Toxics 2022, 10, 54

toxics
Review
Transformation Products of Emerging Pollutants Explored
Using Non-Target Screening: Perspective in the Transformation
Pathway and Toxicity Mechanism—A Review
Thodhal-Yoganandham Suman 1,2 , Soo-Yeon Kim 3 , Dong-Hyuk Yeom 3 and Junho Jeon 1,2, *
1 Department of Environmental Engineering, Changwon National University,

Changwon 51140, Gyeongsangnam-do, Korea; [email protected]
2 School of Smart and Green Engineering, Changwon National University,
Changwon 51140, Gyeongsangnam-do, Korea
3 Gyeongnam Branch Institute, Korea Institute of Toxicology (KIT), Jinju-si 52834, Korea;
[email protected] (S.-Y.K.); [email protected] (D.-H.Y.)
* Correspondence: [email protected]
Abstract: The scientific community has increasingly focused on forming transformation products
(TPs) from environmental organic pollutants. However, there is still a lot of discussion over how
these TPs are generated and how harmful they are to living terrestrial or aquatic organisms. Potential
transformation pathways, TP toxicity, and their mechanisms require more investigation. Non-target
screening (NTS) via high-resolution mass spectrometry (HRMS) in model organisms to identify TPs
and the formation mechanism on various organisms is the focus of this review. Furthermore, uptake,
accumulation process, and potential toxicity with their detrimental consequences are summarized in
various organisms. Finally, challenges and future research initiatives, such as performing NTS in a

model organism, characterizing and quantifying TPs, and evaluating future toxicity studies on TPs,
Citation: Suman, T.-Y.; Kim, S.-Y.;
are also included in this review.
Yeom, D.-H.; Jeon, J. Transformation
Products of Emerging Pollutants
Keywords: environmental contamination; transformation products; non-target screening; transfor-
Explored Using Non-Target
mation pathways; toxicity
Screening: Perspective in the
Transformation Pathway and Toxicity
Mechanism—A Review. Toxics 2022,
10, 54. https://doi.org/10.3390/
toxics10020054 1. Introduction
Concerns about emerging pollutants (EPs) have increased in recent years due to their
Academic Editor: Ilaria Corsi
prevalence in the environment and the potential for deleterious effects on the environ-
Received: 28 December 2021 ment [1–4]. Effluent discharges from industrial wastewater treatment plants (WWTPs),
Accepted: 17 January 2022 municipal, hospital, sewer overflow/sewer leakage, and surface runoff from agricultural or
Published: 24 January 2022 urban areas can all introduce EPs to the aquatic environment [5–9]. A special focus has been
Publisher’s Note: MDPI stays neutral
paid to WWTPs due to the relatively frequent release and high contribution of EPs into the
with regard to jurisdictional claims in environment. Raw influent and treated effluent commonly include EPs at concentrations
published maps and institutional affil- ranging from ng/L to mg/L [10–14]. The socioeconomic composition of the population
iations. feeding into WWTPs impacts the concentrations and types of EPs in wastewaters. EPs
in the water environment have often been accumulated in aquatic organisms and lead to
alterations that endanger the sustainability of aquatic ecosystems [15,16].
According to the network of reference laboratories, research centers, and related or-
Copyright: © 2022 by the authors. ganizations for monitoring emerging environmental substances (NORMAN), chemicals
Licensee MDPI, Basel, Switzerland. that are not covered by systematic environmental monitoring programs can be candi-
This article is an open access article dates for legislative management in the future due to their deleterious consequences and
distributed under the terms and persistence. Water and wastewater treatment regulatory and implementation agencies
conditions of the Creative Commons
assume that so-called priority pollutants account for most human health, environmental,
Attribution (CC BY) license (https://
and economic risk, even though they represent only a small proportion of the known and
creativecommons.org/licenses/by/
yet-to-be-identified chemical substances [17]. Unlike POPs designated in the Stockholm
4.0/).
Toxics 2022, 10, 54. https://doi.org/10.3390/toxics10020054 https://www.mdpi.com/journal/toxics

Toxics 2022, 10, 54 2 of 22
Convention, EPs, including an extensive range of substances, are discussed due to the
scarcity of information on their occurrences and potential risks and thus the absence of
management plan. Recent studies identified many different kinds of new pollutants, in-
cluding perfluorinated compounds, artificial sweeteners, pharmaceuticals and disinfection
byproducts, hormones and UV filters, and benzotriazoles siloxanes, naphthenic acids, musk
fragrances, and TPs [18–20].
Identifying, detecting, and quantifying countless chemicals in the environment are
significant hurdles that scientists and policymakers across the globe are now facing. In
particular, tracking and recognizing TPs are challenging tasks, mainly due to the difficulty
in predicting transformation pathways and the lack of a reference standard for orthog-
onal confirmation via instrumental analysis. Chromatography coupled with the mass
spectrometer technique is the primary method for detecting TPs in the environment and
organisms [21–25]. Recent advances in technology have extended the identification and
quantification capability. For example, high-resolution mass spectrometry (HRMS) features
good mass accuracy, high mass resolving power (greater than 50,000), high picomolar to
femtomolar range sensitivity, and good isotopic abundance accuracy (3–20%) [26,27]. These
merits rely on several operational factors, including scan speed, the mass range for an
analyte, and ionization efficiency. For analysis of polar organic compounds, including
most TPs present in trace amounts, liquid chromatography (LC) connected to HRMS such
as time-of-flight (TOF) or Orbitrap type [28] has often been used. A new generation of
quadrupole preceding tandem HRMS (e.g., QTOF and QExactive Orbitrap) is capable of
highly selective and sensitive analysis for trace pollutants. In addition, the hybrid technique
and sophisticated software processing mass spectrum data enables non-target screening
(NTS, including suspect screening), which is applicable for the identification of less recog-
nized and/or unknown substances such as TPs [28]. HRMS-based NTS has significantly
contributed to a comprehensive understanding of TPs in environments.
Nevertheless, TPs’ occurrences and fate are likely insufficient to evaluate the toxicity
and environmental risk. TPs are, in many cases, more polar and less hazardous than their
parent compounds. Yet, the toxicity and persistence of TPs may vary widely depending
on the alteration of molecular structures [24]. Non-mammalian model species have been
developed over many years as an alternative to investigating harmful substances, since no
toxic compounds can be studied in humans, and a limited number of mammal models are
available [29]. Beneficial qualities such as a short lifespan and a lack of need for specialized
care led to the selection of these non-mammalian models. The adverse effects of TPs have
been studied using various models, including cell lines, earthworms, crustaceans, and fish.
To better comprehend the impact of TPs on the larger organism, the findings of studies
with model organisms are critical.
The primary goal of this study is to provide a summary of the current level of un-
derstanding for the fate of TPs and the ecotoxicological impacts on both terrestrial and
aquatic organisms. We highlight how the advancement of precise mass equipment and
computer/software tools has led to NTS, an essential component of an integrated approach
to TP identification. Finally, we examine some critical features of the advances achieved
in understanding the outcome and toxicity of TPs and the difficulties and possibilities of
identifying whether these TPs can cause environmental issues in the future.
2. Transformation Products
Over the previous century, the industry has generated new chemical products such
as agricultural pesticides, pharmaceuticals, plastics, and dyes; unfortunately, they contain
a broad spectrum of dangerous and/or persistent compounds extensively occurring in
environmental compartments. The synthesized organic compounds can be categorized
according to their molecular structure and functional groups (e.g., ethers, acids, alcohols,
esters, hydroxyl, alkyl halides, and in each group, amines) [30]. There are a variety of
abiotic and biotic processes (e.g., photolysis, hydrolysis, microbial/enzymatic metabolism,
and oxidation) that might result in the formation of TPs, including the breakdown of
Toxics 2022, 10, x FOR PEER REVIEW 3 of 22
Toxics 2022, 10, 54 3 of 22
abiotic and biotic processes (e.g., photolysis, hydrolysis, microbial/enzymatic metabolism,

and oxidation) that might result in the formation of TPs, including the breakdown of the
the parent
parent compounds
compounds (Figure
(Figure 1) [31–33].
1) [31–33]. In theIncase
theof
case of metabolites
metabolites (or biochemically
(or biochemically trans-
transformed
formed products,
products, BTPs),BTPs), the parent
the parent chemical
chemical accumulated
accumulated in biota
in biota is often
is often engaged
engaged to
to phase 2 reactions, leading to conjugated forms, which are easily excreted
phase 2 reactions, leading to conjugated forms, which are easily excreted due to the en- due to the
enhanced
hanced water
water solubility
solubility [34].Some
[34]. SomeTPsTPsare
arebiologically
biologicallyactive
activeand
andare
areof
ofconcern
concern in
in terms
terms
of ecotoxicity [35–37].
of ecotoxicity [35–37].
Figure
Figure 1.
1. AAdiagram
diagramdepicting thethe
depicting transformation processes
transformation that that
processes occuroccur
in organic compounds.
in organic Gen-
compounds.
eral transformation processes in organisms and their environments are represented on the left, while
General transformation processes in organisms and their environments are represented on the left,
the most frequent simulation approaches are shown on the right.
while the most frequent simulation approaches are shown on the right.
Unlike
Unlike other
other compounds,
compounds, emerging
emerging pollutants
pollutants have
have less
less data
data on
on TPs.
TPs. Specific
Specific com-
com-
pounds and their TPs have been identified in waste sources, such as septic systems [38,39],
pounds and their TPs have been identified in waste sources, such as septic systems [38,39],
wastewater treatment
wastewater treatmentplants
plants[34,40–42],
[34,40–42],animal
animalmanure
manure[43,44],
[43,44],and
andlands
lands [45].Gemfibrozil,
[45]. Gemfibro-
zil, ofloxacin,
ofloxacin, ibuprofen,
ibuprofen, irbesartan,
irbesartan, and and venlafaxine
venlafaxine werewere
foundfound in wastewater
in wastewater treatment
treatment facil-
facilities and surface water at concentrations of more than 100 mg/L [46].
ities and surface water at concentrations of more than 100 mg/L [46]. While looking for While looking
for
commoncommon fragments,
fragments, valsartan
valsartan and itsand itsTPs
three three
wereTPs were identified
identified in waters.in waters. O-
O-desmethyl-
venlafaxine and an oxidized form of gemfibrozil TPs were detected more oftenmore
desmethyl-venlafaxine and an oxidized form of gemfibrozil TPs were detected than often
their
parent compounds. Some TPs in wastewater treatment facilities were frequentlywere
than their parent compounds. Some TPs in wastewater treatment facilities fre-
detected
quently
compared detected compared
to the surface to the
waters. surface degradation
Ibuprofen waters. Ibuprofen degradation
products IbB4, IbSW2, products
and Ib1IbB4,
and
IbSW2,
the TPs and Ib1 and theGSWB1
of gemfibrozil, TPs of were
gemfibrozil, GSWB1
the examples were the
(Figure examples
S1, Table 1). (Figure S1, Table
1).
Toxics 2022, 10, 54 4 of 22
Table 1. Pharmaceuticals and metabolites/TPs detected in Effulent waste water and surface wa-
ter samples after retrospective search in Q-TOF- MS data. (Reprinted from [46]. (Copyright
2016, Elsevier)).
Positive Finding (%)

