Wat. Res. Vol. 34, No. 6, pp.

1881±1885, 2000
# 2000 Elsevier Science Ltd. All rights reserved
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PII: S0043-1354(99)00338-3 0043-1354/00/$ - see front matter

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OXIDATIVE TREATMENT OF PHARMACEUTICALS IN

WATER
C. ZWIENERM and F. H. FRIMMEL*M
Engler-Bunte-Institute, Department of Water Chemistry, University of Karlsruhe, Engler-Bunte-Ring 1,
D-76131 Karlsruhe, Germany

(First received 1 December 1998; accepted in revised form 1 July 1999)

AbstractÐEnvironmentally relevant pharmaceuticals were chosen according to human consumption

and occurrence in the aquatic environment like sewage plant e‚uents, rivers and groundwater to
investigate their behavior during oxidative water treatment. Derived from data compilation in literature
the lipid lowering agent clo®bric acid and the analgesic agents ibuprofen and diclofenac were selected.
Analyses of the acidic compounds were carried out after solid-phase extraction and online
derivatization in the GC injector by means of single ion monitoring (SIM) GC/MS. Oxidation
experiments with the aim to degrade the pharmaceuticals were carried out in bench scale using ozone
and ozone/hydrogen peroxide (advanced oxidation process). Under the speci®c reaction conditions only
diclofenac was degraded by ozone to about 3% of its initial concentration. The combined application
of ozone and hydrogen peroxide leading to OH-radical formation improved the degradation eciency
of all investigated compounds. The application of increased oxidant concentration resulted in a better
degradation of all compounds to more than 90% at a concentration of 3.7 mg lÿ1 ozone and 1.4 mg
lÿ1 hydrogen peroxide and to more than 98% at a concentration of 5.0 mg lÿ1 ozone and 1.8 mg lÿ1
hydrogen peroxide. At the applied conditions no reaction products could be detected by GC/MS
analyses after derivatization of acidic functional groups. # 2000 Elsevier Science Ltd. All rights
reserved

Key wordsÐpharmaceuticals, medical compounds, clo®bric acid, ibuprofen, diclofenac, ozone,

