1
ABSTRACT 1
The ci y o Vi o ia-Gas eiz was one o he p obable i s en ances o he SARS-CoV2 in Spain, 2
one o he wo s a ec ed coun ies in he wo ld du ing he i s COVID 19 wa e. D i en by he 3
u gency o he si ua ion, mul iple d ugs wi h an i i al ac i i y we e used o label. Sadly, mos 4
o hese ea men s we e o li le o no bene i and hus, he numbe o pa ien s su e ing om 5
COVID-19 a ended in in ensi e ca e uni s (ICUs) mul iplied. A e being adminis e ed o 6
pa ien s, a a iable p opo ion o hese d ugs each he en i onmen whe e hey may ha e 7
de imen al e ec s, al hough his aspec is usually igno ed by heal hca e p o essionals. In his 8
s udy we measu ed he pa e ns o hospi al d ug use in he ci y o Vi o ia-Gas eiz (Spain) du ing 9
he i s COVID-19 wa e pandemic, ocusing on hose wi h an i i al ac i i y and hose used in 10
he ICUs. Subsequen ly, we measu ed concen a ions o selec ed d ugs in he ci y´s was ewa e 11
ea men plan in luen and e luen and es ima ed he po en ial isk o he en i onmen . The 12
hospi al use o ce ain an i i als and d ugs used o sedo-analgesia we e d ama ically inc eased 13
du ing he i s wa e (cisa acu ium was mul iplied by 25 and lopina i / i ona i by 20). A mean 14
o 1.632 daily de ined doses o hyd oxychlo oquine we e used du ing he pe iod o Feb ua y-15
May 2020. In his s udy we epo he i s posi i e de ec ion o hyd oxychlo oquine e e in he 16
en i onmen . We also show he second posi i e epo o lopina i . Low isk was es ima ed o 17
hyd oxychlo oquine, lopina i and i ona i (Risk quo ien s (RQ) <1), and medium isk o 18
azi h omycin (RQ 0 0.146). 19
20
KEYWORDS 21
COVID-19 pandemic; d ug pollu ion; One Heal h; pha macoepidemiology; LC-q-O bi ap; a ge 22
analysis 23
24
25
D ugs used du ing he COVID-19 i s wa e in Vi o ia-Gas eiz (Spain) and hei p esence in he en i onmen
S. Domingo-Echabu u, M. I azola, A. P ie o, B. Rocano, A. Lopez de To e-Que ejazu, A. Quin ana, G. O i e, U. Le xundi
This is he accep ed manusc ip o he a icle ha appea ed in inal o m in Science o The To al En i onmen 820 : (2022) // A icle ID 153122,
which has been published in inal o m a h ps://doi.o g/10.1016/j.sci o en .2022.153122. © 2022 Else ie unde CC BY-NC-ND license (h p://
c ea i ecommons.o g/licenses/by-nc-nd/4.0/)
2
1. INTRODUCTION
26
Spain was hi ha d by he COVID-19 i s wa e, being conside ed by many as
27
one o he wo s a ec ed coun ies in he wo ld (Ga cia-Bas ei o e al., 2021).
28
Phylo-geog aphic analysis ha e shown ha he ci y o Vi o ia-Gas eiz was one
29
o he p obable i s en ances o he SARS-CoV2 in he coun y (Gomez-
30
Ca balla e al, 2021). Wi h 216% in ensi e ca e uni (ICU) capaci y expanded
31
by Ma ch 18 h, 2020, ou ci y was one o he ha des hi among one o he
32
mos d ama ically a ec ed egions in he wo ld (Ba asa e al., 2020).
33
In hose imes o scien i ic unce ain y, and d i en by he u gency o he
34
si ua ion, many di e en d ugs wi h an i i al ac i i y we e despe a ely
35
adminis e ed o sa e pa ien s´ li es. Sadly, many o his o -label ea men s
36
showed li le o no bene i (Boulwa e e al., 2021, Skippe e al, 2020,
37
Cal acan i e al 2020, RECOVERY, 2020) and some o hem we e e en ha m ul
38
o pa ien s (E ekha e al., 2021). Mo eo e , as he numbe o pa ien s
39
su e ing om COVID-19 a ended in ICUs mul iplied, he amoun o sedo-
40
analgesics and neu omuscula blocking agen s also inc emen ed signi ican ly
41
(Co egido -Luna e al, 2020).