EWW SW
(n = 38) (n = 18)
Irbesartan 92 39
ISW1 87 6
IB3 84 22
IB3 89 22
IB4 32 11
IB5 79 22
Valsartan 79 33
Venlafaxine 87 22
VB1a 92 17
VB1b 92 17
V1 58 6
V2 87 11
Ofloxacin 82 17
Ibuprofen 11 6
IbSW2a 16 11
IbSW2b 8 0
IbB4 34 50
Ib1 21 6
Gemfibrozil 24 22
GSWB1 71 33
According to previous studies, sulfamethoxazole TPs accounted for up to 86% of

the total load in untreated wastewater [47]. Parent compounds have shown to be more
persistent, with TPs accounting for 5% in treated effluent [48]. The peak area ratios of TPs in
wetland were also well recorded in other research [49], with most TPs showing larger peak
ratios at the exit point of the wetland compared to the inlet site. Seven TPs were eventually
verified using reference standards in the study. At the same time, the identifications of
the other TPs achieved high confidence levels by giving diagnostic structural evidence via
fragment elucidations and MS/MS database comparisons.
Organic pollutants and their TPs are excreted and may infiltrate environmental sys-
tems (Figure 2), including groundwater, soil, sediment, and biota. These matrices might be
affected by their occurrences [50–52]. Percussor pollutants such as pharmaceuticals [34,35],
pesticides [31,32,53–55], surfactants [33,56,57], hormones [38,58], and personal care prod-
ucts [36,37] have often been found in the environment. When EPs enter the environment,
they undergo biological and chemical transformations, resulting in molecular weight varia-
tions [59–76] (Table 2). Meanwhile, some TPs have been detected more significantly in the
environment than their parents. Thus, the environmental prevalence of synthetic organic
compounds might be significantly underestimated if TPs are not considered [77–81].
care products [36,37] have often been found in the environment. When EPs enter the en-
vironment, they undergo biological and chemical transformations, resulting in molecular
weight variations [47,60–76] (Table 2). Meanwhile, some TPs have been detected more
significantly in the environment than their parents. Thus, the environmental prevalence
of synthetic organic compounds might be significantly underestimated if TPs are not con-
Toxics 2022, 10, 54 sidered [77–81]. 5 of 22
Figure 2. Contaminants andFigure 2. Contaminants

residues of mycotoxins,and residuespharmaceuticals,
pesticides, of mycotoxins, pesticides, pharmaceuticals,
and brominated and brominated
flame retardants may
flame retardants may enter the environment via various routes, including water, sediment,
enter the environment via various routes, including water, sediment, soil, and groundwater. Hydrolysis, photolysis, me- soil, and
groundwater. Hydrolysis, photolysis, metabolism, and microbial activity are the critical
tabolism, and microbial activity are the critical transformation mechanisms resulting in diverse TP formations that are transforma-
broadly distributed. tion mechanisms resulting in diverse TP formations that are broadly distributed.
Table 2. Possible biologicalTable

