Science of the Total Environment 841 (2022) 156593

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Science of the Total Environment

journal homepage: www.elsevier.com/locate/scitotenv

Ecotoxic effects of microplastics and contaminated microplastics – Emerging

evidence and perspective
Harveen Kaur a, Deepak Rawat a,b, Pankaj Poria a, Udita Sharma a, Yann Gibert c, Abdul Samath Ethayathulla d,
⁎ ⁎⁎ ⁎⁎⁎
Ludovic F. Dumée e,f, , Radhey Shyam Sharma a,g, , Vandana Mishra a,
a
Bioresources and Environmental Biotechnology Laboratory, Department of Environmental Studies, University of Delhi, Delhi 110007, India
b
Department of Environmental Studies, Janki Devi, Memorial College, University of Delhi, Delhi 110060, India
c
University of Mississippi Medical Center, Department of Cell and Molecular Biology, 2500 North State Street, Jackson, MS 39216, USA
d
Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India
e
Khalifa University, Department of Chemical Engineering, Abu Dhabi, United Arab Emirates
f
Research and Innovation Center on CO2 and Hydrogen, Khalifa University, Abu Dhabi, United Arab Emirates
g
Delhi School of Climate Change & Sustainability, Institute of Eminence, University of Delhi, Delhi 110007, India

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• 171 research studies on contaminated

microplastics were analyzed for global
distribution and ecotoxic impacts.
• Sorption-desorption dynamics govern the
bioavailability and toxicity outcome.
• Characteristics of MPs, co-contaminants
and test organisms affect the interaction.
• Despite high ecological relevance, toxicity
of contaminated MPs at population level is
least investigated.
• Ecotoxicological perspective with gaps
and priority areas of research provided.

A R T I C L E I N F O A B S T R A C T

Editor: Thomas Kevin V The high prevalence and persistence of microplastics (MPs) in pristine habitats along with their accumulation across
environmental compartments globally, has become a matter of grave concern. The resilience conferred to MPs using
Keywords: the material engineering approaches for outperforming other materials has become key to the challenge that they
Chemical interactions now represent. The characteristics that make MPs hazardous are their micro to nano scale dimensions, surface varied
Mixture toxicity
wettability and often hydrophobicity, leading to non-biodegradability. In addition, MPs exhibit a strong tendency to
Contaminant adsorption
Environmental relevance
bind to other contaminants along with the ability to sustain extreme chemical conditions thus increasing their resi-
Microplastic pollution dence time in the environment. Adsorption of these co-contaminants leads to modification in toxicity varying from ad-
ditive, synergistic, and sometimes antagonistic, having consequences on flora, fauna, and ultimately the end of the

Abbreviations: ALT, Alanine aminotransferase; AOX, Acyl-CoA oxidase; AST, Aspartate aminotransferase; ATP, Adenosine triphosphate; B[a]P, Benzo[a]pyrene; BDE-209, Decabromodiphenyl
ether; BHA, Butylated hydroxyanisole; BPA, Bisphenol A; CAT, Catalase; CPK, Creatine phosphokinase; DBP, Dibutyl phthalate; DDT, Dichlorodiphenyltrichloroethane; EROD, ethoxyresorufin-O-
deethylase; FOSA, Perfluorooctanesulfonamide; GABA, γ-aminobutyric acid; GGT, Gamma-glutamyl transferase; GPx, Glutathione peroxidase; GR, Glutathione reductase; GST, Glutathione S-
transferase; LDH, Lactate dehydrogenase; LPO, Lipid peroxidation; MPs, Microplastics; MRP, Multidrug resistance protein; MXR, Multi xenobiotic resistance; PA, Poly(amide); PAHs, Polycyclic
aromatic hydrocarbons; PBDE, Polybrominated diphenyl ether; PCBs, Polychlorinated biphenyls; PE, Poly(ethylene); PET, Poly(ethylene terephthalate); PFOS, Perfluorooctanesulfonate; PK,
Pyruvate kinase; PLA, Poly(lactic acid); POPs, Persistent organic pollutants; PP, Poly(propylene); PS, Poly(styrene); PVC, Poly(vinylchloride); ROS, Reactive oxygen species; SOD, Superoxide dis-
mutase; SSRI, Selective serotonin reuptake inhibitor.
⁎ Correspondence to: L.F. Dumée, Khalifa University, Department of Chemical Engineering, Abu Dhabi, United Arab Emirates.
⁎⁎ Correspondence to: R.S. Sharma, Bioresources and Environmental Biotechnology, Laboratory, Department of Environmental Studies, University of Delhi, Delhi 110007, India.
⁎⁎⁎ Correspondence to: V. Mishra, Bioresources and Environmental Biotechnology, Laboratory, Department of Environmental Studies, University of Delhi, Delhi 110007, India.
E-mail addresses: ludovic.dumee@ku.ac.ae (L.F. Dumée), rads26@hotmail.com (R.S. Sharma), mistletoe_h@hotmail.com (V. Mishra).