advanced oxidation, hydroxy radical, water treatment, degradation

INTRODUCTION vironment due to di€use sources. The fate of a

Due to the amount and kind of their application
pharmaceuticals belong to environmentally relevant
compounds. Being produced and applied with the
aim of causing a biological e€ect, their occurrence
in the environment is of ecotoxicological interest.
The possible pollution of the aquatic and the terres-
trial environment can be attributed to di€erent
sources like emission from production sites, direct
disposal of surplus drugs in households, excretion
after application for human and animal medical
care, therapeutic treatment of livestock on ®elds,
and ®nally e‚uents of ®sh farms (Halling-Sùrensen
et al., 1998). Therefore, we have to consider both
point sources like production e‚uents and waste
disposals as well as di€use sources like run-o€ from
®elds and anthropogenic e‚uents as possible routes
of the pharmaceutical compounds to the environ-
ment.
The article will focus on the anticipated exposure
routes of medical compounds into the aquatic en-
*Author to whom all correspondence should be addressed.
Tel.: +721-608-2581; fax: +721-699154; e-mail:
fritz.frimmel@ciw.uni-karlsruhe.de
1881
pharmaceutical can be followed beginning from the
consumption of the active drug by a patient. After
administration the pharmaceuticals and their
metabolites are excreted and reach the sewage sys-
tem. In addition, also surplus drugs in households
are disposed to the waste water. Balances of the
input and output of pharmaceuticals in sewage
treatment plants reveal that during sewage treat-
ment not all pharmaceuticals are removed quanti-
tatively (Ternes, 1998). Consequently they are
found in surface waters. This is of special import-
ance, since surface water is a possible source of
drinking water. In drinking water treatment the
pharmaceuticals can be removed by several techni-
cal processes like ¯occulation, ®ltration, adsorption,
or oxidation. In case of river water treatment,
bank®ltration is often used as the ®rst step. The
medical compounds which are not removed by the
processes applied reach the consumer. Investigations
show this for the city of Berlin (Heberer et al.,
1998). However it should be noticed, that there is
an exceptional situation for the groundwater expo-
sition, which can not be generalized for Germany.
Even though the resulting concentrations can be
1882 C. Zwiener and F. H. Frimmel
Table 1. Amounts of some selected pharmaceuticals applied in Germany (1993) and concentrations found in secondary e‚uents and sur-
face water (from Heberer and Stan 1998; Stumpf et al., 1996)
Agent Applied mass in t aÿ1 Concentration in sewage water in mg lÿ1
Acetylsalic. acid 23±116
Ibuprofen 48±96
Diclofenac 48±72
Beza®brate 38±57
Clo®bric acid 15±21
Feno®bric acid 11±15
expected to be low and the toxicity of the medical
compounds are investigated within the approval
procedure, there has been no reliable information
on the long-term e€ect on humans.
The actual situation of pharmaceuticals in the
aquatic environment can be revealed by means of
several compounds. The amounts of products like
acetylsalicylic acid, ibuprofen, and diclofenac are
usually prescribed up to 100 t in Germany
(Schwabe and Pfa€rath 1996). In the e‚uents of
sewage treatment plants these substances could be
found in the mg lÿ1 concentration range. In river
water these substances could be identi®ed in lower
concentrations (Table 1, Stumpf et al., 1996;
Heberer and Stan 1998; Ternes 1998). Data from 17
water samples collected from groundwater wells of
a drinking water catchment area are shown in
Table 2. The pharmaceuticals are found in the ng
lÿ1 range in groundwater which is in¯uenced by
in®ltrated river water or canal water loaded with
sewage e‚uents (Heberer et al., 1998). The occur-
rence of pharmaceuticals in groundwater reveals
that these substances are not totally removed on
their way through the underground or during bank-
®ltration. The main task of elimination remains for
the technical drinking water treatment steps.
In this work, the environmentally relevant phar-
maceuticals clo®bric acid (lipid lowering agent of
the applied drugs ethyl ester of clo®bric acid, eto®-
brate and ethofyllinclo®brate), ibuprofen, and diclo-
fenac (analgesic agents) were selected according to
the high amounts prescribed and the occurrence in
the e‚uents of sewage treatment plants and in river
water. The aim of the work was ®rst to investigate
the oxidation behavior of these substances under
conditions applied in drinking water treatment with
Table 2. Concentrations of pharmaceuticals found in groundwater
in¯uenced by bank ®ltration and waste water (from Heberer et al.,
1997)
Pharmaceutical Concentration range in mg lÿ1
Acetylsalic. acid Ð
Ibuprofen n.d.±0.2
Diclofenac n.d.±0.3
Phenazon < 0.01±1.25
Clo®bric acid 0.07±7.3
Feno®bric acid n.d.±0.045
n.d.=not detected.
Concentration in surface water in mg lÿ1
0.05±1.51 < 0.05
0.05±3.35 0.05± 0.28
0.005±1.59 0.005±0.49
0.25±4.56 0.005±0.38
0.46±1.56 0.005±0.30
0.05±1.19 0.005±0.17
ozone as well as in advanced oxidation processes
and second to judge the potential of oxidation steps
for the removal of the investigated pharmaceuticals.
EXPERIMENTAL SECTION
Chemicals and materials
All pharmaceuticals were purchased from Aldrich
(Deisenhofen, Germany). 2,4-dichlorobenzoic acid and tri-
methyl sulfonium hydroxide (0.25 molar solution in
methanol) were from Fluka (Buchs, Switzerland), hydro-
gen peroxide (30%), NaCl (p.A.), Na2S2O3 (p.A.) and
HCl (30%, p.A.) from Merck (Darmstadt, Germany),
methanol, and acetone (both HPLC reagent) from Baker
(Griesheim, Germany).
The solid phase extraction (SPE) cartridges with 200 mg
LiChrolut-EN adsorber were purchased from Merck
(Darmstadt, Germany).
Sample preparation
The aqueous sample (200 mL) from the oxidation exper-
iments (cf. oxidative treatment) was acidi®ed to a pH of 2
and passed through the preconditioned SPE cartridge
(200 mg) by means of a gentle vacuum with a ¯ow rate of
10 mL minÿ1. Conditioning was performed successively
with 8 mL methanol, 8 mL acetone, and ®nally 15 mL dis-
tilled water. After drying the cartridge for 1 h by ¯ushing
with nitrogen, the analytes were eluted with four portions
of 1 ml acetone. The solvent was evaporated by a gentle
stream of nitrogen and the residue immediately dissolved
in 200 ml acetone with 2,4-dichlorobenzoic acid (1 mg lÿ1)
as internal standard compound. Thus the analytes are con-
centrated to a factor of 1000. Prior to analysis each
sample was spiked with 20 ml of the derivatization solution
(TMSH in methanol). The recoveries for the pharmaceuti-
cals were in the range of 65% to 85% at a standard devi-
ation of 5% maximum (N = 3).
Analysis
Separation and identi®cation of the analytes were per-
formed according to published methods (Sacher et al.,
1998; Ternes et al., 1998) using a GCQ gas chromatograph
coupled to an iontrap mass spectrometer (Finnigan,
Bremen, Germany). An Optic2 temperature programmed
injector (Ai Cambridge, Cambridge, England) was
installed in the GC for online derivatization of the ana-
lytes. The GC/MS operation parameters are shown in
Table 3. The mass spectral fragment ions for the selective
quanti®cation and other abundant mass fragments for the
identi®cation of the pharmaceuticals are given in Table 4.
The iontrap mass spectrometer enables the acquisition of
chromatograms in the scan mode with almost the same
sensitivity than in the SIM (selected ion monitoring)
mode. Therefore, quanti®cation with the selected recon-
structed ion chromatograms and identi®cation on the
basis of full mass spectra can be done with one GC run.
The standard deviation of the whole procedure was 5%
 Oxidative treatment of pharmaceuticals in water 1883