and chemical transformation
2. Possible reactions
biological and chemicaland associated mass
transformation changes.
reactions and(Reprinted
associatedfrom
mass[82],
changes.
Copy right 2021, Elsevier ). (Reprinted from [82], Copyright 2021, Elsevier).
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Change
Change in in Mass
Mass
Transfor-
Transformation Molecular
Change (Da)
Parent
Parent Chemical Parent Structure Product Structure Reference
Molecular
Formula Change Parent Structure Product Structure Reference
mation Chemical
Formula (Da)
loss
loss
loss
loss ofofnitro
of
of nitro nitro
nitro–NO Chloram-
Chloram-
Chloram-
group 2 + H2222++
–NO
–NO
–NO +HH −44.9851
−44.9851
H−44.9851
−44.9851Chloramphenicol [65]
[65]
[65]
[65]
group
group
group
group phenicol
phenicol
phenicol
phenicol
decarboxyla-
decarboxyla-
decarboxyla-
decarboxylation –CO–CO
2–CO
–CO2222 −43.9898
−43.9898
−43.9898
−43.9898 Ibuprofen
Ibuprofen
Ibuprofen
Ibuprofen [66]
[66]
[66]
[66]
tion
tion
tion
depropylation
depropylation
depropylation –C
–C333H
–C 3H
H6666 −42.0468
−42.0468
Ibuprofen
Ibuprofen [66]
[66]
[66]
reductive
reductivedis-
reductive dis-
dis-
placement
placementof
placement of –Cl
of –Cl+++H
–Cl H
H −33.9611
−33.9611 Triclocarban
Triclocarban [67]
[67]
[67]
chlorine
chlorine
chlorine
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loss
loss
loss of
of nitro
nitro Chloram-
Chloram-
lossof
loss
loss
loss
loss
loss ofnitro
of
of
of
of
of
nitro
nitro
nitro
nitro –NO
nitro
nitro –NO22222222+++++++H
–NO
–NO
–NO H
HH −44.9851
−44.9851
H −44.9851
Chloram-
Chloram-
Chloram-
Chloram-
Chloram-
−44.9851 Chloram-
−44.9851 Chloram- [65]
[65]
[65]
[65]
[65]
loss
loss of
group
of
group
lossgroup
of nitro
nitro
nitro –NO
–NO
–NO 22+ H
HH −44.9851
−44.9851
−44.9851 Chloram-
phenicol
Chloram-
phenicol
phenicol
Chloram- [65]
[65]
[65]
loss
loss
loss
loss of
group nitro
nitro –NO
ofnitro
group
of
of
group nitro –NO
–NO22222+++++H
2 + H −44.9851
H −44.9851 Chloram-
phenicol
Chloram-
phenicol
−44.9851 Chloram-
Chloram-
phenicol [65]
[65]
[65]
group
group
group –NO
–NO
–NO
–NO22 + H Table H
H H −44.9851
−44.9851
−44.9851
−44.9851 phenicol
phenicol
phenicol [65]
[65]
[65]
[65]
group
group
group
group phenicol
2. Cont. phenicol
phenicol
phenicol
decarboxyla-
decarboxyla-
decarboxyla-
decarboxyla-
decarboxyla-Change–CO
decarboxyla-
decarboxyla-
decarboxyla- in 22222
–CO
–CO −43.9898
Mass Ibuprofen [66]
[66]
[66]
decarboxyla-
tion
tion
decarboxyla-
tion
decarboxyla-
Transformation
tion
tion –CO
–CO
–CO
–CO
Molecular 22 −43.9898
222 Change
−43.9898
−43.9898
Ibuprofen
Ibuprofen
Ibuprofen
Parent Chemical Parent Structure Product Structure [66]
[66]
[66]
[66]
Reference
decarboxyla-
tion
tion
decarboxyla-
decarboxyla-
decarboxyla-
tion
tion –CO
–CO
Formula –CO2222 2 2 −43.9898
(Da)
Ibuprofen
Ibuprofen [66]
[66]
[66]
tion
tion
tion –CO
–CO
–CO
–CO2 2
−43.9898
−43.9898
−43.9898
Ibuprofen
Ibuprofen [66]
[66]
[66]
[66]
tion
tion
tion
tion
depropylation
depropylation
depropylation–C3 H
depropylation
depropylation
depropylation –C
–C
–C
–C
–C6 33H
333HHH −42.0468
−42.0468
H6666666 −42.0468
−42.0468
Ibuprofen
Ibuprofen
Ibuprofen
Ibuprofen [66]
[66]
[66]
[66]
[66]
[66]
depropylation
depropylation
depropylation
depropylation –C
–C
–C
–C 33H
333H
H
H 666
−42.0468
−42.0468
−42.0468
Ibuprofen
Ibuprofen
Ibuprofen [66]
[66]
[66]
[66]
depropylation
depropylation
depropylation –C –C
–C
–C333H
3 3H H
3H 6 6 −42.0468
Ibuprofen
Ibuprofen [66]
[66]
[66]
depropylation
depropylation
depropylation
depropylation –C
–C
–C 33H H666666
H −42.0468
−42.0468
−42.0468
Ibuprofen
Ibuprofen [66]
[66]
[66]
[66]
reductive
reductive
reductive dis-
dis-
dis-
reductive
reductive
reductive
reductive
reductive dis-
dis-
dis-
dis-
reductive
placement
placement
reductive
placement dis-
of
of
dis-
of +–Cl
–Cl
of –Cl–ClH + ++ H HH −33.9611
−33.9611
H −33.9611 Triclocarban
Triclocarban [67]
[67]
reductive dis- ++++H −33.9611
−33.9611 Triclocarban [67]
displacement
placement
placement of –Cl
–Cl −33.9611 Triclocarban
Triclocarban
Triclocarban [67]
[67]
[67]
reductive
placement
reductive
placement
reductive
of dis-
chlorine dis-
reductive
placement of
dis-
of
dis-
of –Cl
–Cl
–Cl + H
HH −33.9611
−33.9611
Triclocarban
Triclocarban [67]
[67]
[67]
placement
chlorine
chlorine
placement
chlorine
placement
chlorine
chlorine of
of
of –Cl
–Cl
–Cl + +
+ HH H −33.9611
−33.9611
Triclocarban
Triclocarban [67]
[67]
[67]
placement
chlorine
chlorineof
placement
placement
placement
chlorine
chlorine of
of –Cl
of –Cl
–Cl++++H
–Cl H −33.9611
H −33.9611
H Triclocarban
Triclocarban [67]
[67]
[67]
[67]
chlorine
chlorine
chlorine
chlorine
chlorine
chlorine
chlorine
desethylation
desethylation
desethylation
desethylation –C2 H–C
–C4 22H H −28.0312
−28.0312
44 −28.0312 Lidocaine
Lidocaine
Lidocaine [68]
[68]
[68][68]
desethylation –C
desethylation
desethylation
desethylation
desethylation
desethylation –C2222H
–C
–C
–C
–C
–C
H
2H
222H
H
H44444444
H
−28.0312
−28.0312 Lidocaine
−28.0312
−28.0312
−28.0312
−28.0312
−28.0312
Lidocaine
Lidocaine
Lidocaine
Lidocaine
Lidocaine
Lidocaine
[68]
[68]
[68]
[68]
[68]
[68]
[68]
desethylation
desethylation
desethylation –C
–C
–C 2 2H H
2H 4 4 −28.0312
−28.0312
Lidocaine
Lidocaine [68]
[68]
[68]
desethylation
desethylation –C
desethylation
desethylation –C
–C222H
–C 2 HH4444
2H 4 4 −28.0312
−28.0312
Lidocaine
Lidocaine [68]
[68]
[68]
[68]
Hydroxyla-
Hydroxyla-
Hydroxyla-
Hydroxyla-
Hydroxyla-
dehydration
dehydration
dehydration
dehydration
dehydration –H
–H
–H2222O
dehydration –H2–H
–H
O O
O
2O
O −18.0106
−18.0106
−18.0106
−18.0106
−18.0106
−18.0106 Hydroxyla-
Hydroxyla-
Hydroxylation
Hydroxyla-
Hydroxyla- [69]
[69]
[69]
[69]
[69][69]
dehydration
dehydration
dehydration –H
–H
–H 22O
222OO −18.0106
−18.0106
−18.0106
tion
tion ibuprofen
ibuprofen
Hydroxyla-
ibuprofen
tion
tion ibuprofen
Hydroxyla-
tion ibuprofen
ibuprofen [69]
[69]
[69]
dehydration
dehydration
dehydration –H
–H
–H22O O
2O
−18.0106
−18.0106
tion
tion ibuprofen
Hydroxyla-
tion ibuprofen
Hydroxyla-
Hydroxyla-
ibuprofen [69]
[69]
[69]
dehydration
dehydration
dehydration
dehydration –H
–H
–H 2 O
–H222OO
2O −18.0106
−18.0106
−18.0106 tion
−18.0106 tion
tion ibuprofen
ibuprofen
ibuprofen [69]
[69]
[69]
[69]
tion
tion ibuprofen
tionibuprofen
tion ibuprofen
ibuprofen
reductive
reductive
reductive
reductivedis-
reductive dis-
dis-
dis-
dis-
reductive
reductive
reductive dis-
dis-
dis-
reductive
placement
reductive
placement
reductive
placement dis-
of
of
dis-
of –F
–F ++++H HH −17.9906
−17.9906 Ciprofloxacin
Ciprofloxacin [70]
[70]
[70]
reductive
placement
placement
reductive
placement
placement
reductive
reductive
displacement
reductive
placement
placement of –F +–F
dis-
of
of
dis-
of
dis-
dis-
dis-
of
of H +
–F
–F
–F
–F
–F
–F ++++++H
H
HH −17.9906
−17.9906
−17.9906
−17.9906
H −17.9906
H −17.9906
−17.9906
Ciprofloxacin
Ciprofloxacin
Ciprofloxacin
Ciprofloxacin
Ciprofloxacin
Ciprofloxacin
Ciprofloxacin
[70]
[70]
[70]
[70]
[70]
[70]
[70]
[70]
placement
of fluorine
fluorine
placement
fluorine
fluorine
placement
fluorine
fluorine of
of
of –F
–F–F + HHH −17.9906
−17.9906
Ciprofloxacin
Ciprofloxacin [70]
[70]
[70]
placement
fluorine
placement
fluorine
placement
placement
fluorine of
of –F
of
of –F–F+++H
–F + HH
H −17.9906
−17.9906
Ciprofloxacin
Ciprofloxacin [70]
[70]
[70]
[70]
fluorine
fluorine
fluorine
fluorine
fluorine
fluorine
fluorine
oxidative
oxidative
oxidative dis-
dis-
oxidativedis-
oxidative
oxidative
oxidative
oxidative
oxidative
dis-
dis-
dis-
dis-
dis-
dis-
oxidative
placement
placement
oxidative
oxidative
placement dis-
of
of
dis-
of –Cl
–Cl
of–Cl–Cl ++++OH OH
OH −17.9662
−17.9662 Ceftriaxone
Ceftriaxone [71]
[71]
[71]
oxidative
placement
placement
oxidative
placement
oxidative
placement
displacement
oxidative
oxidative
placement
dis-
of
dis-
of
dis-
of
dis-
dis-
of
–ClOH+
–Cl
–Cl
–Cl
+
–Cl +++++OH
OH
OH
−17.9662
OH−17.9662
OH −17.9662 Ceftriaxone
−17.9662
−17.9662
−17.9662
−17.9662
Ceftriaxone
Ceftriaxone
Ceftriaxone
Ceftriaxone
Ceftriaxone
Ceftriaxone
[71]
[71]
[71]
[71]
[71]
[71]
[71]
placement
chlorine
chlorine
placement of
of –Cl
–Cl OH
OH −17.9662
Ceftriaxone [71]
[71]
[71]
of chlorine
chlorine
placement
chlorine
chlorine
placement
chlorine
placement
placement of
of
of –Cl
–Cl
–Cl++++OH
of –Cl + OHOH −17.9662
−17.9662
OH −17.9662 Ceftriaxone
Ceftriaxone
Ceftriaxone [71]
[71]
[71]
[71]
chlorine
placement
chlorine
chlorine of –Cl OH −17.9662 Ceftriaxone [71]
chlorine
chlorine
chlorine
chlorine
chlorine
chlorine
demethyla-
demethyla-
demethyla-
demethyla-
demethyla-
demethyla-
demethyla-
demethyla- –CH
–CH
–CH2222222 −14.0157
−14.0157 Naproxen
−14.0157 Naproxen
Naproxen [72]
[72]
[72]
demethyla-
tion
tion
demethyla-
tion
demethyla-
tion
demethylationtion –CH
2–CH22
–CH–CH −14.0157
−14.0157
−14.0157
22 −14.0157
Naproxen
Naproxen
Naproxen
Naproxen [72]
[72]
[72]
[72]
demethyla-
tion
tion
demethyla-
demethyla-
demethyla-
tion
tion –CH
–CH
–CH2222 2 −14.0157
−14.0157 Naproxen
Naproxen
−14.0157 Naproxen
Naproxen [72]
[72]
[72]
tion
tion
tion –CH
–CH
–CH
–CH 22
−14.0157
−14.0157
−14.0157
−14.0157 Naproxen
Naproxen
Naproxen [72]
[72]
[72]
[72]
tion
tion
tion
tion
hydrogena-
hydrogena-
hydrogena- Carbamaze-
Carbamaze-
Carbamaze-
hydrogena-
hydrogena-
hydrogena-
hydrogena- 000000 +2.0157
+2.0157 Carbamaze-
Carbamaze-
+2.0157 Carbamaze-
+2.0157
+2.0157 Carbamaze- [73]
[73]
[73]
[73]
[73]
tion
tionhydrogena-
tion
tion
tion reduction
reduction
hydrogena-
reduction
reduction 0 000
hydrogena-
reduction
hydrogenation 0 +2.0157
+2.0157
+2.0157 Carbamaze-
pine
pine
Carbamaze-
pine
Carbamaze-
pine
pine [73]
[73]
[73]
[73]
tion
tionhydrogena-
tion reduction
hydrogena-
reduction
hydrogena-
reduction 0 +2.0157
+2.0157
+2.0157
+2.0157 Carbamaze-
pine
Carbamaze-
pine
Carbamazepine
Carbamaze-
pine [73]
[73]
[73]
[73]
reduction
tion
tion
tion reduction
reduction
reduction 0
0 0
0 +2.0157
+2.0157
+2.0157
+2.0157 pine
pine
pine [73]
[73]
[73]
[73]
tion
tion
tion reduction
tionreduction
reduction
reduction pine
pine
pine
pine
alcohol
alcohol
alcohol
alcoholto
alcohol to
to car-
car-
tocar-
to car-
car- −2H O-desmethyl-
O-desmethyl-
O-desmethyl-
O-desmethyl-
O-desmethyl-
alcohol
alcohol
alcohol to
to
to car-
car-
car- −2H
−2H+++++++O
−2H
−2H O
OO +13.9792
+13.9792 O-desmethyl-
O +13.9792
+13.9792 O-desmethyl- [47]
[47]
[47]
[47]
[47]
alcohol
boxylic
boxylic