http://dx.doi.org/10.1016/j.scitotenv.2022.156593
Received 6 March 2022; Received in revised form 21 May 2022; Accepted 3 June 2022
Available online 9 June 2022
0048-9697/© 2022 Elsevier B.V. All rights reserved.
H. Kaur et al. Science of the Total Environment 841 (2022) 156593

food chain, human health. The resulting environmental fate and associated risks of MPs, therefore greatly depend upon
their complex interactions with the co-contaminants and the nature of the environment in which they reside. Net out-
comes of such complex interactions vary with core characteristics of MPs, the properties of co-contaminants and the
abiotic factors, and are required to be better understood to minimize the inherent risks. Toxicity assays addressing
these concerns should be ecologically relevant, assessing the impacts at different levels of biological organization to
develop an environmental perspective. This review analyzed and evaluated 171 studies to present research status
on MP toxicity. This analysis supported the identification and development of research gaps and recommended prior-
ity areas of research, accounting for disproportionate risks faced by different countries. An ecological perspective is
also developed on the environmental toxicity of contaminated MPs in the light of multi-variant stressors and directions
are provided to conduct an ecologically relevant risk assessment. The presented analyses will also serve as a foundation
for developing environmentally appropriate remediation methods and evaluation frameworks.

1. Introduction
The prevalence and persistence of plastics across various environmental
compartments, either in natural or man-managed ecosystems, are a major
global concern (González-Pleiter et al., 2020; Horton and Barnes, 2020).
Since the discovery of polymeric materials in the 1930s, plastics have be-
come ever stronger, lighter, more durable and cheaper, revolutionizing in-
dustrial processes and lifestyles (Geyer et al., 2017). Accordingly, the global
production and consumption of plastics increased to ~360 million metric
tons in 2018, resulting in a nearly equal annual amount of waste (Ian,
2021). Over 50 % of plastic wastes are either discarded or incinerated,
and only 20 % are being recycled (Geyer et al., 2017).
Depending on their size distribution, plastics can be classified as
macroplastics (>5 mm), microplastics (MPs) (0.1 μm–5 mm) and
nanoplastics (NPs) (<0.1 μm) (GESAMP Joint Group of Experts on the
Scientific Aspects of Marine Environmental Protection, 2015). MPs can
originate as primary or secondary materials. Various industries or effluents
directly dump MPs (primary MPs) as microfibrils and microbeads with dif-
ferent geometries depending on their applications as textiles, personal care
products, paint coatings, and vulcanized tire industries (Boucher and Friot,
2017). While secondary MPs are generated in the environment due to nat-
ural and anthropogenic degradation and fragmentation processes by phys-
ical or chemical forces (Enfrin et al., 2020a; Song et al., 2020, 2017).
Fragmentation increases the number, density, and concentration of MPs
in waterways, affecting all ecological niches over time (Eriksen et al.,
2014). Thus, industries concerning plastic materials such as packaging,
building, construction, or textile industry (Geyer et al., 2017) and wastewa-
ter treatment operations serve as a source of MPs diffusion into oceans
(Enfrin et al., 2019). Moreover, MPs fragmentation during wastewater
treatment also causes membrane fouling, decreasing the removal efficiency
and making most treatment processes inadequate or less efficient (Enfrin
et al., 2020b). Their ubiquitous spread is already adversely affecting fresh-
water, marine, and sewage water systems (Enfrin et al., 2021a). Thus, novel
treatment technologies are urgently required to reduce the burden of MPs/
NPs and limit their impacts on living organisms of surface and groundwater
(Enfrin et al., 2021b, 2021c).
Besides fresh and marine water, MPs have also been reported within liv-
ing organisms (Horton et al., 2017), and their adverse environmental and
health effects have been broadly demonstrated, particularly in aquatic or-
ganisms (Ahrendt et al., 2020; Choi et al., 2020; Yu et al., 2020a). Due to
their size range similar to many planktons and microalgae, aquatic organ-