42
One aspec ha has been as ly igno ed by heal hca e p o ide s is he
43
en i onmen al impac o many o he d ugs used du ing he pandemic. A e
44
being adminis e ed o pa ien s, since a a iable p opo ion o hese d ugs
45
each he en i onmen whe e hey may ha e de imen al e ec s (Ta azona e
46
al., 2021, Fa ias e al., 2021, Elsaid e al., 2021). The eco oxici y o some
47
pha maceu icals used o COVID-19, e. g. azi h omycin and i e mec in is
48
easonably well add essed. Azi h omycin is pa icula ly oxic o
49
cyanobac e ia, and i e mec in shows a mode a e oxici y o ish and algae and
50
an ex emely high oxici y o in e eb a es (Janus In o, 2021a).
51
3
In his s udy we aimed o measu e he pa e ns o hospi al d ug use in Vi o ia-
52
Gas eiz du ing he i s COVID-19 wa e pandemic, ocusing on hose wi h
53
an i i al ac i i y and hose used in he ICUs. Subsequen ly, we ied o measu e
54
hese d ugs concen a ions in he ci y´s was ewa e ea men plan in luen
55
and e luen , o assess hei po en ial eco oxicological e ec s.
56
57
2. METHODS
58
2.1 Hospi al d ug consump ion du ing he COVID-19 i s wa e in Vi o ia-
59
Gas eiz
60
Vi o ia-Gas eiz is he capi al ci y o he Basque Coun y, an au onomous egion
61
loca ed in No he n Spain, whe e wo public acu e-ca e hospi als pe aining o
62
he A aba In eg a ed Heal hca e o ganiza ion (Txago i xu and San iago)
63
a end a popula ion o 248.087 (EUSTAT, 2021). D ug consump ion da a was
64
ob ained om SAP p og am (an en e p ise applica ion so wa e), which is
65
a ailable o Osakide za, he public heal h se ice p o ide since 1998. This
66
da abase con ains in o ma ion abou all d ug consump ion and cos o all
67
public heal hca e hospi als in he au onomous egion. D ug consump ion da a
68
was ob ained o he i s wa e pe iod (Feb ua y-May 2020), and compa ed
69
wi h he same pe iod o m he wo p e ious yea s, i.e.: 2018 and 2019.
70
S udied d ugs we e hose ha we e di ec ly used o ea COVID-19 because o
71
hei an i i al ac i i y, including hyd oxychlo oquine and lopina i / i ona i ,
72
o hei immunomodula o y p ope ies, like he an ibio ic azi h omycin,
73
ba ici inib, ocilizumab, me hylp ednisolone and dexame hasone. O he
74
included d ugs we e: lope amide, because o i s wide use o ea
75
lopina i / i ona i p o oked dia hea; neu omuscula blocking agen s used in
76
ICUs like cisa acu ium and ocu onium; sedo-analgesic d ugs like in a enous
77
4
midazolam, en anyl, emi en anil and p opo ol; an ibio ics like le o loxacin
78
and ce iaxone; b onchodila o s like ip a opium and salbu amol; and low-
79
molecula -weigh hepa in enoxapa in.
80
A e ob aining aw consump ion da a, he numbe o daily de ined doses
81
(DDD) o indi idual d ugs we e calcula ed (WHO ATC, 2021). In he case o
82
cisa acu ium, no DDD is a ailable, so consump ion was a bi a ily no malized
83
conside ing 20 mg.
84
85
2.2 Was e-wa e ea men plan in luen and e luen concen a ions
86
One li e 24h composi e samples (200 mL e e y hou ) o bo h in luen and
87
e luen was e-wa e om he municipal WWTP o he ci y o Vi o ia-Gas eiz
88
(C ispijana) we e collec ed om Ap il 28 h o July 13 h in polyp opylene bo les.
89
Da a on chemical oxygen demand, biological oxygen demand, o al ni ogen,
90
o al phospho us and daily low in he in luen o he WWTP and he da e o
91
each sample a e a ailable as supplemen a y ma e ial (Table S1).