alcohol
boxylic
boxylic
alcohol
boxylic to
to car-
acid
acid
car-
acid
acid
to
acid −2H
−2H
−2H
car- −2H + O
OO +13.9792
+13.9792
metoprolol
metoprolol
O-desmethyl-
metoprolol
metoprolol
O-desmethyl-
metoprolol [47]
[47]
[47]
alcohol
boxylic
boxylic
alcohol
alcohol
alcohol
alcohol
boxylic
boxylic to
to
to to
to car-
acid
acid
car-
car-
acidcar-
acid −2H
−2H ++++O O +13.9792
metoprolol
metoprolol
O-desmethyl-
O +13.9792 O-
O-desmethyl-
metoprolol
metoprolol [47]
[47]
[47]
boxylic
boxylic
boxylicacid
carboxylic acid acid
acid −2H
−2H−2H
+O +
−2H
acid −2H + O + O
O O +13.9792
+13.9792
+13.9792 metoprolol
metoprolol
+13.9792 metoprolol
metoprolol
desmethylmetoprolol [47]
[59]
[47]
[47]
[47]
boxylic
boxylic
ketone/alde-
boxylic
ketone/alde-
boxylic acid
acid
acid metoprolol
2,6-di-tert-bu-
metoprolol
2,6-di-tert-bu-
metoprolol
ketone/alde-
ketone/alde-
ketone/alde-
ketone/alde- 2,6-di-tert-bu-
2,6-di-tert-bu-
2,6-di-tert-bu-
2,6-di-tert-bu-
ketone/alde-
ketone/alde-
ketone/alde- 2,6-di-tert-bu-
2,6-di-tert-bu-
2,6-di-tert-bu-
hyde
hyde
ketone/alde-
hyde
ketone/alde-
hyde
hyde for-
for-
for-
for-
for- −2H
−2H
−2H
−2H
−2H ++
+++OO
OOO +13.9792
+13.9792
+13.9792
+13.9792
+13.9792 tyl-4-
tyl-4-
2,6-di-tert-bu-
tyl-4-
2,6-di-tert-bu-
tyl-4-
tyl-4- [74]
[74]
[74]
[74]
[74]
ketone/alde-
hyde
hydefor-
ketone/alde-
ketone/alde-
ketone/alde-
hyde
hyde for-
for-
for- −2H
−2H++++O
−2H
−2H O O +13.9792
O +13.9792
+13.9792 2,6-di-tert-bu-
tyl-4-
+13.9792 2,6-di-tert-bu-
tyl-4-
2,6-di-tert-bu-
2,6-di-tert-bu-
tyl-4-
tyl-4- [74]
[74]
[74]
[74]
hyde
mation
mation
hyde
mation
hyde
mation
mation
ketone/aldehyde for-
for-
for- −2H
−2H
−2H + +
+ O O
O +13.9792
+13.9792
+13.9792 tyl-4-
methylphenol
methylphenol
tyl-4-
methylphenol
tyl-4-
methylphenol
methylphenol
2,6-di-tert-butyl-4- [74]
[74]
[74]
hyde
mation
hyde
hydemation
hyde
mation for-
for- −2H−2H
for-
for- −2H
−2H
+ O ++
−2H + +OO O +13.9792
O +13.9792
+13.9792
+13.9792 tyl-4-
methylphenol
+13.9792 methylphenol
tyl-4-
methylphenol
tyl-4-
tyl-4- [74]
[74][74]
[74]
[74]
mation
formation
mation
mation methylphenol
methylphenol
methylphenol
methylphenol
mation
mation
mation
mation methylphenol
methylphenol
methylphenol
methylphenol
2-Acetyla-
2-Acetyla-
2-Acetyla-
2-Acetyla-
2-Acetyla-
N/S-oxidation
N/S-oxidation
N/S-oxidation +O
+O
+O +15.9949
+15.9949 2-Acetyla-
2-Acetyla-
+15.9949 minofluorene
2-Acetyla- [75]
[75]
[75]
N/S-oxidation
N/S-oxidation
N/S-oxidation
N/S-oxidation +O
+O
+O
+O +15.9949
+15.9949
+15.9949
+15.9949 2-Acetyla-
minofluorene
2-Acetyla-
minofluorene
2-Acetyla-
minofluorene
minofluorene [75]
[75]
[75]
[75]
N/S-oxidation
N/S-oxidation
N/S-oxidation +O +O +O +O +15.9949 +15.9949
+15.9949 2-Acetyla-
minofluorene
minofluorene
2-Acetyla-
2-Acetyla-
2-Acetyla-
minofluorene
2- [75]
[75]
[75]
N/S-oxidation
N/S-oxidation
N/S-oxidation
N/S-oxidation
N/S-oxidation +O
+O
+O
+O +15.9949
+15.9949
minofluorene
+15.9949Acetylaminofluorene
minofluorene [75]
[75]
[75]
[75]
[75]
minofluorene
minofluorene
minofluorene
minofluorene
Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze-
epoxidation
epoxidation
epoxidation
epoxidation
epoxidation +O
+O
+O
+O
+O +15.9949
+15.9949
+15.9949
+15.9949
+15.9949 Carbamaze-
Carbamaze-
Carbamaze- [73]
[73]
[73]
[73]
[73]
epoxidation
epoxidation
epoxidation
epoxidation +O
+O
+O
+O +15.9949
+15.9949
+15.9949
+15.9949 Carbamaze-
pine
pine
Carbamaze-
pine
Carbamaze-
pine
pine [73]
[73]
[73]
[73]
epoxidation
epoxidation
epoxidation +O
+O
+O +15.9949
+15.9949
+15.9949 Carbamaze-
pine
Carbamaze-
Carbamaze-
pine
Carbamaze-
pine [73]
[73]
[73]
epoxidation
epoxidation
epoxidation
epoxidation
epoxidation +O +O
+O
+O
+O +15.9949
+15.9949
+15.9949
+15.9949 pine
+15.9949 Carbamazepine
pine
pine [73]
[73]
[73]
[73][73]
pine
pine
pine
pine
Toxics 2022, 10, 54 7 of 22
Table 2. Cont.
Toxics2022,
Toxics
Toxics
Toxics
Toxics 2022,10,
2022,
2022,
2022, 10,xxxx
10,
10,
10, xFOR
FORPEER
FOR
FOR
FOR PEERREVIEW
PEER
PEER
PEER REVIEW
REVIEW
REVIEW
REVIEW 7 77 of 22
of
7 of
of 22
22
22
Toxics
Toxics2022,
Toxics
Toxics 2022,10,
2022,
2022, 10,xx
10,
10, xFOR
xx FORPEER
FOR
FOR PEERREVIEW
PEER
PEER REVIEW
REVIEW
REVIEW 7777 of
of
of 22
of 22
22
Toxics
Toxics 2022,
2022, 10,
10, FOR
10,xxxChange
FOR PEER
PEER REVIEW
REVIEW 77 ofof 22
22
22
Toxics2022,
Toxics 2022,10, FORPEER
FOR PEER REVIEW
in REVIEW
Mass 777 ofof 22
of 22
22
Transformation Molecular Parent Chemical Parent Structure Product Structure Reference
Change (Da)
Formula
hydroxylation +O
hydroxylation
hydroxylation
hydroxylation +O
+O
+O +15.9949
+15.9949
+15.9949
+15.9949 Diclofenac
Diclofenac
Diclofenac
Diclofenac [72]
[72]
[72]
[72]
hydroxylation
hydroxylation
hydroxylation
hydroxylation
hydroxylation +O
+O
+O
+O
+O +15.9949
+15.9949
+15.9949
+15.9949
+15.9949 Diclofenac
Diclofenac
Diclofenac
Diclofenac
Diclofenac [72]
[72]
[72]
[72]
[72]
hydroxylation +O +15.9949 Diclofenac [72]
Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze-
hydration
hydration
hydration
hydration +H
+H2 O
+H O
+H22222O
22O
+18.0106
+18.0106
+18.0106 Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze- [73]
[73]
[73]
[73]
hydration
hydration
hydration
hydration +H
+H
+H
+H222222O
+H O
O
O +18.0106
+18.0106 pine
+18.0106 Carbamaze-
+18.0106 pine
pine [73]
[73]
[73]
hydration
hydration +H 2O
O +18.0106
+18.0106 pine
pine [73]
[73]
[73]
pine
pine
pine
pine
Δ-9-tetrahy-
Δ-9-tetrahy-
Δ-9-tetrahy-
Δ-9-tetrahy-
methyl
methyl
methyl to car-
methyl to to
to car-
car- Δ-9-tetrahy-
Δ-9-tetrahy-
∆-9-
Δ-9-tetrahy-
Δ-9-tetrahy-
methyl
methyl
methyl
methyl
methyl
carboxylic to
to
to
to
to
acid car-
car-
car-
car-
–2H
car- –2H
–2H
+
–2H
O
–2H 2 +
+
+
+ O
O
O
O2 22
222 +29.9741
+29.9741
+29.9741
+29.9741
+29.9741 drocanna-
Δ-9-tetrahy-
drocanna-
drocanna-
drocanna-
tetrahydrocannabinol [76]
[76]
[76]
[76]
[76]
boxylic
methyl
boxylic
boxylic to
boxylicacid acid
car-
acid
acid –2H –2H
–2H
–2H +
–2H++++OO
O
O
2 22 +29.9741
+29.9741
+29.9741
O22222 +29.9741 drocanna-
drocanna-
drocanna-
+29.9741 drocanna-
drocanna- [76]
[76]
[76]
[76]
boxylic
boxylic
boxylic
boxylicacidacid
acid
acid
acid binol
binol
binol [76]
boxylic binol
binol
binol
binol
binol
binol
dihydroxyla-
dihydroxyla-
dihydroxyla-
dihydroxyla- Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze-
dihydroxyla-
dihydroxyla-
dihydroxylation
dihydroxyla-
dihydroxyla- 0 000 +31.9898
+31.9898
+31.9898 Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze- [73]
[73]
[73]
[73]
tion
dihydroxyla-
tion 00 +31.9898
+31.9898 pine
Carbamaze-
pine [73]
[73]
tion
tion
tion
tion
tion
tion 0000 +31.9898
+31.9898
+31.9898
+31.9898 pine
pine
pine
pine
pine
pine
[73]
[73]
[73]
[73]
tion pine
Methylpara-
Methylpara-
chlorination
chlorination +Cl-H
chlorination +Cl-H
+Cl-H +Cl-H 33.9612 Methylpara-
Methylpara-
Methylpara-
33.9612 Methylparaben
33.9612 [77]
[77]
[77]
chlorination
chlorination
chlorination
chlorination
chlorination
chlorination
chlorination
+Cl-H
+Cl-H
+Cl-H +Cl-H
+Cl-H
+Cl-H 33.9612 Methylpara-
33.9612
33.9612
33.9612
33.9612
33.9612
33.9612
Methylpara-
Methylpara-
ben
ben
ben
benben
Methylpara- [77]
[77]
[77]
[77]
[77]
[77]
[77]
chlorination +Cl-H 33.9612 ben
ben
ben
ben [77]
ben
Acetamino-
Acetamino-
Acetamino-
dichlorination
dichlorination
dichlorination
dichlorination +2Cl
+2Cl
+2Cl 69.9173
69.9173
69.9173 Acetamino-
Acetamino-
Acetamino- [78]
[78]
[78]
dichlorination +2Cl+2Cl
dichlorination
dichlorination
dichlorination
dichlorination
dichlorination +2Cl
+2Cl
+2Cl +2Cl
+2Cl
69.9173
69.9173
69.9173
69.9173
69.9173
69.9173
Acetamino-
Acetamino-
69.9173 Acetaminophen
phen
Acetamino-
phen
phen
phen
[78]
[78]
[78]
[78]
[78]
[78]
[78]
dichlorination +2Cl 69.9173 phen
phen
phen
phen [78]
phen
Sulfametha-
Sulfametha-
acetylation
acetylation
acetylation
acetylation +C2 +C
+C +C
+C H222222O
+C222222H
H
H2222O O
O
O +42.0106 +42.0106 Sulfametha-
+42.0106
+42.0106 Sulfametha-
Sulfametha-
Sulfametha-
Sulfametha-
Sulfametha-
+42.0106 Sulfamethazine [79]
[79]
[79]
[79]
acetylation
acetylation
acetylation
acetylation
acetylation +C
H
+C
+C 2222H
2 O2 H
2H
H22O O +42.0106
O +42.0106
+42.0106 zine
+42.0106 Sulfametha-
zine
zine
zine [79]
[79]
[79]
[79]
[79]
acetylation
acetylation +C2H2OO
+C 2 H 2 +42.0106
+42.0106 zine
zine
zine [79]
[79]
zine
zine
zine
hydroxyl
hydroxyl
hydroxyl Carbamaze-
Carbamaze-
Carbamaze-
hydroxyl
hydroxyl
hydroxyl
hydroxyl
hydroxyl +Cl
+Cl++++++ OH
+Cl
+Cl OH
OH 51.9718
OH 51.9718
51.9718
51.9718 Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze-
Carbamaze- [78]
[78]
[78]
[78]
chlorination
hydroxyl
chlorination
hydroxyl
chlorination +Cl
+Cl
+Cl
+Cl
+Cl+Cl
+ OH++ + OH
OH
OH
OH 51.9718
51.9718
51.9718
51.9718
51.9718
pine
Carbamaze-
pine
pine
Carbamazepine
[78]
[78]
[78]
[78]
[78]
chlorination
chlorination
chlorination
chlorination
chlorination
chlorination OH 51.9718 pine
pine
pine
pine
pine [78]
chlorination pine
oxidative de-
oxidative
oxidative de-
de- Ampheta-
Ampheta-
Ampheta-
oxidative
oxidative
oxidative
oxidative
oxidative de-
de-
de-
de- −NH
−NH++++++ O
de- −NH
−NH O
O ++++++0.9840
O 0.9840
0.9840
0.9840 Ampheta-
Ampheta-
Ampheta-
Ampheta-
Ampheta- [80]
[80]
[80]
[80]
amination
oxidative
amination
oxidative
amination de- −NH
−NH
−NH
−NH + + O
O
O
O ++ 0.9840
0.9840
0.9840
0.9840 mine
Ampheta-
mine
mine [80]
[80]
[80]
[80]
amination
amination
amination
deamination
amination
amination
−NH
−NH
+ O + O + + 0.9840
0.9840 mine
mine
Amphetamine
mine
mine
mine [80]
[80]
amination mine
methylation
methylation
methylation
methylation 0000 +14.0157
+14.0157
+14.0157
+14.0157 Thiouracil
Thiouracil
Thiouracil
Thiouracil [80]
[80]
[80]
[80]
methylation
methylation 0 +14.0157 Thiouracil [80]
methylation
methylation
methylation 0000 +14.0157
+14.0157
+14.0157
+14.0157 Thiouracil
Thiouracil
Thiouracil
Thiouracil [80]
[80]
[80]
[80]
sulfate conju-
sulfate
sulfate conju-
conju-
sulfate
sulfate
sulfate
sulfate
sulfate conju-
conju-
conju-
conju-
conju- 000 +79.9568
+79.9568
+79.9568 Triclosan
Triclosan
Triclosan [67]
[67]
[67]
gation
sulfate conju-
gation 00 +79.9568
+79.9568 Triclosan
Triclosan [67]
[67]
gation
gation
gation
gation
gation
gation 0000 +79.9568
+79.9568
+79.9568
+79.9568 Triclosan
Triclosan
Triclosan
Triclosan [67]
[67]
[67]
[67]
gation
Sulfametha-
Sulfametha-
acetylation
acetylation +C H222O
+C222H O +42.0106
+42.0106 [79]
[79]
zine
zine
Toxics 2022, 10, 54 8 of 22