Table 3. Operating conditions for GC/MS measurements

Column: DB5 ms 30 m  0.25 mm i.d., 0.25 mm ®lm (J&W, Folsom, CA)

Injector: Splitless/split injection (10 min), Temp.program: 608C (10 s), with 128C sÿ1 to 2608C (1200 s)
Oven 608C (1.5 min), with 208C minÿ1 to 1208C, with 58C minÿ1 to 1608C, with 128C minÿ1 to 2808C (5 min)
Carrier gas: Helium 5.0, linear ¯ow 30 cm sÿ1
MS: Electron impact ionization at 70 eV, Scan mode: 50±350 amu, 2 scans sÿ1, Transferline at 2758C, ion source at 1758C

maximum for spiked samples of surface water for N = 4
in the ng lÿ1 concentration range.
Oxidative treatment
The experimental setup for the oxidation experiments is
shown in Fig. 1. The system consists of a thermostatted,
stirred reactor vessel with continuous ozone feeding.
Ozone is generated by silent electrical discharge from air.
The ozone gas concentration is continuously measured by
UV detection during the experiment and recorded by a
PC, to obtain an exact calculation of the absorbed ozone
mass (Wolf 1997). Hydrogen peroxide was dosed to the
solution at the beginning of the experiment. The reaction
of the oxidants was stopped after de®ned reaction times
by supplying Na2S2O3 solution (20 mg lÿ1) in the sampling
vessel.
As water matrix distilled water and natural surface
water was used. The distilled water was further puri®ed
with a Milli-Q ultra-pure water system (Millipore,
Molsheim, France) and called distilled water throughout
the text.
The natural surface water was from the river Ruhr in
Germany, collected at the raw water inlet of the water
works of Essen on 02/13/97 (b(DOC)=3.7 mg lÿ1;
b(HCOÿ ÿ1 ÿ ÿ1
3 )=122 mg l ; b(NO3 )=23 mg l ; b(NH4 )=
+
tuted aminogroup as a possible center for the reac-
tion with ozone. For the reaction of atrazine with
ozone also the amino group was suggested as the
reaction center. Selective oxidation of atrazine with
ozone leads to desethylatrazine as main reaction
product, which means a dealkylation of the second-
ary amino group (Zwiener et al., 1995).
In general, the reaction of ozone with organic
chemicals can be classi®ed into direct reactions
of ozone with the target molecule and into
hydroxy radical mediated reactions. Direct reac-
tions of ozone are speci®c additions to unsatu-
rated hydrocarbons and electron transfer
reactions (e.g., reactions with phenolate ions).
The radical mediated reactions start with the
generation of OH-radicals initiated by the reac-
tion between hydroxide ions and ozone according
to a chain reaction proposed by Staehelin and
Hoigne (1982, 1985). However, at low or neutral
pH values these radical reactions are of minor

