Karlien Dejaeger

Justine Criquet

Marjolein Vanoppen

Cécile Vignal

Gabriel Billon

Emile R Cornelissen
email: emile.cornelissen@ugent.be.

Identification of disinfection by-product precursors by natural organic matter fractionation: A critical review -invited article

Keywords: trihalomethanes, haloacetic acids, emerging disinfection by-products, resin fractionation, membrane fractionation, chlorination

The presence of natural organic matter in water resources induces the formation of potentially harmful disinfection by-products during drinking water disinfection. However, the identification of disinfection by-product precursors from the complex natural organic matter mixture is very challenging. Therefore, many studies focused on the fractionation of natural organic matter with membranes or resins to better understand how and which organic matter fractions react during chlorination. The outcomes of these studies are rather variable, therefore, a meta-analysis was performed to compare the reactivity of the different fractions towards (un)regulated disinfection byproducts. In this study, we review for the first time the influence of key parameters such as chlorination time and dose, specific ultraviolet absorbance (SUVA 254 = UV absorbance at 254 nm divided by the organic matter concentration) and the column capacity factor used during resin fractionation by collecting results from almost 400 water samples from more than 80 different publications. The major outcomes were: 1) hydrophobic compounds have 10-20 % higher reactivity to both trihalomethane and haloacetic acid formation compared to hydrophilic compounds in waters with high SUVA 254 (>2 L/(mg•m)), while hydrophobic and hydrophilic compounds have equal reactivity in waters with low SUVA 254 . On the other hand, hydrophilic compounds are 20-80 % more reactive towards emerging disinfection by-products, regardless of SUVA 254 ; 2) chlorination time and dose seem to not change the reactivity ratio between the different fractions; 3) an increase in column capacity factor can shift this ratio from hydrophobic to hydrophilic fractions and 4) dead-end, stirred cell ultrafiltration membrane fractionation might not always produce sharply separated fractions, which is mainly due to fouling. Therefore, no clear correlation could be found between membrane fractions and all investigated disinfection by-product groups.

Introduction

Natural organic matter, ubiquitous in sources of drinking water, negatively affects drinking water quality. It can contribute to an undesired taste, odor or color of the drinking water and to the formation of biofilms and (pathogenic) bacterial regrowth by acting as nutrients in the distribution system. Chlorine is the most commonly used disinfectant to inactivate waterborne pathogens and to maintain a disinfectant residual in the distribution network. However, chlorine reacts with natural organic matter to form various disinfection by-products and exposure to these by-products has been associated with health issues such as bladder cancer [START_REF] Diana | Disinfection byproducts potentially responsible for the association between chlorinated drinking water and bladder cancer: A review[END_REF]. More than 700 disinfection by-products have already been identified, where mainly four trihalomethanes and five haloacetic acids are regulated in different countries [START_REF] Richardson | Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: A review and roadmap for research[END_REF]. The USA has set maximum contaminant limits of trihalomethanes and haloacetic acids in drinking water to 80 and 60 µg/L respectively, while trihalomethane levels in the EU cannot exceed 100 µg/L. Haloacetic acid concentrations were recently limited in the EU to 60 µg/L (Council of the European Union, 2020; EPA, 2010). Unregulated disinfection by-products such as haloacetonitriles, haloacetamides or haloketones are formed in lower concentrations (typically low µg/L to ng/L) [START_REF] Richardson | Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: A review and roadmap for research[END_REF]. Nevertheless, the toxicity of these compounds is higher than that of the regulated by-products and thus, these compounds may cause greater public health issues. The presence of bromide and/or iodide in the water matrix leads to the formation of brominated and iodinated disinfection by-products [START_REF] Criquet | Comprehensive Analytical Chemistry[END_REF]. These compounds are even more genotoxic and cytotoxic than their chlorinated analogues, e.g. iodoacetic acid, which is the most genotoxic compound identified to date [START_REF] Dong | Formation of Iodinated Disinfection Byproducts (I-DBPs) in Drinking Water: Emerging Concerns and Current Issues[END_REF][START_REF] Wagner | CHO cell cytotoxicity and genotoxicity analyses of disinfection by-products: An updated review[END_REF].

In the past decades, many research focused on identifying natural organic matter compounds responsible for disinfection by-product formation. However, dissolved organic carbon, i.e. the fraction that passes through a 0.45 µm filter, is a very complex mixture of aromatic and aliphatic hydrocarbons. The concentration, composition and chemistry are highly variable and depend on the natural organic matter source, the season, temperature, pH and ionic strength of the water [START_REF] Filella | Freshwaters: which NOM matters?[END_REF][START_REF] Leenheer | Peer Reviewed: Characterizing Aquatic Dissolved Organic Matter[END_REF]. Therefore, dissolved organic carbon is characterized by bulk parameters such as total organic carbon and specific ultraviolet absorbance at 254 nm (SUVA 254 ) or by more in-depth characterization techniques such as nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy and 3D-fluorescence excitation-emission matrices [START_REF] Filella | Freshwaters: which NOM matters?[END_REF][START_REF] Matilainen | An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment[END_REF]. This characterization is however very difficult due to the simultaneous presence of hundreds of different molecules. Therefore, with fractionation processes, organic matter is split beforehand into several fractions with similar physical or chemical properties. This can be done analytically by the use of chromatographic methods such as high performance-size exclusion chromatography or field flow fractionation, which both split the organic matter by size and shape [START_REF] Matilainen | An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment[END_REF][START_REF] Pan | Characterization of natural organic matter in drinking water: Sample preparation and analytical approaches[END_REF]. [START_REF] Huber | Characterisation of aquatic humic and nonhumic matter with size-exclusion chromatography -organic carbon detection -organic nitrogen detection (LC-OCD-OND)[END_REF] developed a method that consists of liquid chromatography coupled to both an organic carbon detector and organic nitrogen detector. This technique is capable of identifying five different fractions of organic matter; (a) biopolymers, (b) humic substances, (c) building blocks, (d) low molecular weight acids and (e) low molecular weight neutrals.

With analytical fractionation, the different fractions are lost after analysis, because they are not readily available as separate extracts nor in adequate volumes to conduct further experiments.

Therefore, preparative fractionation such as membrane or resin fractionation is performed to split natural organic matter into available fractions or extracts with similar physical (with membranes) or chemical (with resins) properties in sufficient quantities [START_REF] Matilainen | An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment[END_REF][START_REF] Ratpukdi | Rapid Fractionation of Natural Organic Matter in Water Using a Novel Solid-Phase Extraction Technique[END_REF]. Subsequently, researchers seek to correlate these properties to certain water-related issues, such as disinfection by-product formation, bacterial regrowth or membrane fouling behavior which might be overly expressed with a certain fraction. Finally, precise solution strategies can be developed targeting this specific fraction [START_REF] Krzeminski | Natural organic matter fractions and their removal in full-scale drinking water treatment under cold climate conditions in Nordic capitals[END_REF][START_REF] Pi | Size and resin fractionations of dissolved organic matter and characteristics of disinfection by-product precursors in a pilot-scale constructed wetland[END_REF][START_REF] Sambo | Quantification of biodegradable natural organic matter (NOM) fractions and its impact on bacterial regrowth in a South African Water Treatment Plant[END_REF][START_REF] Yin | Fouling behavior of isolated dissolved organic fractions from seawater in reverse osmosis (RO) desalination process[END_REF].

Membrane and resin fractionation are widely used in an attempt to identify disinfection by-product precursors. In this respect, fractionation parameters such as membrane and resin type, or chlorination parameters such as chlorination dose, reaction time, pH and temperature are key factors for the outcome and the interpretation of the results. Although research already looked into the influence of chlorination parameters on bulk samples [START_REF] Hua | DBP formation during chlorination and chloramination: Effect of reaction time, pH, dosage, and temperature[END_REF][START_REF] Iriarte | Trihalomethane formation in ozonated and chlorinated surface water[END_REF], no assessments are done so far on how individual fractions react on certain changes in chlorination parameters.

Therefore, this review will focus for the first time on (i) all the different membrane and resin fractionation approaches used in the identification of disinfection by-product precursors and assess their advantages and drawbacks and, (ii) critically evaluate if certain fractionation and chlorination parameters can influence the formation of both regulated and unregulated disinfection by-products in these fractions and identify their precursors.

Factors controlling fractionation and disinfection by-product formation

Many research has been executed in the past to identify the most important precursors for disinfection by-product formation. However, several approaches were used in these attempts. It is therefore important to identify the parameters that are varied among the different papers, because this can possibly affect the results and outcome. In this review, papers will be separated based on their method and the influence of different parameters will be assessed to make a clear, statistical comparison regarding disinfection by-product formation.

For membrane fractionation, both the membrane material and the pressure can influence the filtration. Overall, regenerated cellulose is used and the pressure varies between 0.2 and 3.5 bar, which is believed not to change the fractionation significantly (section 3.1). Furthermore, it appeared that for resin fractionation, not the resin type, but the column capacity factor (k') is the only parameter that differs largely between papers, having a value of 50 or 100 [START_REF] Leenheer | Comprehensive approach to preparative isolation and fractionation of dissolved organic-carbon from natural-waters and wastewaters[END_REF][START_REF] Malcolm | Quantitative-evaluation of XAD-8 and XAD-4 resins used in tandem for removing organic solutes from water[END_REF]. [START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF] showed a gradual increase in trihalomethane and haloacetic acid formation in a particular fraction when changing the column capacity factor from around 30 to 105 (section 4.1 for further discussion).

Chlorine is the principal disinfectant used in drinking water, an extensively studied reactant for disinfection by-product formation potential and therefore, the only disinfectant reviewed here. Temperature, pH, reaction time and chlorine dose are the 4 main parameters controlling disinfection by-product formation kinetics [START_REF] Hua | DBP formation during chlorination and chloramination: Effect of reaction time, pH, dosage, and temperature[END_REF]. Ambient temperature and neutral pH are reported in all papers collected and will therefore be assumed constant (sections 3 and 4). On the other hand, the reaction time and chlorine dose is very variable among papers. Short reaction times are mostly accompanied with low free chlorine residual (~1 mg Cl 2 /L), while during long exposure, chlorine is added in excess to seek reaction completion (~3 -5 mg Cl 2 /L chlorine residual), as followed by different APHA standard methods for the examination of water and wastewater such as 5710B (sections 3 and 4). While the uniform formation condition test with short reaction time and low chlorine dose illustrates distribution system conditions, the formation potential test determines a maximal amount of disinfection by-products that could be formed through the complete reaction of the disinfection by-product precursors with chlorine in a sample [START_REF] Kanan | Estimation of haloacetonitriles formation in water: Uniform formation conditions versus formation potential tests[END_REF].