hydroxyl
hydroxyl Carbamaze-
Carbamaze-
+Cl
+Cl++ OH
OH 51.9718
51.9718 [78]
[78]
chlorination
chlorination pine
pine
Table 2. Cont.
oxidativede-
oxidative de-Change in Ampheta-
Ampheta-
Transformation −NH
−NH++ O
Molecular O Mass
++0.9840
0.9840 Parent Chemical Parent Structure Product Structure [80]
[80]
Reference
amination Formula
amination Change (Da) mine
mine
methylation
methylation
methylation 0 00 +14.0157
+14.0157
+14.0157 Thiouracil
Thiouracil
Thiouracil [80]
[80]
[80]
sulfate
sulfate
Toxics
Toxics 2022,
conju-
conju-
2022, 10,xxx
10, xFOR
FOR PEER
PEER REVIEW 88ofof22
22
sulfate
Toxics
Toxics
Toxics
Toxics 2022,
2022,
2022,
2022, 10,
10,
10,
10, FOR
xx FOR
FOR
FOR 00 REVIEW
PEER
0 PEER
PEER
PEER REVIEW
REVIEW
REVIEW +79.9568
+79.9568
REVIEW
+79.9568 Triclosan
Triclosan
Triclosan 888
[67]
[67]
[67] of
8 of
of 22
of 22
22
22
gation
gation
conjugation
glycine
glycine conju-
glycine
glycine
glycine conju-
conju-
conju-+C2+C
H+C 2222H
3 NO 2H333NO +57.0215
+57.0215 Benzoic
NO+57.0215 Benzoic
Benzoic acidacid
acid [81]
[81]
[81]
conjugation
gation
gation +C
+C H33333NO
222H NO +57.0215
+57.0215 Benzoic
Benzoic acid
acid [81]
[81]
gation
gation
taurine
taurine conju-
taurine
taurine
taurine conju-
conju-
conju-
+C2+C
+C 2222H
H5 NO
+C H25555S55NO
2H
NO222222S22S+107.0041
NO
55NO S +107.0041
S +107.0041 Bile
Bile
Bile acids
acids
acids [80]
[80]
[80]
conjugation
gation
gation +C 222H +107.0041
+107.0041 Bile
Bile acids
acids
Bile acids [80]
[80]
[80]
gation
gation
2-acetomido-
2-acetomido-
2-acetomido-
2-acetomido-
S-cysteine
S-cysteine
S-cysteine
S-cysteine
S-cysteine +C+C
S-cysteine 2-acetomido-4-
3333H
conjugation +C
conjugation
conjugation
+C
H5 NO
3 +C H25555S55NO
3H
333H
NO222222S22S+119.0041
55NO
NO S +119.0041
S +119.0041
+119.0041
+119.0041 4-chlorome-
4-chlorome-
4-chlorome-
4-chlorome-
chloromethylthiazole
[80]
[80]
[80]
[80]
[80]
[80]
conjugation
conjugation
conjugation thylthiazole
thylthiazole
thylthiazole
thylthiazole
N-acetylcyste-
N-acetylcyste-
N-acetylcyste-
N-acetylcyste-
N-acetylcyste-
N-
ine
ineconjuga-
ine
ine conjuga-+C6+C
conjuga-
conjuga-
acetylcysteine +C
+C
+C 6666H
H8 NO H38888S88NO
6H
666H NO333333S33S+161.0147
NO
88NO S +161.0147
S +161.0147 Naphthalene
+161.0147
+161.0147 Naphthalene
Naphthalene
Naphthalene
Naphthalene [80]
[80]
[80]
[80]
[80]
conjugation
tion
tion
tion
tion
glucuronide
glucuronide
glucuronide +C
glucuronide
glucuronide +C 66H6H
H888888O O66666666+176.0321
88O +176.0321 Testosterone
+176.0321 Testosterone [80]
[80]
conjugation 6 +C
+C 666H
8 O66 O +176.0321
+176.0321 Testosterone
Testosterone [80]
[80]
+C H Testosterone [80]
conjugation
conjugation
conjugation
conjugation
conjugation
S-glutathione
S-glutathione +C
S-glutathione +C10
S-glutathione +C H
10
+C10
10
10
10 H15
10
15
10H N
H15
15
15
15 N333O
15N
15 33O66666
N3333O
O6666 +305.0682 Oxidation
Oxidation Oxidation
Oxidation
S-glutathione 10 15
+C10 H15 N3 OS6 S +305.0682
+305.0682 Oxidation
+305.0682 phenacetin
+305.0682 [81]
[81]
[81]
[81]
[81]
conjugation
conjugation
conjugation
conjugation
conjugation
conjugation SSS S phenacetin
phenacetin
phenacetin
phenacetin phenacetin
3.
3.Nontarget
3.
3. NontargetScreening
Nontarget
Nontarget Screening
Screening
Screening
3. Nontarget Screening
Detection
Detectionof
Detection
Detection ofhighly
of
of highlyresolved
highly
highly resolvedpeaks
resolved
resolved peakswith
peaks
peaks withHRMS
with
with HRMSis
HRMS
HRMS isof
is
is ofthe
of
of themost
the
the mosteffective
most
most effectiveways
effective
effective waysto
ways
ways toiden-
to
to iden-
iden-
iden-
tifyDetection
tify novel
novel of highlysuch
substances
substances resolved
such as
as peaks
TPs
TPs [83].
[83].with
NTS
NTS HRMS is of the
workflows
workflows weremost
were effective ways
established
established in
in the
thetoearly
identify
early 1970s
1970s
tify
tify novel
novel substances
substances such such as as TPs
TPs [83].
[83]. NTSNTS workflows
workflows were were established
established in in the
the early
early 1970s
1970s
novel
to substances such assubstances.
TPs [83]. NTS workflows weremass established in the early 1970s to
to identify
to
to identify unknown
identify
identify unknown substances.
unknown
unknown substances. In
substances. In NTS
In
In NTS methods,
NTS
NTS methods, mass
methods,
methods, mass spectrometers
mass spectrometers and
spectrometers
spectrometers and chromato-
and
and chromato-
chromato-
chromato-
identify
gramsare
grams unknown
areoften substances.
oftenused.
used.Samples In
Samplesin NTS
inNTS methods,
NTSundergo
undergoanmass spectrometers
anextraction
extractionprocedure and
procedureto chromatograms
toretrieve
retrieveana- ana-
grams
grams are
are often
often used.
used. Samples
Samples in
in NTS
NTS undergo
undergo an
an extraction
extraction procedure
procedure to
to retrieve
retrieve ana-
ana-
arelytes.
oftenOnce
used. theSamples in NTS undergo an extraction procedure to retrieve analytes. Once
lytes. Once
lytes.
thelytes.
Once
Once
analytes have theanalytes
the
the analytes
analytes
analytes
been
have
havebeen
have
have
identified,
been
been
been identified,
identified,they
identified,
theyidentified, theymay
they
they maybe
may
may
may be cross-referenced becross-referenced
be
be cross-referenced
cross-referenced
cross-referenced
with databases that
with
with
with databases
databases
databases
withprovide
databases
that
that
that
that provide
provide
provide
provide known
known
known
known elements.
elements.
elements.
elements. The
The
The
The analyte
analyte
analyte
analyte structure
structure
structure
structure would
would
would
would be
be
be
be compared
compared
compared
compared to
to
to
to known
known
known
known com-
com-
com-
com-
known elements. The analyte structure would be compared to known compounds and
pounds
pounds
pounds
pounds and
and
and
and categorized
categorized
categorized
categorized after
after
after
after the
the
the
the analyte
analyte
analyte
analyte components
components
components
components were
were
were
were found.
found.
found.
found. Consequently,
Consequently,
Consequently,
Consequently, there
there
there
there
categorized after the analyte components were found. Consequently, there would be a
would
would
would be
be aaaamixture
mixture of
ofknown
of knownand
known andunknown
and unknown chemical
chemical characteristics
characteristics (Figure
(Figure3).
(Figure 3). The
The chal-
chal-
would
mixture ofbe
be
known mixture
mixture of known
and unknown and
chemicalunknown
unknown chemical characteristics
chemical(Figure
characteristics characteristics (Figure
3). The challenge 3).
3). The
Thethe
with chal-
chal-
lenge
lenge
lenge
lenge with
with
with
with the
the
the
the HRMS
HRMS
HRMS
HRMS tool
tool
tool
tool is
is
is
is that
that
that
that the
the
the
the instrument
instrument
instrument
instrument generates
generates
generates
generates a lot
aaa lot
lot
lot of of
of
of spectrum
spectrum
spectrum
spectrum data
data
data
data that
that
that
that
HRMS tool is that the instrument generates a lot of spectrum data that should be evaluated
should
should be
should
should beevaluated
be
be evaluatedand
evaluated
evaluated andexported
and
and exported in
exported
exported inaaaacontrolled
in
in controlledmanner.
controlled
controlled manner.Additionally,
manner.
manner. Additionally, the
Additionally,
Additionally, theinstrument
the
the instrument
instrument
instrument
may
may
may
mayrunrun
run in
runinin full
infullfullscan
scan
fullscan and
scanandand MS/MS
MS/MS
andMS/MS
MS/MSmodes modes
modes simultaneously
simultaneously
modessimultaneously
simultaneously(i.e., (i.e.,
(i.e.,data-dependent/independent
data-dependent/independent
(i.e.,data-dependent/independent
data-dependent/independent
MS/MS
MS/MSacquisition),
MS/MS
MS/MS acquisition),generating
acquisition),
acquisition), generatingeven
generating
generating evenmore
even
even moredata
more
more datato
data
data tobe
to
to becollected
be
be collectedin
collected
collected inaaaasingle
in
in singlerun.
single
single run.As
run.
run. Asaaaapost
As
As post
post
post
step,
step,
step, software-aid
software-aid
step, software-aid processing
processing
software-aid processing
processing is is
is required
required
is required
required for for
for the
the
for the acquired
acquired
the acquired spectrum
spectrum
acquired spectrum
spectrum data. data.
data. The
The
data. The data
data
The data pro-
pro-
data pro-
pro-
cessing
cessingNTS
cessing
cessing NTSstep
NTS
NTS stepmay
step
step maybe
may
may beperformed
be
be performedusing
performed
performed usingaaaavariety
using
using varietyof
variety
variety offree
of
of freeand
free
free andcommercial
and
and commercialsoftware
commercial
commercial softwaretools,
software
software tools,
tools,
tools,
Toxics 2022, 10, 54 9 of 22
and exported in a controlled manner. Additionally, the instrument may run in full scan and
MS/MS modes simultaneously (i.e., data-dependent/independent MS/MS acquisition),
generating even more data to be collected in a single run. As a post step, software-aid
processing is required for the acquired spectrum data. The data processing NTS step may
be performed using a variety of free and commercial software tools, including:
• XCMS (https://xcmsonline.scripps.edu accessed on: 1 December 2020);
• MZmine (http://mzmine.sourceforge.net/ accessed on: 1 December 2020);
• Non-target, ACD MS/Workbook Suite; and,
• EnviMass (http://www.eawag.ch/forschung/uchem/software/enviMass1 accessed
on: 1 December 2020);
•
Toxics 2022, 10, x FOR PEER REVIEW
vendors’ software, such as TraceFinder/CompoundDiscoverer (Thermo Scientific, Waltham,
9 of 22
MA, USA), Profile-Analysis (Bruker, Billerica, MA, USA), MetaboLynx/MassLynx (Waters,
Milford, MA, USA), MassHunter (Agilent, Santa Clara, CA, USA), and Data Explorer
(Applied Biosystems, Waltham, MA, USA).
Figure 3. Workflow for non-target screening to identify non-targeted peaks with feasible
Figure 3. Workflow for non-target screening to identify non-targeted peaks with feasible molecular structures.
molecular structures.
Choosing
Choosing the the best
best peaks
peaksisisthe
theprimary
primarystep.
step.During
During this
this phase,
phase, it isit critical
is critical to com-
to compare
pare the sample to control or blank sample to remove irrelevant peaks.
the sample to control or blank sample to remove irrelevant peaks. Automated processes Automated pro-
cesses such as mass calibration, adduct componentization, and isotope
such as mass calibration, adduct componentization, and isotope peak matching are aimed peak matching are
aimed at ruling out the unnecessary peaks. According to Kind and Fiehn
at ruling out the unnecessary peaks. According to Kind and Fiehn 2007, heuristic filters 2007, heuristic
filters
describedescribe the chemical
the chemical formulaformula
to the to the mass
exact exactformass
thefor the
hits hits [84].
[84].
It
It is
is possible
possible toto find
find potential
potential structures
structures via
via searching
searching databases
databases such such asas PubChem,
PubChem,
ChemSpider,
ChemSpider, the NIST or structure creation, and DAIOS database. As a result,the
the NIST or structure creation, and DAIOS database. As a result, theassign-
assign-
ment
ment of molecular formula with substructure information can dramatically narrow down
of molecular formula with substructure information can dramatically narrow down
the
the number
number of of candidates
candidates in in databases
databases and
and allow
allow easy
easy access
access toto distinctive
distinctive structures
structures ofof
the
the hits.
hits.
Information
Information on on MS/MS
MS/MS fragmentation
fragmentationmust mustbebecompared
compared to to
in in silico
silico spectral
spectral frag-
fragmen-
mentation
tation fromfrom the library
the library to rank
to rank the candidate
the candidate structures.
structures. A fewAmassfew mass spectrometer
spectrometer da-
databases
tabases provide MS/MS spectrum
provide MS/MS spectrum data, such as: data, such as:
•• MetLin
MetLin (http://metlin.scripps.edu/index.php
(http://metlin.scripps.edu/index.php accessed
accessed on:on:
1 December
1 December 2020).
2020).
• MassBank (http://massbank.ufz.de/MassBank/ accessed on: 1 December 2020);
mzCloud (Thermo)
To date, TPs, which are defined as metabolites secreted by organisms and their deg-
radation products formed by biodegradation, photolysis, and/or hydrolysis, have re-
ceived the most attention in terms of their properties and effects [85–89]. NTS workflows
Toxics 2022, 10, 54 10 of 22
• MassBank (http://massbank.ufz.de/MassBank/ accessed on: 1 December 2020); mz-