isms, especially non-selective feeders, often confuse them as their prey
and ingest them (Pinheiro et al., 2020). These particles not only create a
sense of pseudo satiation (Barnes et al., 2009) but also translocate to vari-
ous organs, triggering immune responses, causing inflammation, and re-
ducing energy reserves (Wright et al., 2013). Although comparitively less
studied, the detrimental effect of MPs toxicity has also been reported in ter-
restrial organisms, such as weight reduction in earthworms and rats
(Huerta Lwanga et al., 2016), and inhibition of growth and reproduction
of soil springtail (Ju et al., 2019).
Due to their characteristic properties like hydrophobic nature, recalci-
trance, and small size, MPs particles may adsorb other contaminants, thus
serving as a cocktail of toxicants (Cole et al., 2011; Lee et al., 2021). This
enables them to act as vehicles for transferring contaminants across long
distances. Such physico-chemical interactions modulate bioavailability,
toxicity, and the pollution potential of the co-contaminants, exerting unpre-
dictable patterns of contaminated MPs (Vieira et al., 2021). The net out-
comes of interactions between MPs and co-contaminants may vary as
synergistic, seen as greater than predicted, antagonistic, seen as lesser
than predicted, and additive, seen as equal to predicted (Syberg et al.,
2015) (Fig. S1). MPs may further inhibit co-contaminant's degradation,
making them recalcitrant, increasing their concentrations and scaling up
their toxic potential (Ma et al., 2016).
Although MPs induce toxicity to flora and fauna, the current risk assess-
ment practices fail to capture the impact of contaminated MPs. Recent stud-
ies focusing on MPs interaction with other ubiquitous contaminants focus
on either a specific category of pollutants like persistent organic pollutants
(POPs) (Rodrigues et al., 2019), or describe the influence of underlying fac-
tors such as the characteristics of MPs or analyzed impacts of co-
contaminants and their ecotoxicological effects (Menéndez-Pedriza and
Jaumot, 2020). According to a recent review, toxicity from contaminated
MPs has become an emerging global concern, but it analyzed only 83 pub-
lications (Bhagat et al., 2021).
In contrast, the present review examined comprehensively 171 publica-
tions, including ~50 % published in 2020–2021 only. This review, there-
fore, presents a critical analysis of (i) the occurrence and nature of
contaminated MPs with different co-contaminants, (ii) the properties of
MPs and contaminated counter-parts governing net toxic effects, (iii) the
environmental factors governing the toxicity, and (iv) the diversity of test
organisms used in toxicity assays to date. A perspective on global health
concerns due to MPs mixture with other contaminants is developed, and a
framework of operation and best practices is proposed. This study demon-
strates the ecological relevance of contaminated MPs and identifies priority
areas of research to support emerging researchers and governmental
authorities.
2. Bibliometric analysis
2.1. Framing of questions, the survey of literature, and inclusion criteria
The prime objective of the review is to develop an understanding of the
toxicity posed by co-exposure of an organism to MPs and other contami-
nants. The outcomes of cumulative toxicity among contaminants were crit-
ically evaluated by ascertaining the ecological relevance of the current
research. A systematic and meticulous search of online databases includ-
ing., PubMed (https://pubmed.ncbi.nlm.nih.gov/), Scopus (https://www.
scopus.com/), Web of Science (https://apps.webofknowledge.com/) and
ScienceDirect (https://www.sciencedirect.com/) was carried out to re-
trieve relevant papers (till 10 June 2021) following the preferred reporting
items for systematic reviews and meta-analyses (PRISMA) guidelines
(Moher et al., 2015). Additional records were also identified by manually
scanning references given at the back of retrieved papers.
The inclusion criteria are specified as under (i) original articles pub-
lished in peer-reviewed journals, (ii) studies investigating the combined
toxic effect of MPs with other pollutants on a test organism, and (iii) studies
concerning the influence of MPs on bioaccessibility and bioaccumulation of

