t1/2 = 4 h). In solutions of iron and DOM, degradation was enhanced significantly compared to DOM alone. ˙OH radicals identified as the main reactive species in the photolysis process||Zeng et al.140|
|S||Only direct photolysis was considered. Degradation was slow (t1/2 = 730 h in May to 77 h in August)||Yamamoto et al.139|
|Summary||—||Direct photolysis of atenolol is of minor importance. Indirect photolysis is the major mechanism. Nitrate seems to be an important species mediating ˙OH radical reactions – a photosensitizing species responsible for atenolol degradation. 3DOM is the other major photosensitizing species responsible for atenolol photodegradation. The importance of ˙OH versus3DOM is not obvious but likely depends on the type of NOM, steady state concentrations, and water chemistry (e.g., nitrate, pH). Overall, photolysis of atenolol is slow||—|
|Recommendation||—||Data for this compound is consistent and quite extensive in the laboratory. Atenolol has only been studied once under natural sunlight with very limited data from the single sunlight study. More photolysis experiments should be conducted under sunlight and in the field||—|
|Clofibric acid (882-09-7)||L||Direct photolysis was slow (t1/2 > 70 h, from plot). Half lives not reported. Indirect photolysis data not given||Doll et al.64|
|L||Direct photolysis was slow (t1/2 = 19.3 h). Degradation was increased most significantly in synthetic natural water containing high DOM and low nitrate and carbonate (t1/2 = 9.5 h). At other various concentrations of DOM, nitrate, and carbonate, degradation was only enhanced slightly. ˙OH radicals were suggested as the primary photosensitizing species||Lam et al.26|
|L, S||Direct and indirect photolysis rates were slow. Direct photolysis was slow (t1/2 ≈ 100 days in sunlight – calculated using measured quantum yield). In the presence of nitrate or humic acids, photolysis was 1.3 or 2.1 times faster, respectively, compared to direct photolysis||Andreozzi et al.41|
|L, S||Direct photolysis was slow in sunlight (t1/2 = 144 h). Indirect photolysis in natural river water increased degradation significantly (t1/2 = 50 h). Approximated that ˙OH radicals accounted for ≈20% of the increased degradation||Packer et al.19|
|S, F||Direct photolysis in pure water did not occur. In natural river water indirect photolysis was slow (t1/2 = 2.4 days)||Radke et al.107|
|Summary||—||Clofibric acid is relatively persistent towards photodegradation. Direct photolysis in some cases is reported to not occur at all for this compound, and at most plays a minor role in degradation. In all cases indirect photolysis significantly increased degradation of clofibric acid, indicating that this is the major photolysis mechanism degrading this compound. ˙OH radicals appear to be largely responsible||—|
|Recommendation||—||Data for clofibric acid is consistent. Clofibric acid has been studied in the lab and field. No recommendations||—|
|17α-Ethinylestradiol (57-63-6)||L||Different light intensities were tested. These results are for high intensity UV-B treatment. Direct photolysis was slow (t1/2 = 18 h). Photolysis in two natural river water samples was reduced (t1/2 = 23–46 h). The river sample with higher DOC concentration resulted in reduced degradation suggesting light screening||Atkinson et al.45|
|L||Direct photolysis in pure water was slow (t1/2 = 28.4 h). In natural river water degradation rates increased significantly (t1/2 = 2.3 h)||Lin et al.18|
|L||Direct photolysis was slow. 10% degraded after 4 h. No other kinetic data given. Rate increased slightly as pH increased. The presence of iron increased degradation rates (half lives not reported)||Liu et al.93|
|L||Only direct photolysis was considered. Degradation was quick (t1/2 ≈ 5 h, estimated from plot). Half lives not reported||Mazellier et al.97|
|L||Direct photolysis was moderate (t1/2 = 7.4 h). Indirect photolysis increased degradation slightly (t1/2 = 5.2 h) in the presence of fulvic acids||Whidbey et al.136|
|L, S||Under lab-light photodegradation was rapid and relatively constant across all matrices. Half lives in pure water (direct photolysis), seawater and two natural river waters (indirect photolysis) ranged from 0.95–1.13 h, indicating that direct photolysis was the primary mechanism. Under sunlight in river water degradation was slow (t1/2 = 106 h)||Matamoros et al.96|
|S, F||Photolysis in natural lake water was considered (direct versus indirect mechanism not separated). Under sunlight in the lake water a half life of 23 hours was observed||Zuo et al.143|
|Summary||—||Photodegradation of 17α-ethinylestradiol is somewhat variable in the literature. Overall photolytic degradation rates ranged from rapid to slow. Most commonly they fell in the moderate range. Indirect mechanisms seem to depend on the type of water and concentration of DOM, since studies report both enhancement and reduction in degradation for indirect photolysis experiments||—|
|Recommendation||—||Data for 17α-ethinylestradiol is variable. More systematic and thorough experiments should be conducted to determine more reliably the extent of direct photolysis and how indirect photolysis mechanisms vary with the presence of natural water constituents||—|
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