Cloud (Thermo)
To date, TPs, which are defined as metabolites secreted by organisms and their degra-
dation products formed by biodegradation, photolysis, and/or hydrolysis, have received
the most attention in terms of their properties and effects [85–89]. NTS workflows have ef-
fectively found the TPs of organophosphate ester from different aquatic organisms [90]. For
example, in Daphnia magna (D. magna), Choi et al. (2020) [91] used NTS to identify the TPs
of flame retardant triphenyl phosphate. For model organisms, various target analyses have
been conducted [92,93]. However, the NTS technique has only been used in a few studies;
therefore, there is a lack of knowledge on novel TPs rising concerns in model organisms.
3.1. Sample Treatment and QA/QC

Despite significant advances in implementing QA/QC practices for analytical pro-
cesses, a substantial nontarget analysis of TPs in organism matrices poses new obstacles.
Consequently, an adequate set of QA/QC techniques based on metrological traceability
of findings is critical for understanding the reasons for unwanted variances and mini-
mizing them. The analytical laboratory should provide clear criteria for the execution
and assessment of each QA/QC activity, identifying the parameter under evaluation and
detailing how parameters might be modified to use the set of QA/QC activities properly.
The analyst should determine the parameter examined for each QA/QC operation and its
excellent decision value based on the study’s unique requirements (i.e., objectives, number
of samples, matrix, and predicted substances) [94,95]. While implementing all the specified
QA/QC steps is not required and is dependent on the project’s objectives, implementing
specific measures for each analytical stage is necessary to provide accurate findings.
3.2. Sample Extraction for Non-Target Screening

For tissue sample extraction, microwave-assisted extraction (MAE), ultrasonic-assisted
extraction (UAE), Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS), and
pressurized liquid extraction (PLE) have been applied in TP studies (Table S1).
3.2.1. Quick, Easy, Cheap, Effective, Rugged, and Safe

Using the QuEChERS approach, minimal solvent consumption, fast extraction, and
effective clean-up can be achieved with minimized cost [96]. In addition, it is highly
customizable, thus becoming a popular pretreatment method for various biota samples.
Analyte characteristics, matrix composition, and analytical method influence efficacy [96].
In general, following a salting-out extraction with solvent (e.g., methanol, acetonitrile, etc.),
the QuEChERS method employs a dispersive solid-phase extraction (d-SPE) to reduce
matrix effects. An example is the following. Tests of QuEChERS for the extraction of
diclofenac and its TPs in bivalves were conducted by Daniele et al. (2016) [97]. A 50 mL
polypropylene centrifuge tube was used to weigh a 100 mg aliquot of homogenized and
freeze-dried sample. Extracts of the target analytes were spiked up to 200 mg/L and
diclofenac-d4 (100 mg/L) in a methanolic mixture, and the solvent was evaporated under a
moderate stream of nitrogen for method development. The dry extract was mixed with
5 mL of water to aid in the salting-out extraction process. It was then mixed with 10 mL
of acetonitrile (ACN) and 200 mL of heptane and vortexed for 15 s. Then, acetate salt was
added, vigorously agitated for 10 s, and vortexed for 20 s. The homogenate was centrifuged
for 3 min at 10,000 rpm to remove the acetate salt. The 6 mL of ACN was transferred to
a 10 mL glass tube. To keep the analytes from evaporating, 200 mL of DMSO was added
with a moderate stream of nitrogen used to evaporate ACN. As a final step, the remaining
DMSO solution was mixed with 50 mL of 13 C phenacetin (1 mg/L in ACN) (Figure S2).
Quantitative analysis for the residue was carried out using LC–MS/MS.
Toxics 2022, 10, 54 11 of 22
3.2.2. Microwave-Assisted Extraction

Two different microwave systems, i.e., closed extraction vessels/multi-mode mi-
crowave ovens and ‘open’ focused microwave ovens, have been used in the laboratory for
extraction. The most often utilized systems today are closed vessel-like systems (Figure S3),
in which the extraction efficiency is determined by applied temperature and pressure.
MAE minimizes sample consumption and extraction time by providing a high throughput
extraction. In certain circumstances, replacing the extraction phase with water instead of
an organic solvent resulted in a more effective extraction [98]. The extraction efficiency was
influenced by the solvent’s volume and properties, the irradiation period, and microwave
power [99]. The target contaminants would decompose due to the high microwave power
and lengthy irradiation [100]. Wang et al. (2012) [101] suggested a technique for determin-
ing nine steroid hormones in fish tissues based on MAE. Under the influence of microwave
radiation, the hormones were extracted with acetonitrile and water. The extract was then
separated with ammonium acetate into an acetonitrile phase. The target analytes in the
phase were concentrated and analyzed using LC–MS/MS. The recovery values for the
method were 78.9–94.3%.
3.2.3. Pressurized Liquid Extraction