2
H. Kaur et al.
a contaminant in a test organism. The computer-based data extraction and
search methodology combined the search terms related to MPs and NPs and
the outcome of interest (toxicity, genotoxicity, cytotoxicity, teratogenicity
and phytotoxicity). Therefore, the following keywords were used with
‘microplastics’ or ‘nanoplastics’ along with the ‘AND’ operation - ‘syner-
gism’, ‘antagonism’, ‘mixture toxicity’, ‘combined effect’, ‘cumulative
effect’, ‘cumulative impact’, ‘additional toxic effect’, ‘joint effect’, ‘coupling
effect’.
2.2. Summarizing the findings and results
The data from mixture toxicity studies were analyzed to reveal global
spatio-temporal patterns, categories of co-contaminants, type of test organ-
ism, duration of the study, type of interaction between the contaminants,
and the ecological relevance of the studies (Table S1). Various factors af-
fecting cumulative toxicity were studied, and an evidence-based synthesis
was carried out.
To determine the ecological relevance, the research on MPs and co-
contaminants was analyzed according to different levels of biological orga-
nization assessed in the toxicity assays. To better visualize the possible in-
teractions between MPs and co-contaminants, heat maps were generated
based on the number of studies reporting synergistic, antagonistic or no-
interaction effects.
3. Ecotoxic potential of contaminated MPs: relevance of mixture
properties, environmental factors, and bioassays
The analysis of 171 research publications dealing with the cumulative
toxic impact of MPs and other contaminants is given in Table S1. Various
variables, including contaminant class, test organism classification, habitat,
experiment duration, MPs chemical type, MPs size, levels of biological orga-
nization investigated, and the net effect of mixture toxicity were analyzed.
The discussion is primarily divided into four parts, the first part with
Section 3.1 deals with the spatio-temporal distribution of the studies. The
second part, Section 3.2, analyzes the factors that influence the ultimate
toxicity. The third part, Section 3.3, includes the perspectives on global
health. The fourth part, Section 3.4, deals with the ecological relevance of
the studies analyzed.
3.1. Temporal and spatial distribution of studies
The analysis of spatio-temporal trends showed that 50 % of the total
studies (171) analyzing toxicity due to interaction of MPs and co-
contaminants were published in 2020–2021. With the growing concerns
of toxicity from contaminated MPs, the research on mixture toxicity has
witnessed exponential growth in the last seven years. This signifies that
MPs toxicity is one of the major contemporary issues requiring immediate
attention. More than 50 % of studies (90 studies) originated from China
(Fig. S2). Countries such as Portugal, Spain, the UK, the USA, the
Netherlands, Denmark, and Germany have investigated the ecotoxic poten-
tial of contaminated MPs. In contrast, most SE Asian and African countries
with high biodiversity regions are yet to undertake in-depth studies on
human health risks associated with contaminated MPs (Fig. S2). Mixture
toxicity associated risks in SE Asian countries need immediate attention be-
cause these countries serve as a hub of textile industries, releasing effluent
rich in primary plastics, plastic waste, and diverse inorganic and organic
contaminants (Rawat et al., 2016). Furthermore, the Asian, African and
Latin American countries are characterized by relaxed policies and legisla-
tion on monitoring and treating industrial effluent, thus enabling the re-
lease of untreated/partially treated industrial effluent in the environment,
carrying a high concentration of MPs and other contaminants. These find-
ings propound an urgent need to undertake environmental risk studies, es-
pecially in countries or areas with a high floral and faunal diversity and host
textile manufacturing industries.
Although the toxicity posed by MPs as sole contaminants has been com-
paratively well documented, the mixture toxicity of MPs has emerged as a