1.2 mg lÿ1; pH 7.5; el. conductivity L=0.5 mS cmÿ1). In

the river water only ibuprofen could be detected at a con-
centration of 0.06 mg lÿ1. Diclofenac, clo®bric acid, and
2,4-dichlorobenzoic acid were all below a concentration of
0.05 mg lÿ1. The occurring concentrations are therefore far
below 1% of the spiked concentration levels and were not
taken into consideration for the oxidation experiments.
Experiments were performed threefold to check repro-
ducibility of the whole procedure.
RESULTS AND DISCUSSION
The chemical structures of the selected pharma-
ceuticals are shown in Fig. 2. They belong to the
chemical classes of phenoxyalcanoic acids (clo®bric
acid), alkylphenylalcanoic acids (ibuprofen), and
phenylsubstituted aminophenylalcanoic acids (diclo-
fenac).
Distilled water and an ozone concentration of
1 mg lÿ1 were used for the ®rst ozone oxidation ex-
periments of the pharmaceuticals. The results show
that ozone reacts as a selective oxidant, since only
diclofenac was degraded readily (Table 5). The
chemical structure of diclofenac shows the substi-
importance regarding degradation reactions of
micropollutants. A possibility to increase the con-
centration of highly reactive OH-radicals in aqu-
eous solution is the combined application of
ozone and hydrogen peroxide. This method
belongs to the so-called advanced oxidation pro-
cesses (AOP), which are based on the common
feature of OH-radical production for oxidation
purposes (von Sonntag et al., 1993).
The application of O3/H2O2 for the pharmaceuti-
cals oxidation at an initial molar ratio of the oxi-
dants of 2:1 (O3/H2O2) is shown in Fig. 3. At an
ozone concentration of 1 mg lÿ1 in distilled water
clo®bric acid and ibuprofen could be degraded to
about half of their initial concentration. Diclofenac
was quantitatively degraded. The enhanced degra-
dation eciency of O3/H2O2 can be attributed to
the oxidation e€ect of the produced OH-radicals.
However, in case of the river water matrix the
degradation eciency for clo®bric acid and ibupro-
fen was signi®cantly decreased. This can be
explained with the presence of so-called radical sca-
vengers, which compete with the pharmaceuticals

Table 4. GC retention times, selected mass fragments for quanti®cation (mQ) and additional typical mass fragments for identi®cation (mI)
of the internal standard and the pharmaceuticals