Finally, specific ultraviolet absorbance (SUVA 254 ) is one of the most frequently used parameters to characterize natural organic matter in a water source. SUVA 254 is defined as the absorbance of UV at 254 nm divided by the organic matter concentration (Ho et al., 2013). This wavelength is especially absorbed by aromatic species [START_REF] Matilainen | An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment[END_REF]. In this review, the threshold between high and low SUVA 254 waters is set at 2 L/(mg•m). Since resin fractionation is mainly based on hydrophobicity, this parameter might have an important role and will be included together with the chlorination time, dose and column capacity factor when assessing the reactivity of different fractions towards disinfection by-product formation.

Membrane fractionation

Principle of membrane fractionation

Generally, a series of ultrafiltration membranes with decreasing molecular weight cut-offs are used to prepare fractions with different size-ranges (Fig. 1a). Regenerated cellulose membranes in deadend stirred cell configuration is the most frequently applied method. The molecular weight cut-off of the membranes range from 0.5 kDa up to 100 kDa or even 500 kDa [START_REF] Chang | Characteristics of organic precursors and their relationship with disinfection by-products[END_REF][START_REF] Goslan | 4th World Water Congress: Innovation in Drinking Water Treatment[END_REF][START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF]Hua and Reckhow, 2007b;[START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Özdemr | Characterization of natural organic matter in conventional water treatment processes and evaluation of THM formation with chlorine[END_REF]Wei et al., 2008b;[START_REF] Xu | Characteristics of organic material in Huangpu River and treatability with the O3-BAC process[END_REF]Zhang et al., 2020b;[START_REF] Zhao | Disinfection characteristics of the dissolved organic fractions at several stages of a conventional drinking water treatment plant in Southern China[END_REF]. Generated membrane fractions are defined as a molecular weight range which is based on the molecular weight cut-off of the membranes used, e.g. molecules that pass a membrane with a molecular weight cut-off of 100 kDa, but are rejected by a membrane with one of 30 kDa are defined as the 30-100 kDa fraction. This will be further called the theoretical molecular weight range of a fraction. However, [START_REF] Goslan | 4th World Water Congress: Innovation in Drinking Water Treatment[END_REF] and [START_REF] Zhao | Disinfection characteristics of the dissolved organic fractions at several stages of a conventional drinking water treatment plant in Southern China[END_REF] characterized their generated membrane fractions with size exclusion chromatography coupled to a ultraviolet detector at 254 nm.

From this, it was concluded that the chromatograms of all fractions from the respective paper are largely overlapping. Furthermore, [START_REF] Zhao | Disinfection characteristics of the dissolved organic fractions at several stages of a conventional drinking water treatment plant in Southern China[END_REF] reported that the apparent mean molecular weight values of the fractions measured from the chromatography were lower than expected from the molecular weight cut-offs.

This observation was also confirmed by other analytical techniques such as flow-field flow fractionation [START_REF] Assemi | Characterization of natural organic matter fractions separated by ultrafiltration using flow field-flow fractionation[END_REF]. Here, the minimum, maximum and mean molecular weight value from each membrane fraction was determined. Fig. 2 shows the difference between the theoretical molecular weight range (crossed pattern bars) and the real molecular weight range of a fraction measured with flow-field flow fractionation (solid bars). Apart from the prominent overlap between the fractions, it can be seen that the 10-30 kDa and > 30 kDa fraction only contain molecules which are much smaller than 10 kDa, meaning that molecules bigger than 10 kDa were not present in the raw water. However, it is contra-intuitive that molecules smaller than 10 kDa were retained by the 30 kDa membrane. For ultrafiltration membrane fractionation, most authors use a dead-end stirred cell configuration. Here, the water flow is perpendicular to the membrane resulting in accumulation of the retained compounds and thereby inducing fouling onto the membrane. This fouling layer will act as an extra barrier, possibly retaining molecules smaller than the molecular weight cut-off of the membrane. Furthermore, the pore sizes of membranes are known not to be uniform, but to have a pore size distribution [START_REF] Mulder | Basic principles of membrane technology[END_REF]. Therefore, molecular weight cut-off is defined as the molecular weight of compounds that are retained by the membrane for only 90 %, which might explain the partial overlap between the fractions [START_REF] Chow | Physical and chemical fractionation of dissolved organic matter and trihalomethane precursors: A review[END_REF][START_REF] Zhao | Disinfection characteristics of the dissolved organic fractions at several stages of a conventional drinking water treatment plant in Southern China[END_REF]).

An alternative approach to perform a membrane fractionation was recently developed by Yin et al.

(2019) (Fig. 1b). With the use of both a nanofiltration and ultrafiltration membrane in spiral wound modules, three distinct fractions from seawater were successfully obtained and characterized by liquid chromatography, namely (i) a fraction containing 95 % biopolymers, (ii) a fraction with 93% humic substances and their building blocks and (iii) a 87 % low molecular weight compound fraction [START_REF] Yin | Fouling behavior of isolated dissolved organic fractions from seawater in reverse osmosis (RO) desalination process[END_REF]. After pretreating a raw water sample with a 0.2 µm filter to remove the particulate matter, nanofiltration was performed to collect the low molecular weight molecules in the permeate stream. Humic substances and biopolymers are rejected by the nanofiltration membrane and are fed to a subsequent ultrafiltration membrane in which humic substances and biopolymers are separated on respectively the permeate and the retentate side. Diafiltration is performed in each step to ensure a higher purity of the fractions [START_REF] Yin | Fouling behavior of isolated dissolved organic fractions from seawater in reverse osmosis (RO) desalination process[END_REF]. Furthermore, the real molecular weight range of the fractions are largely overlapping, meaning that the separation of organic matter based on size was unsuccessful.

Although membrane fractionation is a relatively fast and cheap method through the use of commercially available membranes, it seems to lack the ability to produce sharply separated fractions. The two main causes could be (i) the molecular weight cut-off of a membrane is not strict and (ii) dead-end cell operation causing fouling can influence the retention of all compounds.

Therefore, care should be taken when interpreting the results of different studies using ultrafiltration fractionation, since it is not guaranteed that the fractions really contain the molecular weight range as defined by the molecular weight cut-offs of the ultrafiltration membranes. A crossflow filtration seems more reliable, since it reduces fouling and has the ability to pass the feedwater several times over the membrane, allowing the gradual removal of the desired compounds with diafiltration. This will however dilute the final concentrations in the membrane fractions. The relationship between membrane fractions and disinfection by-product formation is extensively studied and will be discussed in the next section.

Identification of membrane fractions involved in disinfection by-product formation

Fig. 3 represents the specific trihalomethane formation potential after different chlorination times and different specific ultraviolet absorbance (SUVA 254 ) values in several membrane fractions (section 6 for Methods). SUVA 254 is defined as the absorbance of ultraviolet light at 254 nm divided by the organic matter concentration (Ho et al., 2013). From this, it appears that the reactivity for trihalomethane formation increases when the molecular weight of organic material decreases, although the correlation remains weak. After 48 h with low chlorine dose or after 7 days with high chlorine dose, there is a clear difference between the highest and lowest membrane fractions. Here, the < 1 kDa fraction has significantly higher specific formation potential compared to the > 10 kDa fraction. On the other hand, only a small, non-significative discrepancy is seen between the highest (> 10 kDa) and lowest (< 1 kDa) membrane fractions after 24 h (low chlorine dose) or 72 h (high chlorine dose). It seems that SUVA 254 has no influence on the results, since fractionated waters with either high or low SUVA 254 give a same trend in specific trihalomethane formation potential (Fig. 3a,c). Moreover, di-halogenated acetic acid formation follows the same relationship as trihalomethanes between molecular weight and formation potential, since the < 1 kDa fraction has significantly higher formation potential compared to 3-10 kDa and > 10 kDa fraction (Fig. 4a). This trend is not visible at all for tri-halogenated acetic acid formation, where all 4 fractions have the same formation potential behavior (Fig. 4b). When overall specific haloacetic acid formation potential is measured, a small increase in reaction potential is seen after 7 days of reaction for lower molecular weight fractions, although it was not significant (Fig. 4d). However, after 72 h, an opposite trend is noticeable with a maximum formation potential in the 5-10 kDa fraction (Fig. 4c). No assessment of the effect of SUVA 254 could be made due to a lack of data. Table S1 provides the data collected for emerging disinfection by-products, but this dataset is too limited to draw any conclusion [START_REF] Ge | Characteristics and removal mechanism of the precursors of N-chloro-2,2-dichloroacetamide in a drinking water treatment process at Taihu Lake[END_REF][START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Hua | Characteristics of low and high SUVA precursors: Relationships among molecular weight, fluorescence, and chemical composition with DBP formation[END_REF][START_REF] Lin | A comparison of carbonaceous, nitrogenous and iodinated disinfection by-products formation potential in different dissolved organic fractions and their reduction in drinking water treatment processes[END_REF][START_REF] Zhang | Variations of disinfection byproduct precursors through conventional drinking water treatment processes and a real-time monitoring method[END_REF]Zhang et al., 2020b). Also in literature, conflicting trends between specific trihalomethane formation potential and molecular weight range are stated. For example, the specific formation potential is reported to increase when the molecular weight of the fractions decreases, while on the other hand authors have reported a peak in specific formation potential in medium molecular weight fractions. In contradiction to the above findings, increasing formation potential with increasing molecular weight have also been reported and some studies show no correlation at all between the formation potential and molecular weight. Conflicting conclusions exist as well for both specific di-halogenated and tri-halogenated acetic acid formation potentials and emerging disinfection by-products [START_REF] An | Relationship between THMs/NDMA formation potential and molecular weight of organic compounds for source and treated water in Shanghai, China[END_REF][START_REF] Avsar | Physical characterisation of natural organic matter and determination of disinfection by-product formation potentials in Istanbul surface waters[END_REF][START_REF] Chang | Characteristics of organic precursors and their relationship with disinfection by-products[END_REF][START_REF] Chiang | NOM characteristics and treatabilities of ozonation processes[END_REF][START_REF] Gang | Relationship of chlorine decay and THMs formation to NOM size[END_REF][START_REF] Ge | Characteristics and removal mechanism of the precursors of N-chloro-2,2-dichloroacetamide in a drinking water treatment process at Taihu Lake[END_REF][START_REF] Goslan | 4th World Water Congress: Innovation in Drinking Water Treatment[END_REF][START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF]Hua and Reckhow, 2007b;[START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Hua | Characteristics of low and high SUVA precursors: Relationships among molecular weight, fluorescence, and chemical composition with DBP formation[END_REF][START_REF] Karapinar | Seasonal variations of NOM composition and their reactivity in a low humic water[END_REF][START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Lin | A comparison of carbonaceous, nitrogenous and iodinated disinfection by-products formation potential in different dissolved organic fractions and their reduction in drinking water treatment processes[END_REF][START_REF] Liu | NOM reactivity with chlorine in low SUVA water[END_REF][START_REF] Özdemr | Characterization of natural organic matter in conventional water treatment processes and evaluation of THM formation with chlorine[END_REF][START_REF] Pi | Size and resin fractionations of dissolved organic matter and characteristics of disinfection by-product precursors in a pilot-scale constructed wetland[END_REF][START_REF] Pramanik | Comparisons between biological filtration and coagulation processes for the removal of dissolved organic nitrogen and disinfection by-products precursors[END_REF]Wei et al., 2008a;Wei et al., 2008b;[START_REF] Xu | Characteristics of organic material in Huangpu River and treatability with the O3-BAC process[END_REF][START_REF] Xu | Measurement of dissolved organic nitrogen in a drinking water treatment plant: Size fraction, fate, and relation to water quality parameters[END_REF][START_REF] Zhang | Variations of disinfection byproduct precursors through conventional drinking water treatment processes and a real-time monitoring method[END_REF]Zhang et al., 2020b;[START_REF] Zhang | Characterization of natural organic matter and disinfection byproducts formation potential in pilot-scale coagulation-ultrafiltration membrane combined process in winter[END_REF][START_REF] Zhang | Characteristics of molecular weight distribution of dissolved organic matter in bromide-containing water and disinfection by-product formation properties during treatment processes[END_REF][START_REF] Zhao | Molecular size distribution of dissolved organic matter in water of the Pearl River and trihalomethane formation characteristics with chlorine and chlorine dioxide treatments[END_REF][START_REF] Zhao | Disinfection characteristics of the dissolved organic fractions at several stages of a conventional drinking water treatment plant in Southern China[END_REF].