92
A o al o 16 samples we e subsequen ly anspo ed o he labo a o y a he
93
Uni e si y o he Basque Coun y (UPV/EHU) and s o ed a -20°C un il hei
94
p ocessing. Wa e was il e ed (cellulose il e s 0.7 μm, 90 mm, Wha man) and
95
spiked wi h a deu e a ed s anda d mix and p ocessed acco ding o a me hod
96
p e iously alida ed (Gonzalez-Gaya e al., 2021). B ie ly, h ee eplica es o
97
250 mL (e luen ) and 100 mL (in luen ) we e ex ac ed using in-house made
98
SPE ca idges con aining 100 mg o ca ionic exchange (ZT-WCX), 100 mg o
99
anionic exchange (ZT-WAX) and 300 mg e e se phase (HRX) so ben s om
100
bo om o op. Condi ioning was done wi h 10 mL o MeOH: e hyl ace a e (1:1,
101
/ ) and 10 mL Milli-Q wa e , and a e sample loading, he ca idges we e
102
elu ed wi h 12 mL o MeOH: e hyl ace a e (1:1, / ) con aining 2% ammonia
103
5
and 12 mL o MeOH: e hyl ace a e (1:1, / ) 1.7 % o mic acid. Bo h ex ac s
104
we e combined, e apo a ed on a Tu bo ap (Zyma k, Hopkin on, USA) a 40 °C
105
unde a gen le N2 low and econs i u ed on 250 µL MeOH: Milli-Q wa e (1:1,
106
/ ). Final ex ac s we e il e ed wi h sy inge il e s (PP, 0.22 μm, 13 mm, Jasco
107
Analí ica, Mad id, Spain) on o ambe ch oma og aphy ials and analyzed in a
108
The mo Scien i ic Dionex Ul iMa e 3000 UHPLC coupled o a The mo Scien i ic
109
Q Exac i e Focus quad upole-O bi ap mass spec ome e (UHPLC-q-O bi ap)
110
equipped wi h a hea ed ESI sou ce (HESI, The mo-Fishe Scien i ic, CA, USA) a
111
he condi ions p e iously epo ed (González-Gaya e al., 2021).
112
In he alida ion o he analy ical p ocedu e used in his wo k sa is ac o y
113
esul s we e ob ained and a e a ailable as supplemen a y ma e ial (Table S3).
114
Eigh calib a ion le els wi hin 0.1 ng/g and 50 ng/g we e injec ed in iplica e
115
o he de e mina ion o ins umen al LODs and LOQs. Ins umen al LODs we e
116
es ima ed as he lowes concen a ion de ec ed in he h ee injec ion
117
eplica es, and in he case o ins umen al LOQs, as he lowes concen a ion
118
de ec ed wi h a ela i e s anda d de ia ion (RSD) o less han 30% and a
119
closeness o he ue concen a ion alues o mo e han 70%. The p ocedu al
120
LODs and LOQs we e s ablished as he heo e ical concen a ion measu able
121
and quan i iable in a wa e sample (a mix u e o di e en was ewa e samples)
122
aking in o accoun he ins umen al LODs and LOQs, he absolu e eco e ies
123
and he p econcen a ion ac o o he a ge compounds.
124
The ela i e eco e y was calcula ed as he pe cen age a io o he compound
125
concen a ion es ima ed om he in e nal calib a ion o he heo e ical
126
concen a ion, using six Milli-Q wa e samples spiked wi h all compounds o
127
in e es .
128
6
The RSD alues o he h ee eplica es analysed anged be ween 1 and 30%,
129
wi hin he s anda ds de ined by he Eu opean Commission, which indica es an
130
RSD alue ≤ 30% as accep able (EUR-LEX, 2002).
131
132
2.3 Repo ed en i onmen al concen a ions o selec ed d ugs in he
133
li e a u e and eco oxici y da a
134
To ind ou epo ed en i onmen al concen a ions o he d ugs used o ea
135
COVID-19 inpa ien s in he li e a u e, we used The Pha maceu ical Da abase
136
published by he Ge man En i onmen Agency – Umwel bundesam (UBA,
137
2019).