Compound Retention time mQ (abundance) mI (abundance) m/z

in min m/z

2,4-Dichlorobenzoic acid 7.28 173 (100) 206 (30), 204 (42), 175 (70), 147 (13), 145 (18)
Clo®bric acid 8.42 128 (100) 230 (10), 228 (30), 171 (6), 169 (22), 130 (30)
Ibuprofen 9.20 161 (100) 220 (56), 177 (23), 121 (19), 119 (17), 117 (20), 105 (13), 91 (13)
Diclofenac 15.52 214 (80) 311 (40), 309 (81), 279 (20), 277 (31), 244 (41), 242 (100), 216 (39), 179 (25)
1884 C. Zwiener and F. H. Frimmel
Fig. 1. Experimental set-up of the oxidation reactor and
reaction parameters (1 applied electrical power; 2 in sol-
ution).
for the OH-radicals and by this decrease the degra-
dation kinetics of the pharmaceuticals. The OH-
scavenging capacity of a water is de®ned as the sum
over the products of the concentration of all solutes
which can react with OH-radicals, multiplied with
the rate constants for the reactions. Examples for
scavengers are bicarbonate and carbonate ions, as
well as the dissolved organic carbon (DOC). The
importance of a scavenging reaction can be esti-
mated by considering the concentration of the sca-
vengers and the corresponding rate constants in
comparison to the substance which has to be elimi-
nated. In the solutions investigated the pharmaceu-
ticals were present in a concentration of 10ÿ8 mol
lÿ1, whereas bicarbonate ions (2  10ÿ3 mol lÿ1)
and DOC (3  10ÿ3 g lÿ1) show a much higher con-
centration in the river water. For the pharmaceuti-
cals the rate constants of the reaction with OH-
radicals can be deduced from tabulated values of
molecules with similar structures or substructures
(e.g., phenylacetate, aniline, 2,4-dichlorophenoxya-
cetic acid; Buxton et al., 1988; Haag and Yao,
1992) to be close to di€usion controlled (109 ± 1010
l molÿ1sÿ1). The rate constant for the reaction
between OH-radicals and bicarbonate ions was
determined to be 8.5  106 l molÿ1sÿ1 (Buxton et
al., 1988). This reveals, that the product of the con-
centration and the rate constant of bicarbonate is
two to three orders of magnitude higher than that
of the pharmaceuticals. The in¯uence of natural or-
ganic substances, which are the main part of the
DOC, is less clear, since these substances can react
Fig. 2. Chemical structures of the selected pharmaceuti-
cals.
Fig. 3. Elimination of pharmaceutical (x) by the combined
reaction of ozone and hydrogen peroxide (O3/H2O2) in
distilled water and in river water (C0(x)=2 mg lÿ1, reaction
time=10 min; error bars: 1 s, N = 3).
as scavengers as well as radical chain promoters
(Xiong et al., 1992).
To increase the degradation kinetics of the phar-
maceuticals in river water the OH-radical concen-
tration has to be increased, which can be done by
increasing the applied oxidant concentrations. The
results of the degradation experiments with elevated
O3/H2O2 concentrations are shown in Fig. 4. At an
ozone concentration of 3.7 mg lÿ1 and a hydrogen
peroxide concentration of 1.4 mg lÿ1 (molar ratio
of 2:1) the concentration of clo®bric acid and ibu-
profen could be lowered below 10% of their initial
values in river water. It is interesting to note, that
satisfying degradation eciency was obtained when
the applied ozone concentration was equal to the
DOC value of the river water (3.7 mg lÿ1). It is
likely to assume that the ozone is consumed by the
DOC. As a rule of thumb, sucient ozone for reac-
tions with hydrogen peroxide was only available at
an initial ozone concentration similar to the DOC
value of the investigated river water.
At an oxidant concentration of 5 mg lÿ1 ozone
and of 1.8 mg lÿ1 hydrogen peroxide the pharma-
ceuticals were almost quantitatively degraded in
river water to 2.1% (clo®bric acid), 0.6% (ibupro-
fen) and 0.1% (diclofenac) of the initial concen-
tration. These results reveal the degradability of the
pharmaceuticals by OH-radical mediated reactions
of AOP. The oxidant concentration needed depends
on both the reaction kinetics of the pharmaceuticals
and the OH-scavenging capacity of the matrix of
the treated water.
No degradation products could be detected
during the oxidation experiments by GC/MS after
Table 5. Percentage of pharmaceutical (x) after reaction with
ozone in distilled water (C0(x)=2 mg lÿ1, b0(ozone)=1 mg lÿ1,
reaction time=10 min)
Compound C(x)/C0(x) in % Relative standard deviation
(N = 3) in %
Clo®bric acid 92 5
Ibuprofen 88 8
Diclofenac 3.2 0.4
 Oxidative treatment of pharmaceuticals in water
Fig. 4. Elimination of pharmaceutical (x) by AOP (O3/
H2O2) in river water (C0(x)=2 mg lÿ1, reaction
time=10 min; error bars: 1 s, N = 3).
derivatization of the samples with TMSH applying
the above mentioned analysis procedure. Further
investigations should focus on the degradation
pathway of the pharmaceuticals and the character
of the metabolites produced.
CONCLUSIONS
From the investigated three environmentally rel-
evant substances only diclofenac was suciently
degraded by using the selective oxidant ozone alone
at a concentration generally applied in drinking
water treatment. The application of AOP (e.g., O3/
H2O2) improved the degradation eciency of all
investigated pharmaceuticals signi®cantly. However,
the degradation eciency of an AOP is limited by
the radical scavenging capacity of the matrix of the
treated water. This limitation can be overcome by
increasing the oxidant concentration. The most suit-
able way to rule out the OH-scavenging capacity is
the performance of oxidation experiments with
di€erent oxidant concentrations and deduce the aim
determining conditions for the treatment. It has
also to be taken into account that the ozone con-
sumption by organic matter (DOC) is of fundamen-
tal importance. For instance, for a sucient
degradation of the pharmaceuticals (>90%) the
ozone concentration has to be equal to the DOC
value. In drinking water treatment higher oxidant
concentrations and the combination application of
ozone and hydrogen peroxide are recommended for
a close to quantitative degradation of pharmaceuti-
cals. A sound assessment of the eciency of the
process and of its physiological relevance need
further information on the main degradation pro-
ducts and on the pathway of their formation.
AcknowledgementsÐThe authors would like to thank A.
Wolf for the sophisticated realization of the ozonation ex-
periments and O. Frank for his competent analytical
work.
1885
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