In addition, [START_REF] Hua | Characteristics of low and high SUVA precursors: Relationships among molecular weight, fluorescence, and chemical composition with DBP formation[END_REF] analyzed waters with both high and low SUVA 254 values, including commercial humic acid as high SUVA 254 source and a surface water as low SUVA 254 source. Here, high molecular weight compounds (> 30 kDa) contributed the most to specific regulated and unregulated disinfection by-product formation potential. Precursors from high SUVA 254 waters showed a clear humic-acid like signal with high molecular weight, while precursors from low SUVA 254 waters showed a high molecular weight protein-like signal. On the other hand, both high and low molecular weight fractions have been indicated as having high regulated and unregulated disinfection formation potential consisting of humic acid-like and/or soluble microbial by-product-like compounds (Hua et al., 2007;Zhang et al., 2020b). The latter ones cover a wide range of molecular weight (0.5-50 kDa) [START_REF] Barker | A review of soluble microbial products (SMP) in wastewater treatment systems[END_REF]. Furthermore, [START_REF] Zhang | Role of NOM molecular size on iodo-trihalomethane formation during chlorination and chloramination[END_REF] showed with commercial humic acids that the formation of iodinated trihalomethanes increases with molecular weight.

The aforementioned SUVA 254 or molecular weight correlations were however not visible when data from all papers were taken together. Regarding the previous discussion on overlapping fractions in membrane fractionation (section 3.1), this could be an important drawback in the studies which intended to discriminate disinfection by-product formation on molecular weight. It would be beneficial to optimize the membrane fractionation approach. A possible starting point for this could be the fractionation protocol developed by [START_REF] Yin | Fouling behavior of isolated dissolved organic fractions from seawater in reverse osmosis (RO) desalination process[END_REF] (section 3.1). Analyzing trihalomethanes and haloacetic acid formation potentials on well-defined fractions might clarify the most important natural organic matter precursors.

Another observation made in literature is that the lowest molecular weight fractions produce relatively more brominated disinfection by-products and therefore, it has been stated that low molecular weight compounds are more reactive towards bromine [START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF][START_REF] Xu | Characteristics of organic material in Huangpu River and treatability with the O3-BAC process[END_REF].

Nonetheless, the bromide-to-total organic carbon ratio in the different fractions will change depending on the retention of both organics and bromide during membrane filtration. When the concentration of bromide is adjusted to the initial concentration for all fractions, either the previous statement is confirmed or no specific trend is seen in bromide incorporation for the different fractions (Hua and Reckhow, 2007b;[START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF].

In summary, the relationship between molecular weight and disinfection by-product formation appeared to be very weak. Alternatively, natural organic matter is split based on hydrophobicity instead of size by the usage of resins. These different techniques will be elaborated in the next section.

Resin fractionation 4.1 Principle of resin fractionation

In resin fractionation, a liquid sample is fed to a polymeric resin adsorbing organic matter which is subsequently eluted using a solvent of suitable polarity [START_REF] Minor | Structural characterization of dissolved organic matter: a review of current techniques for isolation and analysis[END_REF]. [START_REF] Aiken | Comparison of XAD Macroporous Resins for the Concentration of Fulvic Acid from Aqueous Solution[END_REF] introduced this technique for the first time using commercially available non-polar XAD-resins. The resins can be composed of styrene-divinylbenzene or methyl-methacrylate polymers [START_REF] Daignault | A review of the use of XAD resins to concentrate organic compounds in water[END_REF][START_REF] Kim | Characterization of natural organic matter in conventional water treatment processes for selection of treatment processes focused on DBPs control[END_REF]. Several modifications have been made over the years to optimize this method [START_REF] Matilainen | An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment[END_REF]. XAD-8 and XAD-4 are the main resins used in the different fractionation methods. Since XAD-8 is no longer commercially available, XAD-7HP, DAX-8 or C18 silica resins have been used as alternatives. XAD-8 and DAX-8 show very comparable physical and chemical properties and their comparability for aquatic use has been proven [START_REF] Chow | Comparison of DAX-8 and XAD-8 resins for isolating disinfection byproduct precursors[END_REF]. XAD-7HP has the same chemical structure as XAD-8 (polymethyl-methacrylate), but XAD-7HP has a larger surface area and is more porous [START_REF] Pan | Characterization of natural organic matter in drinking water: Sample preparation and analytical approaches[END_REF]. XAD-4 is composed of non-ionic styrene divinylbenzene polymer and C18 resins are composed of hydrocarbons bonded to a silica matrix and have generally higher recoveries than XAD-resins [START_REF] Minor | Structural characterization of dissolved organic matter: a review of current techniques for isolation and analysis[END_REF].

The simplest resin fractionation method generates a hydrophobic and hydrophilic fraction using a single XAD-8 resin at pH 2 (Fig. 5a). Adsorption onto XAD-resins occurs through aromatic π-electron and hydrophobic interactions [START_REF] Bond | Disinfection Byproduct Formation and Fractionation Behavior of Natural Organic Matter Surrogates[END_REF]. Therefore, compounds that are not retained are defined as hydrophilic compounds. The less hydrophilic compounds are adsorbed on the XAD-8 resin and defined as the hydrophobic fraction [START_REF] Aiken | Comparison of XAD Macroporous Resins for the Concentration of Fulvic Acid from Aqueous Solution[END_REF][START_REF] Jung | The relationship between disinfection by-products formation and characteristics of natural organic matter in raw water[END_REF][START_REF] Kim | Characterization of natural organic matter in conventional water treatment processes for selection of treatment processes focused on DBPs control[END_REF]Kim et al., 2006b;[START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF][START_REF] Thurman | Preparative isolation of aquatic humic substances[END_REF]. They are eluted with sodiumhydroxide at pH 11. Increasing the pH will ionize carboxyl and phenolic hydroxyl groups and desorb the hydrophobic compounds [START_REF] Aiken | Comparison of XAD Macroporous Resins for the Concentration of Fulvic Acid from Aqueous Solution[END_REF]).

An additional step has been added to this method by passing the hydrophilic fraction over a XAD-4 resin at pH 2 (Fig. 5b). The fraction that is not retained, is the hydrophilic (non-acid) fraction. The fraction that is retained by XAD-4 and eluted at pH 13 with sodiumhydroxide or acetonitrile is called the transphilic or hydrophilic acid fraction [START_REF] Aiken | Isolation of hydrophilic organicacids from water using nonionic macroporous resins[END_REF][START_REF] Croué | Isolation of Humic and Non-Humic NOM Fractions: Structural Characterization[END_REF][START_REF] Golea | THM and HAA formation from NOM in raw and treated surface waters[END_REF][START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF]Hua and Reckhow, 2007b;[START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Leenheer | Comprehensive isolation of natural organic matter from water for spectral characterizations and reactivity testing[END_REF][START_REF] Li | Characterization of dissolved organic matter from surface waters with low to high dissolved organic carbon and the related disinfection byproduct formation potential[END_REF][START_REF] Malcolm | Quantitative-evaluation of XAD-8 and XAD-4 resins used in tandem for removing organic solutes from water[END_REF][START_REF] Rho | Rapid and Effective Isolation of Dissolved Organic Matter Using Solid-Phase Extraction Cartridges Packed with Amberlite XAD 8/4 Resins[END_REF][START_REF] Song | Isolation and fractionation of natural organic matter: evaluation of reverse osmosis performance and impact of fractionation parameters[END_REF][START_REF] Tubić | Insight into changes during coagulation in NOM reactivity for trihalomethanes and haloacetic acids formation[END_REF][START_REF] Xu | Characteristics of organic material in Huangpu River and treatability with the O3-BAC process[END_REF]. The hydrophobic fraction is retained in a similar way as in the previous method with XAD-8, only the pH used to desorb the fraction is different (pH 11 vs. 13). A 100% effective elution at pH 13 is obtained due to the (complete) ionization of carboxyl and phenolic hydroxyl groups and a near 100% carbon recovery is obtained by co-current elution of a 75/25 acetonitrile/water mixture [START_REF] Aiken | Comparison of XAD Macroporous Resins for the Concentration of Fulvic Acid from Aqueous Solution[END_REF][START_REF] Croué | Isolation of Humic and Non-Humic NOM Fractions: Structural Characterization[END_REF]. A very elaborate resin fractionation splits natural organic matter into six fractions: hydrophobic acids, bases, neutrals and hydrophilic acids, bases and neutrals (Fig. 5c). More detailed information on organic species present in the water is obtained with this fractionation, which can facilitate subsequent analysis in different research fields, such as disinfection by-product formation. The most common method is to pass the sample through the XAD-8 resin twice. After the first run at pH 10 or without pH adjustment, hydrophobic bases are recovered by desorption with hydrochloric acid, which protonates the basic compounds. The second run is performed at pH 2, after which hydrophobic acids are eluted with sodiumhydroxide. This is the same approach as in the previous methods to obtain the overall hydrophobic fraction. The hydrophobic neutral fraction is obtained by (freeze-) drying the XAD-8 resin and extracting the compounds from the resin with methanol. DAX-8 and Bond Elute ENV cartridges (styrene-divinyl benzene) are also used for this purpose.