138
Eco oxici y da a (P edic ed no-e ec concen a ion: PNEC) was looked o each
139
indi idual pha maceu ical. When no da a was a ailable, Ecological S uc u e
140
Ac i i y Rela ionship ool (ECOSAR 2.0) om he Uni ed S a es En i onmen
141
P o ec ion Agency was used (ECOSAR, 2021) was used o es ima e PNECs. Then,
142
a ac o o 25 was used o co ec he impac o dilu ion o he e luen in
143
su ace wa e (Kelle e al., 2015).
144
3. RESULTS
145
3.1 Hospi al d ug consump ion du ing he COVID-19 i s wa e in
146
Vi o ia-Gas eiz
147
Figu e 1 illus a es he d ugs which consump ion was mo e d as ically
148
inc emen ed. In e es ingly, he a e age use o cisa acu ium was mul iplied by
149
25 and lopina i / i ona i by 20. Al hough he hospi al use o
150
hyd oxychlo oquine was no egis e ed be o e he i s wa e, a mean o 1.632
151
DDD use du ing he pe iod o Feb ua y-May 2020 was eco ded. A comple e lis
152
o he de ailed consump ion o he selec ed d ugs du ing he i s wa e
153
7
pandemic compa ed o he same pe iod du ing he wo p e ious yea s can be
154
consul ed as supplemen a y ma e ial (Table S2).
155
-inse igu e 1-
156
157
Was e-wa e ea men plan in luen and e luen concen a ions
158
Concen a ions o selec ed d ugs de ec ed in he WWTP in luen and e luen
159
a e a ailable in Figu e 2.
160
-Inse igu e 2-
161
3.2 Concen a ions and eco oxici y
162
Table 1 shows a summa y o he a ailable in o ma ion in he li e a u e abou
163
he p esence in di e en en i onmen al ma ices o some o he mos ele an
164
d ugs used du ing he i s COVID-19 wa e, and eco oxici y da a (PNECs and
165
RQ).
166
-Inse able 1-
167
4. DISCUSSION
168
Vi o ia-Gas eiz was one o he mos a ec ed ci ies ea ly in he i s COVID-19
169
wa e pandemic. On Ma ch 18, 2020, a 216 % expansion in ICUs capaci y was
170
equi ed o a end c i ically ill pa ien s.
171
In his s udy we ha e shown ha he use o cisa acu ium was mul iplied by
172
25, and lopina i / i ona i by 20, compa ed wi h p e-pandemic pe iod. The
173
highes lopina i / i ona i / use was egis e ed on Ma ch, wi h 7.503 DDDs.
174
Tha would equal o 250 pa ien s aking a daily lopina i / i ona i dose du ing
175
ha mon h (app oxima ely 1/1.000 pe sons om Vi o ia-Gas eiz was
176
hospi alized and aking his an i i al d ug on Ma ch 2020).
177
8
Fo mos o hese d ugs, he e is sca ce in o ma ion abou hei po en ial
178
dele e ious e ec s in he en i onmen . Ta azona e al p edic ed he po en ial
179
eco oxicological consequences o some ele an d ugs used du ing his
180
pandemic (Ta azona e al, 2021). Quan i a i e s uc u e-ac i i y ela ionship
181
(QSAR) es ima ions p edic ed ha hyd oxychlo oquine (a me aboli e o he
182
an imala ial chlo oquine) is sligh ly less oxic han chlo oquine o aqua ic
183
o ganisms. So he au ho s ex apola ed he chlo oquine a PNEC alue (120
184
µg/L) o hyd oxychlo oquine. An assessmen ac o (AF) o 100 was used o
185
de i e his alue om algal oxici y da a. O he au ho s epo ha he mos
186
sensi i e o ganism o his an imala ial d ug is he c us acean (Daphnia magna),
187
wi h a no obse ed e ec concen a ion (NOEC 21 days, ep oduc ion) o 85.8
188
µg /L (Janus In o, 2021a). The same au ho s epo ha his d ug is s po en ially
189
pe sis en (0% deg ada ion in 28 days). We ound a maximum concen a ion o
190
0.071 µg/L, which is below he 2 µg/L Eu opean Medicines Agency (EMA)
191
de aul es ima ion (1% popula ion ea ed). As a as we a e conce ned, in his
192
s udy we p o ide he i s de ec ion o his d ug in a WWTP e luen . Expec ed
193
en i onmen al isk appea s o be low, wi h a RQ <1 (Table 1).