PLE is a simple and comprehensive extraction process that enables quantitative re-
coveries with minimal effort on method development. A general procedure is as follows.
The cell is put on the carousel once the sample has been entered and mixed with the inert
substance. The sample cell is rotated on the carousel before transferring to the oven and
immediately sealed under pressure. The cell is then filled with solvent and held in the
range for a user-defined time at a persistent pressure and temperature. After collecting
the extracted analytes in a vial, the cell is washed and purged with nitrogen gas. These
phases form a cycle. The overall extraction time is, in general, 15–45 min. PLE increases the
extraction of contaminants from solid materials using standard solvents at raised pressure.
It may result in a large percentage of matrix interference being extracted [102]. Pressurized
hot water extraction offers an alternative as an ecologically gentle approach [103].
3.2.4. Ultrasonic-Assisted Extraction

The UAE extraction process includes homogenizing, freeze-drying, sieving, centrifug-
ing, ultrasonication, and clean-up processes [104]. UAE is a fast and efficient way to extract
natural chemicals and contaminants from food and environmental samples, with extraction
efficiency equivalent to traditional methods [105]. The UAE approach is a low-cost alterna-
tive to contemporary extraction procedures that are simple and may be employed with any
solvent. Dorival-Garc’a et al. (2013) explored the productivities of PLE, UAE, and MAE
techniques and identified that the methods had similar extraction times, with PLE and
MAE providing the best extraction yield [106]. The proposed UAE is an alternative because
it is simple to employ, has equal solvent volumes, and has similar precision and sensitivity.
Wilkinson et al. (2007) compared the MAE and UAE methods to build a methodology for
determining 13 chemicals in aquatic plants and benthic organisms. The UAE-SPE technique
offered the best results [89]. Qu et al. (2017) used UAE to minimize extraction time and
enhance extraction efficiency to analyze amide herbicide residues in fish [105].
4. Transformation Pathway in a Model Organism

In vitro and in vivo metabolic processes may transform organic pollutants into highly
reactive metabolites. The principal biotransformation routes accompany reduction, oxi-
dation, and/or hydrolysis during the phase I reaction. In contrast, the phase II reaction
mainly features conjugation reactions. Phase II reactions are biosynthetic, as active enzymes
connect the metabolite produced by phase I responses to an endogenous polar molecule,
resulting in a conjugate. Many endogenous compounds with high polarity (e.g., sugar,
amino acids, sulphates, etc.) are used in conjugation, and the resultant conjugates are
mostly ionized and highly water soluble. Furthermore, specialized active transport systems
Toxics 2022, 10, 54 12 of 22
identify the moieties employed for conjugation, assisting translocation across plasma mem-
branes and increasing the excretion rate [107,108]. The endoplasmic reticulum, lipoprotein
membranes stretching from mitochondria and nucleus to the plasma membranes of cells,
are the primary sources of phase I enzymes in cells. As lipophilic substances preferentially
diffuse into lipid membranes the presence of phase I enzymes in lipid membranes has
crucial implications for biotransformation [109].
Phase I reactions are more typically related to the production of reactive and more
hazardous metabolites; yet, phase II processes, as well as combinations of phase II and
phase I processes, may be considered an intoxication procedure [110,111]. However, there
is evidence that metabolites of pollutants such as tetrabromobisphenol-A, trenbolone,
triclosan, and bisphenol A retain the bioactive moieties and preserve inherent toxicity
comparable to the parent compound [112–114]. Methylation in biological systems can
produce hydrophobic and bioaccumulative metabolites, often observed in fungus, plants,
and bacteria [115]. Compound biotransformation studies are vital to understand the
reactivity and toxicity of organisms. Bioaccumulation and toxicity of organic pollutants
are heavily influenced by biotransformation, while this process is still poorly understood
for emerging contaminants [116]. There have been limited investigations for TPs of EPs in
specific organisms, as follows.
4.1. Algae
Cymbella sp. were studied for their ability to biotransform triclosan. The results
demonstrated that triclosan and its potential hazardous metabolites had a high toxic
impact on Cymbella sp., with 72 h EC50 of 324.9 mg/L. In diatom cells, 11 metabolites
were found and with potential degradation pathways. The transformative reactions of
triclosan in Cymbella sp. included methylation, hydroxylation, amino acids conjunction,
dichlorination, and glucuronidation, which resulted in biologically active products (e.g.,
methyl triclosan) and conjugation products (e.g., or oxaloacetic acid conjugated or triclosan
glucuronide) [117].
4.2. Freshwater Crustaceans

Biotransformation pathways in freshwater crustaceans have been little understood,
except in a study using Gammarus pulex (G. pulex) and Daphnia magna (D. magna). For 24 h,
G. pulex and D. magna were exposed to a modest dose of biocides and pharmaceuticals
and sacrificed to identify their metabolites. Each species produced 25 and 11 metabolites,
respectively, for terbutryn, irgarol, venlafaxine, and tramadol, mainly via oxidation and
conjugation reactions. Affinity in the synthesis of metabolites, such as oxidation and
demethylation products, were found for venlafaxine and tramadol, which have an identical
backbone structure. Tramadol and venlafaxine were oxidized at the amine or cyclic C-H
bond, while irgarol and terbutryn were oxidized at the terminal methyl group (MTE258B,
MIR270B, MIR270A, MTE258A, and MIR286) (Figure 4) [118]. In Gammarus pulex (G. pulex)
and Hyalella azteca (H. azteca), Fu et al. (2020) found a substantial pathway for diclofenac
metabolism [119]. The LC–HRMS/MS data collected from the test species were used to
identify metabolites utilizing NTS procedures. As a result, 281 metabolites were identified
based on the isotopic signature of chlorine (Cl). H. azteca and G. pulex had nine distinct
diclofenac metabolites.
Toxics 2022, 10,
Toxics 2022, 10, 54
x FOR PEER REVIEW 1313of
of 22
22
Figure 4. Proposed biotransformation pathways of irgarol and terbutryn in freshwater crustaceans. Note that R2 is the
Figure 4. Proposed biotransformation pathways of irgarol and terbutryn in freshwater crustaceans.
hydroxylated moiety of R1. The sky-blue shaded area indicates a pathway including glutathione conjugation followed by
Note that R2 is the hydroxylated moiety of R1. The sky-blue shaded area indicates a pathway
subsequent reactions to form cysteine conjugates, reported for the first time in the test organisms. (Reprinted from [118],
Copy right 2021, ACS ). including glutathione conjugation followed by subsequent reactions to form cysteine conjugates,
reported for the first time in the test organisms. (Reprinted from [118], Copyright 2013, ACS).
4.3.
4.3. Fish
Fish
Metabolites
Metabolites of of diclofenac
diclofenac were
were also identified in
also identified in vertebrates.
vertebrates. Oncorhynchus
Oncorhynchus mykiss,
mykiss,
have
have produced hydroxylate and conjugate of diclofenac with glucuronic acid,
produced hydroxylate and conjugate of diclofenac with glucuronic acid,glutathione,
glutathione,
and
and sulfate.
sulfate. Other
OtherEPs,
EPs,including
includingpharmaceuticals
pharmaceuticals (propranolol,
(propranolol, carbamazepine)
carbamazepine) andandin-
secticides (diazinon, azoxystrobin, and fipronil), were found in the S9 extract
insecticides (diazinon, azoxystrobin, and fipronil), were found in the S9 extract of troutof trout liver
[120]. It wasItrevealed
liver [120]. that each
was revealed of theoffive
that each the parents had had
five parents ten distinct metabolites.
ten distinct The The
metabolites. pri-
mary metabolic mechanisms were oxidation, dealkylation, S-oxidation, and
primary metabolic mechanisms were oxidation, dealkylation, S-oxidation, and epoxidation. epoxidation.
The
The formation
formation of of metabolites
metabolites for
for fipronil
fipronil and
and diazinon
diazinon waswas enhanced
enhanced as as increasing
increasing car-
car-
bamazepine
bamazepine concentration in the binary exposure, whereas the transformation kinetic
concentration in the binary exposure, whereas the transformation kinetic for
for
propranolol
propranolol andand azoxystrobin
azoxystrobin was
was decreased.
decreased. Toxic
Toxic diazoxon
diazoxon and and less
less toxic
toxic pyrimidinol,
pyrimidinol,
among
among significant
significantdiazinon
diazinonmetabolites,
metabolites,were
werepromptly
promptly formed
formed byby
S9 S9
after the the
after binary ex-
binary
posure
exposure with carbamazepine.
with carbamazepine.
Earthworm
4.4. Earthworm
High-production-volume surfactants,
High-production-volume surfactants, also
also known
known as
as polyfluoroalkyl
polyfluoroalkyl phosphate
phosphate es-
es-
ters (PAPs), are employed in the packaging industry and food contact paper. PAPs PAPs can
perfluoroalkyl carboxylic acids, which
transform into perfluoroalkyl which are
are highly
highly bioaccumulative
bioaccumulative and
andper-
per-
sistent in the environment, although their fate remains unknown in terrestrial species. To To
investigate biotransformation, Zhu et al. (2021) subjected M. guillelmi to soil
soil contaminated
contaminated
with 6:2
with 6:2 fluorotelomer
fluorotelomer phosphate
phosphate diester
diester (6:2
(6:2 diPAP).
diPAP). According
According to
to in
in vitro
vitro desorption
desorption
tests [121], 6:2 diPAP desorbed from soil was considerably accumulated in gut digesting
Toxics 2022, 10, 54 14 of 22
tests [121], 6:2 diPAP desorbed from soil was considerably accumulated in gut digesting
fluid. Phase I products included perfluoropentyl propanoic acid, perfluorohexanoic acid,
2-perfluorohexyl ethanoic acid, perfluoropentanoic acid, and perfluoroheptanoic acid, all
of which confirmed that β and α oxidation occurred in earthworms. As a phase II product,
6:2 fluorotelomer alcohol–sulfate conjugate was found at unusually high quantities in earth-
worms for the first time, which may be the principal mechanism by which earthworms
remove 6:2 diPAP.
4.5. Human Cell Lines

Using human skin subcellular fractions, the in vitro metabolism of 2-ethylhexyl-2,3,4,5-
tetrabromobenzoate (EH-TBB) and a mixture of Bis(2-ethylhexyl) tetrabromphthalate (BEH-
TEBP), EH-TBB, and triphenyl phosphate was evaluated for the first time. Analysis of EH-
TBB and THP utilizing UPLC-Q-Exactive Orbitrap identified the two primary metabolites,
tetrabromobenzoic acid (TBBA) and diphenylphosphate (DPhP). It was assumed that
CYP450 enzymes were responsible for the dermal biotransformation of TPhP and EH-TBB,
but no stable metabolites were found for BEH-TEBP [122].
5. Toxicity Effect of TPs on the Model Organism