Subsequently, the hydrophilic compounds are split into acids, bases and neutrals by the use of ion exchange resins. The water sample at pH 2 is introduced to a cation exchange resin (AG-MP-50/Dowex MSC/Strata X-C) which retains the hydrophilic base compounds [START_REF] Chang | Characterization and isolation of natural organic matter from a eutrophic reservoir[END_REF][START_REF] Chang | Characteristics of organic precursors and their relationship with disinfection by-products[END_REF][START_REF] Chen | Disinfection by-products and their precursors in a water treatment plant in North China: Seasonal changes and fraction analysis[END_REF][START_REF] Goss | Trihalomethane formation potential of DOC fractions isolated from two Canadian Prairie surface water sources[END_REF]Kanokkantapong et al., 2006b;[START_REF] Lamsal | Characterization and removal of natural organic matter by an integrated membrane system[END_REF][START_REF] Leenheer | Comprehensive approach to preparative isolation and fractionation of dissolved organic-carbon from natural-waters and wastewaters[END_REF][START_REF] Marhaba | Modified dissolved organic matter fractionation technique for natural water[END_REF][START_REF] Ratpukdi | Rapid Fractionation of Natural Organic Matter in Water Using a Novel Solid-Phase Extraction Technique[END_REF][START_REF] Zhang | Characterization of isolated fractions of dissolved organic matter from sewage treatment plant and the related disinfection by-products formation potential[END_REF][START_REF] Zhang | Fluorescence spectroscopic characterization of DOM fractions isolated from a filtered river water after ozonation and catalytic ozonation[END_REF]. These are all strong acid, sulfonated resins with different backbone structures. AG-MP-50 consists of a polystyrene backbone, while Dowex MSC has a styrene-divinylbenzene structure [START_REF] Leenheer | Comprehensive approach to preparative isolation and fractionation of dissolved organic-carbon from natural-waters and wastewaters[END_REF][START_REF] Meyer | Integration of ion exchange resin materials for a downstream-processing approach of an imine reductase-catalyzed reaction[END_REF][START_REF] Ratpukdi | Rapid Fractionation of Natural Organic Matter in Water Using a Novel Solid-Phase Extraction Technique[END_REF]. A weak anion exchange resin (WA10/Duolite A7/IRA 93/Strata X-AW) retains the hydrophilic acid fraction at pH 2, while the hydrophilic neutral compounds are not retained. The anion exchange resins all consist of amine functionality (primary, secondary or tertiary) with different backbones, going from polystyrene, to acrylic polymers and even phenol-formaldehyde condensation matrices. Duolite A7 suffers from severe resin bleeding [START_REF] Kananpanah | Developing a new model to predict mass transfer coefficient of salicylic acid adsorption onto IRA-93: Experimental and modeling[END_REF][START_REF] Leenheer | Comprehensive approach to preparative isolation and fractionation of dissolved organic-carbon from natural-waters and wastewaters[END_REF][START_REF] Marhaba | Modified dissolved organic matter fractionation technique for natural water[END_REF][START_REF] Miyazaki | Protonation and ion exchange equilibria of weak base anionexchange resins[END_REF][START_REF] Ratpukdi | Rapid Fractionation of Natural Organic Matter in Water Using a Novel Solid-Phase Extraction Technique[END_REF]. Ammoniumhydroxide or sodiumhydroxide are used to desorb both fractions. Ammoniumhydroxide returns the resins in their hydrogen (cation exchange resin) or free-base form (anion exchange resin) [START_REF] Chang | Characterization and isolation of natural organic matter from a eutrophic reservoir[END_REF][START_REF] Chang | Characteristics of organic precursors and their relationship with disinfection by-products[END_REF][START_REF] Chen | Disinfection by-products and their precursors in a water treatment plant in North China: Seasonal changes and fraction analysis[END_REF][START_REF] Goss | Trihalomethane formation potential of DOC fractions isolated from two Canadian Prairie surface water sources[END_REF]Kanokkantapong et al., 2006b;[START_REF] Lamsal | Characterization and removal of natural organic matter by an integrated membrane system[END_REF][START_REF] Leenheer | Comprehensive approach to preparative isolation and fractionation of dissolved organic-carbon from natural-waters and wastewaters[END_REF][START_REF] Marhaba | Modified dissolved organic matter fractionation technique for natural water[END_REF][START_REF] Ratpukdi | Rapid Fractionation of Natural Organic Matter in Water Using a Novel Solid-Phase Extraction Technique[END_REF][START_REF] Zhang | Characterization of isolated fractions of dissolved organic matter from sewage treatment plant and the related disinfection by-products formation potential[END_REF][START_REF] Zhang | Fluorescence spectroscopic characterization of DOM fractions isolated from a filtered river water after ozonation and catalytic ozonation[END_REF].

Resin fractionation is a very common, relatively cheap and widely applied technique with the use of commercially available resins. The method can be either fast (into hydrophobic-hydrophilic) or timeconsuming (into their respective acids, bases and neutrals). It simultaneously concentrates and fractionates organic matter, but there have been some doubts about possible changes in the chemical and/or physical nature of the water matrix due to the extreme pH-alterations [START_REF] Matilainen | An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment[END_REF][START_REF] Swietlik | Reactivity of natural organic matter fractions with chlorine dioxide and ozone[END_REF]. Furthermore, different column capacity factors are used among different authors. This factor is defined as and is directly proportional to the volume of water applied on a certain resin volume [START_REF] Leenheer | Comprehensive approach to preparative isolation and fractionation of dissolved organic-carbon from natural-waters and wastewaters[END_REF]. The higher the value, the lower the percentage of hydrophobic compounds that is retained on a XAD-8 column for one water sample which can influence further assessments [START_REF] Song | Isolation and fractionation of natural organic matter: evaluation of reverse osmosis performance and impact of fractionation parameters[END_REF]. Also, flow rate and bed height of the column influence the adsorption equilibrium as both parameters change the contact time between adsorbate and adsorbent [START_REF] Patel | Fixed-bed column adsorption study: a comprehensive review[END_REF]. These parameters are, however, very often lacking in the method sections.

In general, studies investigating disinfection by-product precursors with resin fractionation use one of the abovementioned resins and fractionation techniques. The only parameter that varies substantially is the column capacity factor which will therefore be considered in the next section when comparing the results of these studies.

Resin fractions involved in disinfection by-product formation 4.2.1 Trihalomethanes

When looking at the simplest fractionation technique, namely splitting natural organic matter into a hydrophobic and hydrophilic fraction, results are quite consistent (Fig. 6, section 6 for Methods). The hydrophobic fraction produces the highest specific trihalomethane formation potential regardless of chlorination time and SUVA 254 (k' = 100 or undefined). Specific ultraviolet absorbance (SUVA 254 ) is defined as the absorbance of ultra violet light at 254 nm divided by the organic matter concentration (Ho et al., 2013). Up to 72 h and low chlorine dose, hydrophobic moieties have 20 % higher specific formation potential compared to the hydrophilic fraction (Fig. 6a). After 7 days, the difference between the medians even increases to 60 %, although the boxplots themselves show more variability (Fig. 6b). After 7 days reaction time with high chlorine dose, both fast and slow reacting compounds will form trihalomethanes, thereby scattering the data [START_REF] Chang | Characteristics of organic precursors and their relationship with disinfection by-products[END_REF][START_REF] Chiang | NOM characteristics and treatabilities of ozonation processes[END_REF][START_REF] Chiang | Effects of pre-ozonation on the removal of THM precursors by coagulation[END_REF][START_REF] Galapate | Transformation of dissolved organic matter during ozonation: Effects on trihalomethane formation potential[END_REF][START_REF] Goss | Comparison of three solid phase extraction sorbents for the isolation of THM precursors from manitoban surface waters[END_REF][START_REF] Hyung Kim | Characterization of NOM in the Han River and evaluation of treatability using UF-NF membrane[END_REF][START_REF] Imai | Trihalomethane formation potential of dissolved organic matter in a shallow eutrophic lake[END_REF][START_REF] Jung | The relationship between disinfection by-products formation and characteristics of natural organic matter in raw water[END_REF]Kim et al., 2006a;[START_REF] Kim | Characterization of natural organic matter in conventional water treatment processes for selection of treatment processes focused on DBPs control[END_REF][START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Kueseng | Enhanced Coagulation for Removal of Dissolved Organic Matter and Trihalomethane Formation Potential from Raw Water Supply in Sri-Trang Reservoir, Thailand[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF][START_REF] Musikavong | Reduction of fractionated dissolved organic matter and their trihalomethane formation potential with enhanced coagulation[END_REF]. The hydrophobic fraction has previously been implicated as the primary source of trihalomethane precursors with some exceptions [START_REF] Chow | Physical and chemical fractionation of dissolved organic matter and trihalomethane precursors: A review[END_REF]. The discrepancies have been allocated to differences in chlorination methods, but no thorough assessment was made. When the hydrophilic fraction is passed over the XAD-4 resin to generate the transphilic (or hydrophilic acid) fraction and the hydrophilic non-acid fraction, the situation becomes more complex, because the SUVA 254 value of the raw water influences the specific trihalomethane formation potential of the different fractions (Fig. 7). When SUVA 254 of the raw water is high (> 2 L/(mg•m)), the hydrophobic and transphilic fraction have a similar reaction potential (~30 %) to trihalomethane formation at short reaction times and low chlorine dose, while hydrophobic compounds have significantly higher specific trihalomethane formation potential compared to the transphilic and hydrophilic fraction at long reaction times with high chlorine dosage (Fig. 7a,c).