194
The e is much mo e in o ma ion o he mac olid an ibio ic azi h omycin,
195
which is included in he Eu opean moni o ing p og am unde he Wa e
196
F amewo k Di ec i e (Gomez-Co es, 2021). The Ge man En i onmen al
197
Agency´s Pha maceu ical Da abase con ains mo e han one hund ed epo s o
198
posi i e de ec ions o his d ug, which has shown o be pa icula ly oxic o
199
cyanobac e ia (Mic ocys is ae uginosa) wi h a PNEC o 0.02 μg/L (OECD g ow
200
inhibi ion es , NOEC wi h an AF o 10) (Tell e al., 2021). This alue is below
201
he highe measu ed concen a ion in ou s udy, which was 0.073 µg/L
202
indica ing a po en ial isk o he en i onmen (Risk quo ien RQ= 0.146).
203
9
Rega ding he an i i al lopina i , we ound a concen a ion o 0.033 µg/L. The
204
Swedish en i onmen al classi ica ion o pha maceu icals s a es ha “lopina i
205
has high po en ial o bioaccumula ion” (log Dow = 4.7, which is >4) (Janus
206
In o, 2021b). So a , he e is jus one addi ional epo o i s p esence in he
207
en i onmen in he Ge man da abase om Sou h A ica. The s udy o Ta azona
208
e al (Ta azona e al., 2021) clea ly e lec s he sca ce a ailable
209
eco oxicological in o ma ion on hese medicinal p oduc s (wi h he ema kable
210
excep ion o osel ami i ). They concluded ha “despi e he unce ain ies in he
211
ex apola ion o he eco oxici y da a, a ailable in o ma ion sugges s ha he
212
p edic ed concen a ions o he an i i al and pha macokine ic boos e s a e in
213
he ange o he gene ic PNEC alues o an i i als, and ha speci ic a en ion
214
is equi ed o suble hal e ec s on ish”. Howe e , we ound no expe imen al
215
da a ega ding lopina i eco oxici y. ECOSAR ool 2.0 p edic s a ch onic alue
216
(geome ical mean o he NOEC and LOEC) o 4.5 µg/L o Daphnids (ECOSAR,
217
2021). Thus, he RQ o his d ug is p edic ed o be low (RQ=2.9 x 10-3). In he
218
case o i ona i , he same ool p edic s a ch onic alue o 2.5 µg/L o ish
219
(RQ= 4.6 X 10-3).
220
We belie e ha he po en ial ecological impac o an i i als on i uses p esen
221
in he en i onmen has no been su icien ly add essed so a . Ve y ecen ly
222
Ku oda and co-wo ke s p edic ed he occu ence, eco oxicological isk and
223
acqui ed esis ance o an i i als associa ed wi h COVID-19 in en i onmen al
224
wa e s (Ku oda e al., 2021). They sugges ed ha he emo al e iciencies a
225
con en ional WWTPs will emain low o hal o he subs ances, and ha high
226
concen a ions migh be p esen in e luen s and hus pe sis in he
227
en i onmen . They also es ima ed a high eco oxicological isk in ecei ing i e
228
wa e s o lopina i and i ona i , and medium isk o hyd oxychlo oquine
229
16
UBA. Ge man En i onmen Agency, 2019. Umwel bundesam . Fü Mensch und Umwel .
388
A ailable a : h ps://www.umwel bundesam .de/en/da abase-pha maceu icals-in he-
389
en i onmen -0 [Accessed Ma ch 17, 2021].
390
WHO Collabo a ing Cen e o D ug S a is ics Me hodology. ATC/DDD Index. A ailable a :
391
h p://www.whocc.no/ a c_ddd_index/ [Accessed Ma ch 17, 2021].
392
Wood TP, Du enage CS, Rohwe E. The occu ence o an i- e o i al compounds used o
393
HIV ea men in Sou h A ican su ace wa e . En i on Pollu . 2015 Ap ;199:235-43. doi:
394
10.1016/j.en pol.2015.01.030.