5.1. Potential Bioactivation Mechanisms
Biotransformation may undergo a two-step process. In the first phase, including re-
duction, oxidation, and/or hydrolysis, the enzymes interact with the EPs and convert them
into water-soluble metabolites, in many cases facilitating excretion from the body [123–125].
The biotransformation process generates a variety of intermediate and final metabolites
that might result in any of the following outcomes: toxicity, inertness in the body, or safe
elimination [125]. Cytochrome P 450 group enzymes CYP1 are active in the first step of
EPs biotransformation [123]. There must be an equilibrium between the generation of
oxygen atoms and other natural processes such as biotransformation to avoid any un-
wanted consequences. In phase II processes, metabolites generated in phase I become
more water-soluble. Glutathione-S-transferase aids in phase II conjugation processes with
glutathione (GST). Antioxidant protection is provided by this enzymatic activity [126].
Phase I metabolites may induce cytotoxicity if they do not undergo the phase II procedure.
Due to biotransformation, cell death is caused when the hazardous compounds produced
in phase I surpass the organism’s ability to conjugate them via phase II (Figure 5) [127]. The
Toxics 2022, 10, x FORCYP1A enzymes produce a majority of the biotransformation products. Figure 5 shows the
PEER REVIEW 15 o
balance of activities of phase I and phase II enzymes, which define the type and effects of
the metabolites generated in the biotransformation process, as the process of detoxification
or toxification is depicted.
Figure 5. Schematic biotransformation processes result either in toxic or safe products.
Figure 5. Schematic biotransformation processes result either in toxic or safe products.
5.2. Cases for the Formation of Toxic TP

TPs formed by photoinduced degradation of carbamazepine (e.g., acridine, acrido
Toxics 2022, 10, 54 15 of 22
5.2. Cases for the Formation of Toxic TP

TPs formed by photoinduced degradation of carbamazepine (e.g., acridine, acridone)
have been evaluated for toxicity [128]. Toxic effects reached their maximum for Pseudokirch-
neriella subcapitata (P. subcapitata) and Vibrio fischeri (V. fischeri). Exposure of D. magna to
mixed TPs resulted in immobility after 45 min. Based on estimated EC50 , NOEC, and
LOEC, the EC50 for D. magna was 0.71 mg/L for acridine and 1.49 mg/L acridone, but the
NOEC value for carbamazepine was 30 mg/L for this species. Acridine was found to be the
most hazardous to algae (EC50 = 0.61 mg/L) and V. fischeri (EC50 = 5.34–6.90 mg/L) in the
experiments [128]. Grabarczyk et al. (2020) also found that carbamazepine-10,11-epoxide
was still harmful to diverse organisms compared to the parent. At 100 mg/L, the lumi-
nescence inhibition rate of V. fischeri by Carbamazepine-10,11-epoxide was 30%, whereas
the effect was 42% for carbamazepine. Lemna minor (L. minor) showed similar responses
to the epoxide TP and the parent at 50 mg/L (the epoxide inhibits growth by 32% and
carbamazepine by 49%). Both were critical to the growth of green algae (48 %). Similar
inhibitions were observed for R. subcapitata (15 %) and L. minor (11%) exposed to 10,11-
dihydro-10-hydroxycarbamazepine. On the other hand, for D. magna, both metabolites of
carbamazepine were ineffective, while 24% of the exposed species to the parent was found
to be immobilized [92].
Boillot et al. (2015) investigated the internal concentrations of carbamazepine and
oxcarbazepine-10-hydroxy-10,11-dihydrocarbamazepine in biota. After the exposure of
Mytilus galloprovincialis to the chemicals for a week, concentrations in media and biota
were measured and evaluated for bioconcentration. According to the evaluation, 10-
hydroxy-10,11-dihydrocarbamazepine showed slightly higher bioconcentration factors
than carbamazepine. Carbamazepine-10,11-epoxide and acridine accumulated in the
mussel following the exposure. Both chemicals were found in the digestive glands and gills.
Acridine was also detected in mantels and measured in digestive glands. This might imply
that metabolites can be accumulated in organisms due to direct uptake of the chemical
from the media and/or as a resultant of metabolization from the parent [129].
Similarly, carbamazepine was found in fish after 48 h of exposure in the study of Valdés et al.
(2016) [130]. The gills and muscle of J. multidentata contained 2-hydroxycarbamazepine (48 to
107 × 10−6 mg/g wet weight), while the epoxide TP (41 × 10−6 and 60 × 10−6 mg/g wet
weight) was also found. It is indicated that exposed organisms biotransform carbamazepine
and accumulate at similar concentrations. Another study provided information on the TPs of
β- blockers and their toxicity. The harmful effects of propranolol investigated on B. calyciflorus
and P. subcapitata exposed at concentrations from 1 and 10 mg/L. The findings for both species
demonstrated that the irradiated sample had a greater EC50 value (lower toxicity) than the
parent compounds at each stage of the experiment (6, 24, 48 h). During photolysis, the toxicity
was decreased by 1.8 to 3 times [131]. The opposite findings were observed in research of pho-
todegradation products of metoprolol and atenolol [132]. Their photo-TPs had a greater level of
toxicity than the parent compound. A significant increase in luminescence inhibition of V. fischeri
was seen after 16 and 32 min of metoprolol and atenolol irradiation (Toolaram et al. (2017)).
6. Challenges and Perspectives for TP Study

The TPs relevant literature has demonstrated a growing requirement for realistic
methodologies to examine the ecotoxicity of TPs. More research is required on the effects,
interactions, uptake, and translocation of TPs in organisms due to the rising manufacture
of pharmaceuticals, insecticides, and industrial chemicals (e.g., organophosphate flame
retardants). One of the main focuses of this review is on how NTS has been used in the
model organism, TPs pathway, and toxicity effects. In terms of the ecological consequences
of TPs, a number of studies revealed a wide range of outcomes showing increased or
reduced toxicity on model species. TP formations in biota are primary consequences of
phase I and phase II reactions after the parent molecule is introduced into the organism.
At this step, the parent chemical goes through numerous phases of oxidation, hydrolysis,
and enzymatic reaction, all of which might influence the TP structure and toxicity. The
Toxics 2022, 10, 54 16 of 22
transformation route has been found to enhance or reduce ROS production, survival rate,
and bioavailability of TPs in model organisms in previous research.
Furthermore, the hypothesized route has yet to be defined as having a direct influence
on the toxicological effects of TPs. Thus, more research should be carried out to determine
the impact of TPs. A reliable model must be developed to define and assess TPs with a live
organism. As a prerequisite, it is critical to identify as many TPs as possible with reliable
information on the chemical structures. Currently, most research relies on target screening
for identification, while a few studies have been performed on the unknown TPs using
NTS in the absence of reference standards. Even though the identification confidence is not
always reliable, efforts and trials to find novel TPs must be continued. As a helpful tool, the
software-aid approach can predict the transformation products and pathways [124–126].
In parallel, ecotoxicology investigations should also include NTS for their potential signifi-
cance in the characterization of unknown TPs and their toxicological consequences.
HRMS, combined with advanced hardware and software, has helped detect unknown
migrants from emerging contaminants. Since ESI is the most extensively utilized ionization
source, a significant trend toward using HRMS in LC for non-targeted analysis has been
noticed in recent years. The developing field of NTS is characterized by both a very compli-
cated scientific setting and a fundamental methodological framework. Each stage of the
process in this discipline presents considerable obstacles requiring analytical improvement.
Tissue samples need different methods and procedures for other environmental samples
such as water and sediments. Efforts to obtain improved consolidation and comparability
of data gathered from multiple studies, particularly for use in regulatory and policy sup-
port contexts, need a strict harmonization approach. However, to sustain its potential for
discovery and exploratory study, this expanding area needs a high degree of adaptability.
A combination of LC-HRMS and GC-HRMS is necessary to cover many EPs and their
numerous TPs, requiring high-level equipment and extensive technical competence.
On the other hand, to handle the complexity of NTS data, it is essential to use cutting-
edge computational tools, many of which are still in development. Furthermore, analytical
techniques combined with informatic skills must be practically implemented to expand
knowledge on TPs and characterize both TPs and the parent pollutants.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/

10.3390/toxics10020054/s1, Figure S1: The contaminants selected and their metabolites/TPs in
different EWW samples; Figure S2: The diagram of separation process of diclofenac and transforma-
tion product; Figure S3: (A) Schematic view for a closed-vessel MAE system and (B) Commercial
MAE instrument from Milestone and Carousel with 40 positions; Table S1 Summary for sample
extraction method.
Author Contributions: T.-Y.S.: Conceptualization, Investigation, Writing—Original review, Method-
ology, Validation, Visualization, Software. S.-Y.K.: Data curation, Formal analysis. D.-H.Y.: Data
curation, Formal analysis, Investigation. J.J.: Conceptualization, Funding acquisition, Project admin-
istration, Writing—Review & editing. All authors have read and agreed to the published version of
the manuscript.
Funding: This work was supported by the Korea Environment Industry and Technology Institute
(KEITI) through “The Chemical Accident Prevention Technology Development Project” funded by
the Korea Ministry of Environment (MOE) (project number: 2016001970002).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: As this a review article, the data supporting the results can be found in
the respective references in the manuscript.
Acknowledgments: Graphic design (2,3,5) supplemented by BioRender.
Conflicts of Interest: The authors declare no conflict of interest.
Toxics 2022, 10, 54 17 of 22
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1 Department of Environmental Engineering, Changwon National University,

Toxics 2022, 10, 54. https://doi.org/10.3390/toxics10020054 https://www.mdpi.com/journal/toxics

Toxics 2022, 10, 54 3 of 22

abiotic and biotic processes (e.g., photolysis, hydrolysis, microbial/enzymatic metabolism,

Positive Finding (%)

According to previous studies, sulfamethoxazole TPs accounted for up to 86% of

Figure 2. Contaminants andFigure 2. Contaminants

Table 2. Possible biologicalTable

Toxics 2022, 10, 54 6 of 22

Toxics 2022, 10, 54 8 of 22

• MassBank (http://massbank.ufz.de/MassBank/ accessed on: 1 December 2020); mz-

3.1. Sample Treatment and QA/QC

3.2. Sample Extraction for Non-Target Screening

3.2.1. Quick, Easy, Cheap, Effective, Rugged, and Safe

3.2.2. Microwave-Assisted Extraction

3.2.3. Pressurized Liquid Extraction

3.2.4. Ultrasonic-Assisted Extraction

4. Transformation Pathway in a Model Organism

4.2. Freshwater Crustaceans

4.5. Human Cell Lines

5. Toxicity Effect of TPs on the Model Organism

Figure 5. Schematic biotransformation processes result either in toxic or safe products.

Figure 5. Schematic biotransformation processes result either in toxic or safe products.

5.2. Cases for the Formation of Toxic TP

5.2. Cases for the Formation of Toxic TP

6. Challenges and Perspectives for TP Study

Supplementary Materials: The following are available online at https://www.mdpi.com/article/

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