Conversely, when the SUVA 254 level is below 2 L/(mg•m), hydrophilic organics have equally important trihalomethane formation potential as hydrophobic organics at short reaction times (~40 %), while transphilic organic matter seems slightly more reactive after 7 days of reaction and high chlorine dose (Fig. 7b,d) [START_REF] Agbaba | Effects of water matrix and ozonation on natural organic matter fractionation and corresponding disinfection by-products formation[END_REF][START_REF] Chowdhury | Characteristics of Natural Organic Matter and Formation of Chlorinated Disinfection By-Products from Two Source Waters that Respond Differently to Ozonation[END_REF][START_REF] Fang | Characterization of Dissolved Organic Matter and Its Derived Disinfection Byproduct Formation along the Yangtze River[END_REF][START_REF] Goslan | Seasonal variations in the disinfection by-product precursor profile of a reservoir water[END_REF][START_REF] Goslan | 4th World Water Congress: Innovation in Drinking Water Treatment[END_REF][START_REF] Hanigan | MIEX® and PAC for removal of hydrophilic DBP precursors[END_REF][START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF]Hua and Reckhow, 2007b;[START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Li | Characterization of dissolved organic matter from surface waters with low to high dissolved organic carbon and the related disinfection byproduct formation potential[END_REF][START_REF] Lin | Effects of UV/H2O2 on NOM fractionation and corresponding DBPs formation[END_REF][START_REF] Lin | A comparison of carbonaceous, nitrogenous and iodinated disinfection by-products formation potential in different dissolved organic fractions and their reduction in drinking water treatment processes[END_REF][START_REF] Liu | NOM reactivity with chlorine in low SUVA water[END_REF]Molnar et al., 2012a;Molnar et al., 2013;Molnar et al., 2012b;[START_REF] Musikavong | Formation of trihalomethanes of dissolved organic matter fractions in reservoir and canal waters[END_REF][START_REF] Niu | Characterization of the precursors of trihalomethanes and haloacetic acids in the Yuqiao Reservoir in China[END_REF][START_REF] Phetrak | Analysis of trihalomethane precursor removal from sub-tropical reservoir waters by a magnetic ion exchange resin using a combined method of chloride concentration variation and surrogate organic molecules[END_REF][START_REF] Pi | Size and resin fractionations of dissolved organic matter and characteristics of disinfection by-product precursors in a pilot-scale constructed wetland[END_REF][START_REF] Roccaro | Relationships between trihalomethanes, haloacetic acids, and haloacetonitriles formed by the chlorination of raw, treated, and fractionated surface waters[END_REF][START_REF] Smith | Fractionation of natural organic matter in the Nile River: Implications for treated water quality[END_REF][START_REF] Tubić | Insight into changes during coagulation in NOM reactivity for trihalomethanes and haloacetic acids formation[END_REF][START_REF] Wang | Removal of DBP precursors in micro-polluted source waters: A comparative study on the enhanced coagulation behavior[END_REF]Wei et al., 2008a;Wei et al., 2008b;[START_REF] Xu | Characteristics of organic material in Huangpu River and treatability with the O3-BAC process[END_REF][START_REF] Xue | Comparison of dissolved organic matter fractions in a secondary effluent and a natural water[END_REF][START_REF] Zhang | Variations of disinfection byproduct precursors through conventional drinking water treatment processes and a real-time monitoring method[END_REF][START_REF] Zhao | Disinfection By-Product Precursors Removal by Enhanced Coagulation and Their Distribution in Chemical Fractions[END_REF][START_REF] Zhi-Sheng | Characterization of NOM and THM formation potential in reservoir source water[END_REF].

Overall, the hydrophobic fraction is an important contributor to trihalomethane formation at high SUVA 254 , especially at long reaction times with high chlorine dosage, while both hydrophobic and hydrophilic compounds are important at low SUVA 254 . This observation could not be verified in the previous fractionation, since only 5 water samples were found to have low SUVA 254 values. From these 5 samples, 4 of them were chlorinated with a low dose between 24 and 72 h. Here, the ratio of 60 % trihalomethane formation from the hydrophobic fraction and 40 % from the hydrophilic fraction was valid, except for one sample that had a ratio of 53 % versus 47 %. The only water sample analyzed after 7 days and high chlorine dose showed a ratio of only 37 % trihalomethane formation from hydrophobic compounds and 63 % from hydrophilic compounds [START_REF] Chiang | Effects of pre-ozonation on the removal of THM precursors by coagulation[END_REF][START_REF] Hyung Kim | Characterization of NOM in the Han River and evaluation of treatability using UF-NF membrane[END_REF][START_REF] Imai | Trihalomethane formation potential of dissolved organic matter in a shallow eutrophic lake[END_REF]Kim et al., 2006a;[START_REF] Kim | Characterization of natural organic matter in conventional water treatment processes for selection of treatment processes focused on DBPs control[END_REF].

Disinfection by-product formation investigated with natural organic matter surrogates has shown that activated aromatic moieties in the presence of an electron-donating and ortho-para directing group have high rate constants towards chlorine reactivity, because hypochlorous acid (an electrophile) preferentially reacts with electron-rich functionalities in organic molecules. These moieties will also contribute to high SUVA 254 values and reside in the hydrophobic fraction (Bond et al., 2012a;[START_REF] Bond | Disinfection Byproduct Formation and Fractionation Behavior of Natural Organic Matter Surrogates[END_REF]. When the SUVA 254 value is low, other chemical functionalities with lower reactivities, such as amino acids or carbohydrates (hydrophilic compounds), will become important especially after longer reaction time and high chlorine dose (Bond et al., 2012a).

Nonetheless, the behavior of the transphilic fraction for both high and low SUVA 254 conditions is less clear. This fraction has been characterized as having greater heteroatom and carboxyl content than the hydrophobic fraction, but also as having a number of similar properties with the hydrophobic fraction [START_REF] Aiken | Isolation of hydrophilic organicacids from water using nonionic macroporous resins[END_REF]. The C/O, C/H and C/N atomic ratios gradually decrease from hydrophobic to transphilic to hydrophilic [START_REF] Croué | Isolation of Humic and Non-Humic NOM Fractions: Structural Characterization[END_REF]. Furthermore, fractionation of surrogates with different polarities could not identify molecules having clear transphilic character. Surrogates ending up in the transphilic fraction were evenly distributed in either the hydrophobic or hydrophilic fraction [START_REF] Bond | Disinfection Byproduct Formation and Fractionation Behavior of Natural Organic Matter Surrogates[END_REF]. This implies that depending on the natural organic matter composition of the water source, the transphilic fraction can have more hydrophobic or hydrophilic character, which will influence its specific trihalomethane formation potential.

Within the hydrophobic fraction in both resin fractionation methods, humic acids are the most important precursors. Humic acids precipitate when acidifying the hydrophobic fraction to pH = 1, while fulvic acids remain dissolved [START_REF] Agbaba | Effects of water matrix and ozonation on natural organic matter fractionation and corresponding disinfection by-products formation[END_REF][START_REF] Goslan | Seasonal variations in the disinfection by-product precursor profile of a reservoir water[END_REF][START_REF] Goslan | 4th World Water Congress: Innovation in Drinking Water Treatment[END_REF][START_REF] Jung | The relationship between disinfection by-products formation and characteristics of natural organic matter in raw water[END_REF]Molnar et al., 2012a;Molnar et al., 2012b;[START_REF] Tubić | Insight into changes during coagulation in NOM reactivity for trihalomethanes and haloacetic acids formation[END_REF][START_REF] Zhi-Sheng | Characterization of NOM and THM formation potential in reservoir source water[END_REF]. Limited data was found for specific trihalomethane formation potential after fractionation of natural organic matter into hydrophobic and hydrophilic acids, bases and neutrals (Fig. S1). At short reaction times, the hydrophobic acid fraction seems equivalent to the hydrophilic base fraction, although the dataset was too small to find statistical differences. The SUVA 254 was low, so it confirms the statement that both hydrophobic and hydrophilic fractions are important in low SUVA 254 waters, and possibly, in more detail the hydrophobic acid and hydrophilic base fraction. At long chlorination times, however, it is the hydrophobic and hydrophilic base fraction and to a lesser extent the hydrophobic neutral fraction that have the highest specific trihalomethane formation potential, especially compared to hydrophilic neutrals [START_REF] Chang | Characterization and isolation of natural organic matter from a eutrophic reservoir[END_REF][START_REF] Chen | Disinfection by-products and their precursors in a water treatment plant in North China: Seasonal changes and fraction analysis[END_REF][START_REF] Fan | Characterization, DBPs formation, and mutagenicity of different organic matter fractions in two source waters[END_REF][START_REF] Goss | Trihalomethane formation potential of DOC fractions isolated from two Canadian Prairie surface water sources[END_REF][START_REF] Lamsal | Characterization and removal of natural organic matter by an integrated membrane system[END_REF][START_REF] Lin | Investigation of DOM and THMFP in two reservoir waters of Changchun (China)[END_REF][START_REF] Marhaba | The variation of mass and disinfection by-product formation potential of dissolved organic matter fractions along a conventional surface water treatment plant[END_REF]Panyapinyopol et al., 2005a;Panyapinyopol et al., 2005b;[START_REF] Rakruam | Reduction of DOM fractions and their trihalomethane formation potential in surface river water by in-line coagulation with ceramic membrane filtration[END_REF][START_REF] Sharma | Role of precursors in the formation of trihalomethanes during chlorination of drinking water and wastewater effluents from a metropolitan region in western India[END_REF][START_REF] Włodyka-Bergier | The influence of organic matter quality on the potential of volatile organic water chlorination products formation[END_REF][START_REF] Yee | Hydrophobicity characteristics of natural organic matter and the formation of THM (Pencirian Kehidrofobikan Sebatian Organik Semulajadi dan Pembentukan THM)[END_REF][START_REF] Yee | Dissolved organic matter and its impact on the chlorine demand of treated water[END_REF]. Bases are defined as electron donors, thereby promoting the reaction with the electron poor hypochlorous acid (Bond et al., 2012a). Furthermore, hydrophilic bases have been characterized as amide-like compounds, while the hydrophilic neutral fraction mainly contains lignin and lipids [START_REF] Wang | Isolation and characterization of hydrophilic dissolved organic matter in waters by ion exchange solid phase extraction followed by high resolution mass spectrometry[END_REF]. From Fig. S1, there is thus an indication that lignin and lipids are recalcitrant to the formation of trihalomethanes, while amide-like compounds might be important precursors. The occurrence of the hydrophobic acid fraction is less straightforward, however, this is only based on 3 water samples.

The column capacity factor k' seems to have no influence on the results. Where the factor k' is 100 in the hydrophobic-hydrophilic fractionation, it is 50 in the hydrophobic-transphilic-hydrophilic fractionation. However, in the latter resin technique, data was found where both values have been used during a 72h chlorination time with high chlorine dose (Fig. S2). Changing k' from 50 to 100 will result in less adsorption of hydrophobic and transphilic compounds on XAD-8 and XAD-4 respectively and this results into a changing trend in specific trihalomethane formation potential from the hydrophobic fraction as most important precursor (Fig. S2a) to the hydrophilic fraction (Fig. S2b) [START_REF] Liu | NOM reactivity with chlorine in low SUVA water[END_REF][START_REF] Pi | Size and resin fractionations of dissolved organic matter and characteristics of disinfection by-product precursors in a pilot-scale constructed wetland[END_REF][START_REF] Roccaro | Relationships between trihalomethanes, haloacetic acids, and haloacetonitriles formed by the chlorination of raw, treated, and fractionated surface waters[END_REF][START_REF] Song | Isolation and fractionation of natural organic matter: evaluation of reverse osmosis performance and impact of fractionation parameters[END_REF][START_REF] Zhang | Variations of disinfection byproduct precursors through conventional drinking water treatment processes and a real-time monitoring method[END_REF]. So, although the column capacity factor k' value did not affect the comparison between two fractionation techniques, it stays important to be aware of this value at all times.