395
Table S1. Physicochemical da a abou he in luen o he municipal WWTP o Vi o ia-Gas eiz (C ispijana) du ing he i s wa e
RAW WASTEWATER
Da e
Flow
To al ni ogen
Chemical oxigen demand
Biological oxigen demand
To al phospho us
(m3/day)
(mgN/l)
(mgO/l)
(mgO/l)
(mg/l)
Ap il 28, 2020
138.300
36,1
372
240
3,79
Ap il 29, 2020
109.900
38,3
362
210
4,01
May 4, 2020
108.900
45,6
475
280
4,75
May 7, 2020
89.400
51,9
514
310
5,03
May 11, 2020
191.600
27,2
330
150
3,45
May 14, 2020
144.600
31,1
260
140
3,09
May 18, 2020
104.160
47,5
410
250
4,51
May 21, 2020
95.808
44,5
462
270
5,15
May 25, 2020
83.328
50,9
522
300
5,34
June 1, 2020
75.744
60,2
666
380
6,13
June 8, 2020
81.120
48,7
457
290
5,02
June 15, 2020
77.760
55,7
523
300
5,43
June 22, 2020
76.224
55,6
614
330
5,80
June 29, 2020
68.928
58,0
645
380
6,05
July 6, 2020
66.912
57,7
738
390
6,93
July 13, 2020
73.440
50,6
628
320
5,19
Table S2. Hospi al d ug use in Vi o ia-Gas eiz.
PRE-PANDEMIC
FIRST WAVE
2018
2019
Mean
2020
Mean
Mul iplying
ac o
D ug
Use in COVID-19
ATC
DDD
Feb ua y
Ma ch
Ap il
May
Feb ua y
Ma ch
Ap il
May
Feb ua y
Ma ch
Ap il
May
Hyd oxiclho oquin (mg)
An i i al
P01BA02
516 mg
-
-
-
-
-
-
-
-
-
-
2.611.200
752.800
6.000
842.500
No p e-pandemic
egis e ed consump ion
Cisa acu ium (mg)
Neu omuscula blocke
M03AC11
No a ailable
310
960
900
970
250
1.260
1.950
1.200
1.110
990
55.340
46.380
7.700
27.603
24,9
Lopina i / i ona i
(mg)
An i i al
J05AR10
800 mg
271.200
95.400
223.20
0
154.000
223.232
114.80
0
192.00
0
96.200
105.100
67.200
6.002.600
2.223.200
3.200
2.074.050
19,7
Lope amide (mg)
An i-dia heal
A07DA03
10 mg
400
678
498
1.188
726
462
804
1.364
570
920
5.384
2.500
520
2.331
4,1
Ba ici inib (mg)
Inmunomodula o y
L04AA37
4 mg
336
336
672
896
1.976
2.112
2.688
2.016
1.224
4.022
6.448
3.512
1.260
3.811
3,1
Azy h omycin (mg)
Inmunomodula o y
J01FA10
300 mg
115.000
128.10
0
108.10
0
103.800
133.600
103.60
0
118.00
0
117.900
115.850
154.200
899.500
241.600
95.000
347.575
3,0
Midazolam (mg)
Sedoanalgesic
N05CD08
15 mg
20.488
20.805
22.635
23.193
21.275
23.910
23.388
22.478
22.358
17.446
102.070
80.645
20.870
55.258
2,5
Fen anil i (mg)
Sedoanalgesic
N01AH01
No a ailable
315
228
209
265
279
318
259
348
273
360
1.206
762
337
666
2,4
Ip a opium (mg)
B onchodila o
R03BB01
No a ailable
1.310
1.262
1.246
1.087
1.186
1.219
1.015
1.261
1.240
1649
3551,5
1463,5
725,5
1.847
1,5
Rocu onium (mg)
Neu omuscula blocke
M03AC09
No a ailable
19.550
11.750
17.150
22.350
18.200
20.300
14.200
23.050
16.025
19.800
23.850
35.250
17.350
24.063
1,5
Ce iaxone (g)
An ibio ic
J01DD04