Finally, the hydrophilic fraction seems more sensitive to the formation of brominated trihalomethanes [START_REF] Agbaba | Effects of water matrix and ozonation on natural organic matter fractionation and corresponding disinfection by-products formation[END_REF][START_REF] Chiang | Effects of pre-ozonation on the removal of THM precursors by coagulation[END_REF][START_REF] Goss | Trihalomethane formation potential of DOC fractions isolated from two Canadian Prairie surface water sources[END_REF][START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF]Hua and Reckhow, 2007b;[START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Li | Characterization of dissolved organic matter from surface waters with low to high dissolved organic carbon and the related disinfection byproduct formation potential[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF][START_REF] Molnar | The effects of matrices and ozone dose on changes in the characteristics of natural organic matter[END_REF]Molnar et al., 2012b;[START_REF] Musikavong | Reduction of fractionated dissolved organic matter and their trihalomethane formation potential with enhanced coagulation[END_REF][START_REF] Musikavong | Formation of trihalomethanes of dissolved organic matter fractions in reservoir and canal waters[END_REF][START_REF] Niu | Characterization of the precursors of trihalomethanes and haloacetic acids in the Yuqiao Reservoir in China[END_REF]Panyapinyopol et al., 2005a;Panyapinyopol et al., 2005b;[START_REF] Tubić | Insight into changes during coagulation in NOM reactivity for trihalomethanes and haloacetic acids formation[END_REF][START_REF] Włodyka-Bergier | The influence of organic matter quality on the potential of volatile organic water chlorination products formation[END_REF][START_REF] Xu | Characteristics of organic material in Huangpu River and treatability with the O3-BAC process[END_REF]. In this regard, it is important to keep the same bromide-to-total organic carbon ratio in all fractions. XAD-resins are non-ionic resins thereby not retaining ions [START_REF] Aiken | Comparison of XAD Macroporous Resins for the Concentration of Fulvic Acid from Aqueous Solution[END_REF][START_REF] Daignault | A review of the use of XAD resins to concentrate organic compounds in water[END_REF]. Most of the bromide ions will therefore elute with the hydrophilic fraction. These bromide ions will compete with organic carbon in the reaction with chlorine (rate constant k (HOCl/Br -) = 1550•1/Ms) to produce bromine, which subsequently reacts with the total organic carbon to produce brominated disinfection by-products [START_REF] Criquet | Comprehensive Analytical Chemistry[END_REF]. Bromine reactions towards phenolic moieties, which are important constituents of natural organic matter, are up to three orders of magnitude greater than for chlorine. This higher reactivity explains the tendency of brominated disinfection by-product formation even for a low bromide concentration [START_REF] Criquet | Reaction of bromine and chlorine with phenolic compounds and natural organic matter extracts -Electrophilic aromatic substitution and oxidation[END_REF][START_REF] Heeb | Oxidative treatment of bromide-containing waters: Formation of bromine and its reactions with inorganic and organic compounds -A critical review[END_REF]. When the bromide-to-total organic carbon ratio is adjusted in all fractions, hydrophilic moieties are still more reactive towards bromine. This implies that bromination occurs with aliphatic precursors while chlorination is more related to aromatic precursors (Hua and Reckhow, 2007b;[START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF].

In summary, hydrophobic compounds produce the highest specific trihalomethane formation potential, regardless of SUVA 254 or chlorination time, while hydrophilic compounds cannot be ignored when the SUVA 254 of the raw water is low. Finally, base compounds are identified as one of the most important precursors for trihalomethane formation. Haloacetic acids, as the second regulated disinfection by-product family, have also been the focal point in research with resin fractionation and results from these studies will be discussed in the next section.

Haloacetic acids

Fig. 8 shows the results from the hydrophobic-hydrophilic fractionation. As for the trihalomethanes, the hydrophobic fraction has 60 % contribution to the total specific haloacetic acid formation potential, while this is 40 % for the hydrophilic fraction at shorter reaction times, low chlorine dose and high specific ultraviolet absorbance (SUVA 254 ) (Fig. 8a, section 6 for Methods) [START_REF] Jung | The relationship between disinfection by-products formation and characteristics of natural organic matter in raw water[END_REF][START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF]. SUVA 254 is defined as the absorbance of ultraviolet light at 254 nm divided by the organic matter concentration (Ho et al., 2013). Two water samples analyzed after 7 days and high chlorine concentrations also showed around 89% specific formation potential from the hydrophobic fraction compared to only 11% from the hydrophilic fraction [START_REF] Chang | Characteristics of organic precursors and their relationship with disinfection by-products[END_REF][START_REF] Chiang | NOM characteristics and treatabilities of ozonation processes[END_REF]. On the contrary, three water samples with low SUVA 254 showed that hydrophilic compounds have by far the highest reaction potential at short reaction times and low chlorine dose (Fig. 8b) (Hyung [START_REF] Kim | Characterization of natural organic matter in conventional water treatment processes for selection of treatment processes focused on DBPs control[END_REF]Kim et al., 2006a;[START_REF] Kim | Characterization of natural organic matter in conventional water treatment processes for selection of treatment processes focused on DBPs control[END_REF].

Furthermore, in the hydrophobic-transphilic-hydrophilic fractionation, the hydrophobic and hydrophilic fraction are significantly different from the transphilic fraction, but not significantly different with each other at low SUVA 254 , especially after 7 days of chlorination time with high chlorine dose (Fig. 9). Where the hydrophilic fraction has almost 30% higher specific haloacetic acid formation potential compared to the hydrophobic fraction when organic matter is split into hydrophobic-hydrophilic only (Fig. 8b), hydrophobic and hydrophilic compounds contribute both to 30-40% of the total specific haloacetic acid formation potential when the fractionation is done into hydrophobic-transphilic-hydrophilic (Fig. 9b,d) [START_REF] Fang | Characterization of Dissolved Organic Matter and Its Derived Disinfection Byproduct Formation along the Yangtze River[END_REF][START_REF] Li | Characterization of dissolved organic matter from surface waters with low to high dissolved organic carbon and the related disinfection byproduct formation potential[END_REF][START_REF] Niu | Characterization of the precursors of trihalomethanes and haloacetic acids in the Yuqiao Reservoir in China[END_REF]. This might be explained by the different column capacity factors k' used between the 2 fractionation techniques (k'=100 vs. k'=50). Limited data after 72h chlorination time with high chlorine dose shows that the contribution of the hydrophilic fraction becomes higher when this k'-factor changes from 50 to 100 which is in agreement with the higher reaction potential seen for hydrophilic compounds in the hydrophobic-hydrophilic fractionation (Fig. S3) [START_REF] Liu | NOM reactivity with chlorine in low SUVA water[END_REF][START_REF] Pi | Size and resin fractionations of dissolved organic matter and characteristics of disinfection by-product precursors in a pilot-scale constructed wetland[END_REF][START_REF] Roccaro | Relationships between trihalomethanes, haloacetic acids, and haloacetonitriles formed by the chlorination of raw, treated, and fractionated surface waters[END_REF][START_REF] Zhang | Variations of disinfection byproduct precursors through conventional drinking water treatment processes and a real-time monitoring method[END_REF].

Waters fractionated into hydrophobic-transphilic-hydrophilic moieties with high SUVA 254 shows that the hydrophobic fraction has a higher formation potential to some degree when comparing the medians, although not significant (Fig. 9a,c). The transphilic fraction is in general the least important fraction to specific haloacetic acid formation potential [START_REF] Chowdhury | Characteristics of Natural Organic Matter and Formation of Chlorinated Disinfection By-Products from Two Source Waters that Respond Differently to Ozonation[END_REF][START_REF] Fang | Characterization of Dissolved Organic Matter and Its Derived Disinfection Byproduct Formation along the Yangtze River[END_REF][START_REF] Hanigan | MIEX® and PAC for removal of hydrophilic DBP precursors[END_REF][START_REF] Karapinar | Seasonal variations of NOM composition and their reactivity in a low humic water[END_REF][START_REF] Li | Characterization of dissolved organic matter from surface waters with low to high dissolved organic carbon and the related disinfection byproduct formation potential[END_REF]Molnar et al., 2012a;[START_REF] Qadafi | Haloacetic Acids Formation Potential of Tropical Peat Water DOM Fractions and Its Correlation with Spectral Parameters[END_REF][START_REF] Roccaro | Relationships between trihalomethanes, haloacetic acids, and haloacetonitriles formed by the chlorination of raw, treated, and fractionated surface waters[END_REF][START_REF] Tubić | Insight into changes during coagulation in NOM reactivity for trihalomethanes and haloacetic acids formation[END_REF][START_REF] Wang | Removal of DBP precursors in micro-polluted source waters: A comparative study on the enhanced coagulation behavior[END_REF][START_REF] Zhao | Disinfection By-Product Precursors Removal by Enhanced Coagulation and Their Distribution in Chemical Fractions[END_REF]. Data for the fractionation of the hydrophobic and hydrophilic fraction into their acids, bases and neutrals is limited to 72 h and 7 days of chlorination, high chlorine dose and 7 water samples (Fig. S4). The bases seem to have a slightly higher influence in specific haloacetic acid formation potential compared to the other fractions which is in agreement with the preference of the electrophilic hypochlorous acid to react with bases (Bond et al., 2012a;[START_REF] Chen | Disinfection by-products and their precursors in a water treatment plant in North China: Seasonal changes and fraction analysis[END_REF][START_REF] Fan | Characterization, DBPs formation, and mutagenicity of different organic matter fractions in two source waters[END_REF]Kanokkantapong et al., 2006a;Kanokkantapong et al., 2006b;Kanokkantapong et al., 2006c;[START_REF] Lamsal | Characterization and removal of natural organic matter by an integrated membrane system[END_REF][START_REF] Marhaba | The variation of mass and disinfection by-product formation potential of dissolved organic matter fractions along a conventional surface water treatment plant[END_REF]. Some research evaluated the formation of di-halogenated and tri-halogenated acetic acids separately (Fig. S5). The formation potential of the hydrophobic fraction for tri-halogenated acetic acids is significantly (~20 %) higher compared to the hydrophilic and transphilic fraction independent from the column capacity value (Fig. S5c,d). On the other hand, di-halogenated acetic acid formation potential is 20% higher in the hydrophobic fraction at high SUVA 254 and column capacity factor k' of 100, while the hydrophilic fraction has the highest reaction potential at high and low SUVA 254 and k'factor of 50 (Fig. S5a,b). It has been stated that dichloroacetic acid and trichloroacetic acid follow a different reaction pathway and that trichloroacetic acid and trihalomethanes are generated by common intermediates. This has been concluded by surrogate analysis, where trichloroacetic acid precursors tend to be more hydrophobic and dichloroacetic acid precursors have more aliphatic structures (Bond et al., 2012a). These statements could not be completely confirmed with the collected data. However, it should be noted that these data were drawn from three different papers only and more research should be done to clarify these assumptions (Hua and Reckhow, 2007b;[START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF]. Furthermore, some data on bromide incorporation show a higher reactivity of hydrophilic fractions to produce brominated haloacetic acids (Hua and Reckhow, 2007b;[START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF][START_REF] Li | Characterization of dissolved organic matter from surface waters with low to high dissolved organic carbon and the related disinfection byproduct formation potential[END_REF][START_REF] Liang | Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water[END_REF]Molnar et al., 2012a;[START_REF] Niu | Characterization of the precursors of trihalomethanes and haloacetic acids in the Yuqiao Reservoir in China[END_REF][START_REF] Qadafi | Haloacetic Acids Formation Potential of Tropical Peat Water DOM Fractions and Its Correlation with Spectral Parameters[END_REF][START_REF] Tubić | Insight into changes during coagulation in NOM reactivity for trihalomethanes and haloacetic acids formation[END_REF][START_REF] Włodyka-Bergier | The influence of organic matter quality on the potential of volatile organic water chlorination products formation[END_REF].

To summarize, the precursors of haloacetic acids are found to be very similar to the precursors of trihalomethanes. They have hydrophobic character when SUVA 254 is high, although less pronounced than for the trihalomethanes, but have both hydrophobic and hydrophilic origin with SUVA 254 is low.

While chlorination time does not affect the outcome, there is an indication that the column capacity factor does change the formation potential behavior in the different fractions. Besides the studies on regulated disinfection by-products, more attention arose in the last years to assess the precursors of emerging disinfection by-products and the results of these studies will be presented in the final section.

Emerging disinfection by-products

Emerging or unregulated disinfection by-products, such as haloacetamides, haloacetonitriles, nitrosamines or haloketones, have received increased attention due to their higher toxicity compared to regulated disinfection by-products [START_REF] Wagner | CHO cell cytotoxicity and genotoxicity analyses of disinfection by-products: An updated review[END_REF]. However, studies on the formation of these by-products in different membrane or resin fractions with chlorine are nowadays still limited. Most research focused on the formation of emerging disinfection by-products after chloramination. Chloramine can significantly reduce the formation of trihalomethanes and trihalogenated acetic acids, but will greatly increase the formation of emerging nitrogenous disinfection by-products such as N-nitrosodimethylamine [START_REF] Chu | Precursors of Dichloroacetamide, an Emerging Nitrogenous DBP Formed during Chlorination or Chloramination[END_REF]Hua and Reckhow, 2007a;[START_REF] Lin | A comparison of carbonaceous, nitrogenous and iodinated disinfection by-products formation potential in different dissolved organic fractions and their reduction in drinking water treatment processes[END_REF][START_REF] Wang | Removal of DBP precursors in micro-polluted source waters: A comparative study on the enhanced coagulation behavior[END_REF].

A small number of studies focused on the formation of emerging disinfection by-products in resin fractions disinfected with chlorine, i.e. haloacetamides, haloacetonitriles, halonitromethanes, haloaldehydes and haloketones. Insufficient data was collected for the last family to discuss a trend.

Studies on emerging disinfection by-products are most often executed with high chlorine dose even at short reaction times, possibly because they are formed in very low concentrations during drinking water disinfection [START_REF] Richardson | Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: A review and roadmap for research[END_REF].

Despite chlorination time, dose or specific ultra violet absorbance (SUVA 254 ), hydrophilic compounds clearly have a higher tendency to form emerging disinfection by-products (section 6 for Methods) (Ho et al., 2013). SUVA 254 is calculated by dividing the ultraviolet absorbance at 254 nm by the organic matter concentration. Fig. 10 and Figure S6 show a specific formation potential that is 20-80 % higher for the hydrophilic fraction compared to the hydrophobic or transphilic fraction for most families included [START_REF] Fang | Characterization of Dissolved Organic Matter and Its Derived Disinfection Byproduct Formation along the Yangtze River[END_REF][START_REF] Ge | Characteristics and removal mechanism of the precursors of N-chloro-2,2-dichloroacetamide in a drinking water treatment process at Taihu Lake[END_REF][START_REF] Hu | Dissolved organic matter fractions and disinfection by-product formation potential from major raw waters in the waterreceiving areas of south-to-north water diversion project, China[END_REF][START_REF] Hu | Halonitromethane formation potentials in drinking waters[END_REF][START_REF] Hua | Correlation between SUVA and DBP formation during chlorination and chloramination of NOM fractions from different sources[END_REF][START_REF] Lin | A comparison of carbonaceous, nitrogenous and iodinated disinfection by-products formation potential in different dissolved organic fractions and their reduction in drinking water treatment processes[END_REF][START_REF] Molnar | The effects of matrices and ozone dose on changes in the characteristics of natural organic matter[END_REF]Molnar et al., 2012b;[START_REF] Roccaro | Relationships between trihalomethanes, haloacetic acids, and haloacetonitriles formed by the chlorination of raw, treated, and fractionated surface waters[END_REF][START_REF] Tan | The shadow of dichloroacetonitrile (DCAN), a typical nitrogenous disinfection by-product (N-DBP), in the waterworks and its backwash water reuse[END_REF]Zhang et al., 2020a;[START_REF] Zhang | Variations of disinfection byproduct precursors through conventional drinking water treatment processes and a real-time monitoring method[END_REF]. Halonitromethanes show no significant difference between the formation potentials of all 3 fractions, despite the aspect of the graph (Fig. 10c). This is supported by studies performing disinfection by-product formation tests on surrogates. Proteinaceous material together with amino acids have been identified as haloacetonitrile precursors, while haloacetamides can also be formed through the hydrolysis of haloacetonitriles. However, studies on hydrophilic surrogates showed very low yield for trichloronitromethane, except for glycine (Bond et al., 2012b).

The influence of the column capacity factor k' stays inconclusive, because either a k'-factor of 50 is used or the value is missing in the studied papers. There is a small indication that the value is less important in the analysis of emerging disinfection by-products, since hydrophilic compounds also had the highest contribution in a water sample with a k' of 100 for haloacetonitriles and 2 water samples with a k' of 15 for halonitromethane [START_REF] Hu | Halonitromethane formation potentials in drinking waters[END_REF][START_REF] Roccaro | Relationships between trihalomethanes, haloacetic acids, and haloacetonitriles formed by the chlorination of raw, treated, and fractionated surface waters[END_REF]. Furthermore, elaborate resin fractionation in acids, bases and neutrals is hardly executed for emerging disinfection byproducts. The results for haloacetonitrile, halo-aldehyde and trichloronitromethane are presented in Fig. S7, but no statistical differences or trends could be highlighted [START_REF] Chu | Precursors of Dichloroacetamide, an Emerging Nitrogenous DBP Formed during Chlorination or Chloramination[END_REF][START_REF] Fan | Characterization, DBPs formation, and mutagenicity of different organic matter fractions in two source waters[END_REF][START_REF] Włodyka-Bergier | The influence of organic matter quality on the potential of volatile organic water chlorination products formation[END_REF]. In synopsis, emerging disinfection by-products clearly have hydrophilic precursors regardless of SUVA 254 , chlorination time or dose. This meta-analysis determined the parameters affecting the identification of disinfection by-product precursors, because no assessments were done so far in the past. This review identified hydrophobic compounds as having high trihalomethane and haloacetic acid formation potential especially for high SUVA 254 and low k'-factor values. Hydrophilic moieties are overall the most important precursors for the formation of emerging disinfection by-products, but can also not be neglected as trihalomethane and haloacetic acid precursor when SUVA 254 of the raw water is low and high column capacity factors are used. Furthermore, this study could not identify the disinfection by-product precursors based on molecular weight, which might be explained by an unsharp separation of natural organic matter during membrane fractionation. A graphical summary of all results can be found in Fig. 11. Future research should focus on the development of an alternative membrane fractionation method to have sharply, defined and separated size-based fractions. This allows to clearly mark the effect of a certain physical property to disinfection by-product formation. Furthermore, it is important to report the k' value used in resin fractionation, because it can influence the disinfection by-product formation in the different fractions. In addition, fraction analysis for disinfection by-product formation with chlorine is currently limited to regulated disinfection by-product, with only minor research done in this field for emerging disinfection by-product. These groups of disinfection byproduct are formed in lower concentrations, but could exhibit a higher toxicity, and therefore, may cause greater public health problems. Therefore, further research should focus on the formation of a broader group of disinfection by-product in different membrane and resin fractions to increase knowledge on natural organic matter precursors and therefore provide safer drinking water now and in the future.

Methods

Data collection

The Scopus library was used to collect papers from the last 2 decades as a continuation of the review paper of [START_REF] Chow | Physical and chemical fractionation of dissolved organic matter and trihalomethane precursors: A review[END_REF] which was at that time only focused on trihalomethanes. The criteria for selecting a paper were water source (i.e. fresh water), disinfectant (i.e. chlorine) and the use of preparative fractionation. Natural waters were selected from all over the world, since it is believed that this natural organic matter pool is universal due to the natural processes of synthesis and degradation [START_REF] Zark | Universal molecular structures in natural dissolved organic matter[END_REF]. Since treatment processes can influence the organic matter composition, e.g. leakage of soluble microbial products from biological activated carbon, only raw water sources were included [START_REF] Hong | Leakage of soluble microbial products from biological activated carbon filtration in drinking water treatment plants and its influence on health risks[END_REF]. With all these criteria, 83 papers were selected, resulting in data collection from 396 water samples from all over the world with a high number of publications in the United States and Asia (Fig. S8).