2 g
2.534
2.640
2.371
2.136
2.385
2.504
2.532
2.997
2.572
2.829
6.316
3.145
2.410
3.675
1,4
Salbu amol (mg)
B onchodila o
R03CC02
No a ailable
11.513
9.645
8.415
7.718
10.610
9.468
7.180
9.825
9.556
8.928
26.943
9.813
5.508
12.798
1,3
Tocilizumab (mg)
Inmunomodula o y
L04AC07
20 mg
21.196
27.408
32.846
31.704
26.364
31.404
23.996
25.140
29.406
20.796
78.640
38.100
19.024
39.140
1,3
P opo ol (g)
Sedoanalgesic
N01AX10
No a ailable
983
1.058
917
1.116
1.149
1.177
947
1.162
1.118
1.495
1.854
1.373
821
1.386
1,2
Mo phine i (mg)
Sedoanalgesic
N02AA01
30 mg
75.830
71.250
97.010
104.740
33.990
54.400
83.270
81.795
62.825
64.300
80.080
76.650
49.960
67.748
1,1
Enoxapa in (g)
Th ombop ophylaxis
B01AB05
20 mg
502
573
527
500
533
543
560
553
558
509
507
703
542
565
1,0
Remi en anil (mg)
Sedoanalgesic
N01AH06
No a ailable
1.842
1.892
1.822
2.075
1.659
1.416
1.183
1.712
1.654
1.643
1.500
1.576
1.520
1.560
0,9
Le o loxacin (g)
An ibio ic
J01MA12
500 mg
1.153
951
776
709
767
772
741
697
861
537
1.105
557
270
617
0,7
Dexame hasone (mg)
Inmunomodula o y
H02AB02
1,5 mg
36.581
40.420
33.676
33.936
23.297
40.283
25.822
25.004
40.352
28.258
43.184
21.171
16.231
27.211
0,7
Me ilp ednisolone (g)
Inmunomodula o y
H02AB04
20 mg
173
195
153
187
178
191
205
189
193
128
143
120
124
129
0,7
Table S3. Su oga es, ela i e eco e ies (R %), ins umen al and p ocedu al limi s o de ec ion (LOD) and quan i ica ion (LOQ),
ionisa ion mode and coe icien o de e mina ion (R2) o each compound s udied. *CAL: Ex e nal calib a ion. These compounds
could no be co ec ed o due o he lack o sui able su oga es o co ec ion. Thei eco e y, ma ked wi h **, is absolu e, no
ela i e and has been applied o he sample esul s.
Compound
Su oga e
R %
Ins umen al
P ocedu al
Ionisa ion
R2
LOD
(ng/g)
LOQ
(ng/g)
LOD
(ng/L)
LOQ
(ng/L)
Azi h omycin
*CAL
67**
2.5
8.5
5.2
17.2
Posi i e
0.9975
Hid oxychlo oquine
*CAL
57**
1.4
4.6
2.8
9.4
Posi i e
0.9888
Lopina i
Azoxys obin-
(cianophenoxi-d4)
89
1.0
3.3
2.0
6.8
Posi i e
0.9948
Ri ona i
*CAL
62**
4.8
16.0
9.7
32.5
Posi i e
0.9859
Table S4. Concen a ion da a o each day (ng/L)
28
Ap
29
Ap
4
Ma
7
Ma
11
Ma
14
Ma
18
Ma
21
Ma
25
Ma
1
Jun
8
Jun
15
Jun
22
Jun
29
Jun
6
Jul
13
Jul
28
Ap
29
Ap
4
Ma
7
Ma
11
Ma
14
Ma
18
Ma
21
Ma
25
Ma
1
Jun
8
Jun
15
Jun
22
Jun
29
Jun
6
Jul
13
Jul
INFLUENT
EFLUENT
Azi h omycin
51
28
25
51
9
27
4
6
73
47
69
43
51
42
Hyd oxychlo o
-quine
32
32
57
71
32
Lopina i
2
11
14
9
7
4
27
33
32
27
29
12
1
12
13
1
12
1
8
7
12
27
5
Ri ona i
22
2
28
22
16
22
24
32
22
2
24
34
16
38
12
13
16
15
8
15
16
14
16
11
13
19
16
23