Data processing

The data was uniformized to be able to compare all papers with each other. First, the specific disinfection by-product formation potential from each fraction was collected or calculated, if not readily available. This is a normalization parameter defined as the amount of a certain by-product compound or family formed per unit dissolved organic carbon (generally expressed as µg/mgC). In some cases, especially for membrane fractionation, the specific formation potential of different fractions were merged to one single value to obtain a better comparison, e.g. < 0.5 kDa and 0.5-1 kDa fraction were merged to < 1 kDa. This was done using the following formula [START_REF] Kitis | Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation[END_REF]:

With n the number of fractions to merge in one water sample, m i the mass of fraction i and sDBPFP the specific disinfection by-product formation potential. These values were converted into percentages for each fraction in the following way:

Fig. 1

 1 Fig. 1 (a) Dead-end ultrafiltration membrane fractionation of natural organic matter into five fractions (F1-5). Their molecular weight range is based on the molecular weight cut-off of the membrane (presented in the upper right corner of the rectangle) (b) Crossflow membrane fractionation by Yin et al. (2019) using consecutive nano-(NF) and ultrafiltration (UF) processes to split organic matter present in seawater into biopolymers (F.BP), humic substances & building blocks (F.HS&BB) and low molecular weight molecules (F.LMW). Demineralized (DI) water is added during the process to increase the purity of the fractions. Reprinted from [Water Research, 159, Wenqiang Yin, Xin Li, Stanislaus Raditya Suwarno, Emile R. Cornelissen, Tzyy Haur Chong, Fouling behavior of isolated dissolved organic fractions from seawater in reverse osmosis (RO) desalination process,385-396, copyright (2019)] with permission from Elsevier

Fig. 2

 2 Fig. 2 Visualization of the results from Assemi et al. (2004) where organic matter in water samples from (a) Hope valley and (b) Myponga reservoir was fractionated into 5 fractions by dead-end ultrafiltration membrane fractionation and subsequently analyzed by flow-field flow fractionation (Flow-FFF). Each fraction is plotted on the x-axis and their theoretical molecular weight (MW)-range is determined by the molecular weight cut-off of each membrane. This range is visualized by cross pattern bars plotted on the y -axis. Flow-field flow fractionation (Flow-FFF) was used to determine the real molecular weight-range of each fraction, which is shown by solid bars plotted on the y-axis. A magnification of (a) and (b) between 0 and 10 kDa is given on the right side of these graphs. It is clear that the real molecular weight range of a fraction can differ substantially from its theoretical range.

Fig. 3

 3 Fig. 3 Specific trihalomethane formation potential (%) in different membrane fractions after (a) 24h, high or not available (NA) specific ultraviolet absorbance at 254 nm (SUVA 254 ), low chlorine dose (5 water samples) (b) 48h, high and low SUVA 254 , low chlorine dose (6 water samples) (c) 72h, low SUVA 254 or not available, high chlorine dose (5 water samples) and (d) 7 days, SUVA 254 is high, low or not available, high chlorine dose (29 water samples). * = statistical difference, ° = outlier. The specific trihalomethane formation potential slightly increases towards smaller molecular weight fractions. SUVA 254 or chlorine dose seem not to have an influence on this trend.

Fig. 4

 4 Fig. 4 Specific haloacetic acid formation potential (%) in different membrane fractions after (a) 48h, dihalogenated acetic acids (di-HAA), high and low specific ultraviolet absorbance at 254 nm (SUVA 254 ), low chlorine dose (6 water samples) (b) 48h, tri-halogenated acetic acids (tri-HAA), high and low SUVA 254 , low chlorine dose (6 water samples) (c) 72h, low SUVA 254 or not available (NA), high chlorine dose (6 water samples) and (d) 7 days, SUVA 254 is high, low or not available, high chlorine dose (14 water samples). * = statistical difference, ° = outlier. Specific di-halogenated acetic acid formation is higher towards lower molecular weight fractions, while all fractions have the same formation potential for tri-halogenated acetic acids. No correlation was established when all haloacetic acids are included.

Fig. 5

 5 Fig. 5 Resin fractionation schemes to split natural organic matter (NOM) based on hydrophobicity. The numbers on the pumps represent the sequence of adsorption-desorption. HPO = hydrophobic, HPI = hydrophilic, TPI = transphilic. A = acid, B = base, N = neutral. Yellow = XAD-8, XAD-7HP or DAX-8 resin; black = XAD-4 resin; orange = Duolite A7, IRA 93 or WA10 resin; grey = AG-MP-50, Dowex MSC resin (a) HPO-HPI fractionation, (b) HPO-TPI-HPI fractionation. Acetonitrile can also be used as desorbent instead of sodiumhydroxide, (c) HPO(A+B+N)-HPI(A+B+N) fractionation. The water solution is acidified to pH =2 after the first run

Fig. 6

 6 Fig. 6 Specific trihalomethane formation potential (%) in the hydrophobic (HPO) and hydrophilic (HPI) fraction after (a) 24h-48h-72h, high and low specific ultraviolet absorbance at 254 nm (SUVA 254 ), the column capacity factor (k') is between 0-100, but in most cases 100, low chlorine dose (25 water samples) (b) 7 days, SUVA 254 and k' in general not available (NA), high chlorine dose (SUVA 254 is 3x high, 1x low and k' is 2x 50 and 1x 100) (16 water samples). * = statistical difference. Hydrophobic compounds clearly have a higher specific trihalomethane formation potential compared to hydrophilic compounds irrespective of SUVA 254 or k'.

Fig. 7

 7 Fig. 7 Specific trihalomethane formation potential (%) in the hydrophobic (HPO), transphilic (TPI) and hydrophilic (HPI) fraction after (a) 24h-48h, high specific ultraviolet absorbance at 254 nm (SUVA 254 ), the column capacity factor k' is 50 (1x 100) or not available (NA), low chlorine dose (13 water samples) (b) 24h-48h, low SUVA 254 , k' is 50 or not available, low chlorine dose (7 water samples) (c) 7 days, high SUVA 254 , k' is 50 or not available, high chlorine dose (39 water samples) and (d) 7 days, low SUVA 254 , k' is 50 or not available, high chlorine dose (11 water samples). * = statistical difference, ° = outlier. When the SUVA 254 of the raw water is greater than 2 L/(mg•m), the HPO fraction contributes the most to trihalomethane formation, especially at long chlorination time with high chlorine dose. When the SUVA 254 is below 2, the hydrophobic and hydrophilic fraction have equal trihalomethane formation potential. The contribution of the tra nsphilic fraction is very variable

Fig. 8

 8 Fig. 8 Specific haloacetic acid formation potential (%) in the hydrophobic (HPO) and hydrophilic (HPI) fraction after (a) 24h-72h, high specific ultraviolet absorbance at 254 nm (SUVA 254 ), column capacity factor k' is between 0-100, but in most cases 100, low chlorine dose (15 water samples) (b) 48h-72h, low SUVA 254 , k' is 100, low chlorine dose (3 water samples). * = statistical difference. The hydrophobic fraction has significantly higher specific haloacetic acid formation potential compared to the hydrophilic fraction when SUVA 254 is high, while the opposite is seen when SUVA 254 of the raw water is low

Fig. 9

 9 Fig. 9 Specific haloacetic acid formation potential (%) in the hydrophobic (HPO), transphilic (TPI) and hydrophilic (HPI) fraction after (a) 24h, high specific ultraviolet absorbance at 254 nm (SUVA 254 ), column capacity factor k' is 50 (1x 100) or not available (NA), low chlorine dose (5 water samples) (b) 24h, low SUVA 254 , k' is 50 or not available, low chlorine dose (5 water samples) (c) 7 days, high SUVA 254 , k' is 50 or not available, high chlorine dose (12 water samples) and (d) 7 days, low SUVA 254 , k' is not available, high chlorine dose (5 water samples). * = statistical difference, ° = outlier. Data from (c) suggest that hydrophobic moieties have slightly higher tendency to form haloacetic acids when the SUVA 254 of the raw water is high (>2 L/(mg•m)). Conversely, at low SUVA 254 values, both hydrophobic and hydrophilic moieties have equal and consistently higher specific haloacetic acid formation potential compared to the transphilic fraction.

Fig. 10

 10 Fig. 10 Specific disinfection by-product formation potential (%) in the hydrophobic (HPO), transphilic (TPI) and hydrophilic (HPI) fraction after 24h and both high and low specific ultraviolet absorbance at 254 nm (SUVA 254 ) values of (a) halo-aldehydes (HAL), column capacity factor k' is not available (NA), low chlorine dose (5 water samples) (b) haloacetonitriles (HAN), k' is not available (1x 100), low chlorine dose (6 water samples) and (c) halonitromethanes (HNM), k' is not available (2x 15), low chlorine dose (7 water samples). * = statistical difference. From the data, it is clear that all families are preferentially formed in the hydrophilic fraction, although this was not statistically significant for the halonitromethanes

Fig. 11

 11 Fig. 11 Overview scheme of the conclusions drawn in this meta-analysis. NOM = natural organic matter. There is an indication that ultrafiltration membrane fractionation cannot produce sharply separated fractions. Therefore, no correlation was found between disinfection by-product formation and molecular weight. During resin fractionation, chlorination time and dose do not affect the ratio of disinfection by -product formation between the different fractions, while the specific ultraviolet absorbance at 254 nm (SUVA 254 ) and the column capacity factor k' do have an effect on this ratio.

Funding This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement [No 847568].

With n the number of fractions collected from a certain water sample and sDBPFP the specific disinfection by-product formation potential.

With this conversion, the relative difference in the specific reaction potential of different fractions towards disinfection by-product formation can be visualized. Therefore, these data were plotted into boxplots to examine the overall relative difference between distinct fractions to a certain disinfection by-product formation deduced from all studied papers. The box itself is ranged within the 1 st and 3 rd quartile (25 th and 75 th percentile) with a horizontal line for the 2 nd quartile (median). This is also called the interquartile range. The whiskers represent the data that lie within 1.5 times the interquartile range above and below the box. Data exceeding this range were identified as outliers and are represented as dots. The outliers were not removed from the dataset before the statistical analysis.

A two-tailed t-test (2 datasets) or a one-way ANOVA (> 2 datasets) were executed when the assumptions for normality and equal variances were valid. The Shapiro-Wilk test was used to see if the data was normally distributed. The F-test (2 datasets) or the Bartlett-test (> 2 datasets) were used to check if all datasets had equal variances. Not-normally distributed data was first transformed in an attempt to make them normally distributed. If these transformations were not successful, nonparametric tests such as the Mann-Whitney U test (2 datasets) or the Kruskall-Wallis test (> 2 datasets) were executed. For all tests included, the null hypothesis was rejected when the p-value was smaller than 0.05. Professor Emile Cornelissen would like to acknowledge the FWO-SBO

Acknowledgments