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Science of the Total Environment 841 (2022) 156593
concern only in the past decade (Fig. S2). Such studies received additional
impetus when Arenicola marina (lugworm) upon ingestion of MPs adhered
to polychlorinated biphenyls (PCBs) showed a high bioaccumulation of
contaminant mixture, decreasing survival rates up to 55 %, lowering feed-
ing rates up to 65 %, and reducing resilience to fight oxidative stress up to
30 % (Browne et al., 2013). Another study corroborated these findings and
showed that feeding and survival rates of lugworms decreased on ingestion
of contaminated MPs (Besseling et al., 2013). It may be noted that lug-
worms serve as a critical food source for coastal animals such as fish,
birds, and other worms (Besseling et al., 2013). In addition, lugworms in-
crease oxygen, reduce methane levels, and help sand transportation across
the beach environment (Timmermann et al., 2006; Volkenborn et al.,
2007). Therefore, alterations in these processes due to MPs-induced toxicity
in lugworms have adverse implications on biomass, biodiversity, and eco-
system functions, which are still underestimated. After realizing the unat-
tended aspects of mixture toxicity on biodiversity-related functions, the
research on absolute and cumulative impacts of MPs mixture toxicity has
gained momentum, resulting in an increased evidence on mixture toxicity
(Fig. S2).
3.2. Ecotoxicological fate of MPs: an outcome of intricate interactions among pol-
lutants and other factors
MPs, mostly present as a mixture of primary or secondary forms, are
subject to different interactions with other environmental chemicals
(Fig. S1). However, absorption and adsorption of co-contaminants onto
MPs coupled with bioavailability of co-contaminants determine the envi-
ronmental fate of MPs and ecotoxic potential of contaminated MPs
(Rodrigues et al., 2019).
As the resultant toxicity during assays is the net outcome of complex in-
teractions between MPs, co-contaminants, and organisms, the major deter-
minants influencing toxicity include (i) sorption kinetics and bioavailability
of contaminants, (ii) properties and characteristics of MPs, (iii) properties
and characteristics of co-contaminants, (iv) the test organism species, and
(v) environmental factors. Complex interactions among these factors dic-
tate the ultimate environmental fate of MPs along with their toxicological
implications. Understanding these interactions is vital for predicting envi-
ronmental risks, revealing the underlying toxicity pathways, and develop-
ing methods to alleviate MP toxicity in the environment.
3.2.1. MPs–Co-contaminants interactions: sorption kinetics and bioavailability
Absorption is driven by weak Van der Waals forces and mostly occurs at
high contaminant's concentrations. Low concentrations favor adsorption
and involve relatively strong forces like electrostatic and covalent besides
Van der Waals interactions (Menéndez-Pedriza and Jaumot, 2020;
Rodrigues et al., 2019). Non-polar MPs like PE and PP usually show electro-
static and Van der Waal interaction, whereas the polar MPs like PVC and PS
show hydrogen bonding and π-π interaction (Zhang et al., 2021d).
An in-depth understanding of the sorption mechanism between MPs
and co-contaminants using sorption isotherms and models is vital in
predicting the environmental outcome of the mixture toxicity. Depending
on the equilibrium sorption capacity and rate constant, sorption kinetics
can be measured as the first order, second order, pseudo-first order, and
pseudo-second order reactions. Various isotherm models provide a mecha-
nistic understanding of the type of interaction; however, the Freundlich and
Langmuir models are the most common for MPs (Fu et al., 2021). Due to dif-
ferences in the surface properties and structures, the various MPs polymer
types and co-contaminants show different sorption efficiencies. Sorption af-
finity to PAH and pyrene among different MPs followed the order PE > PS >
PVC. Moreover, a monolayer coverage followed pseudo-second order kinet-
ics, fitting the Langmuir isotherm model (Wang and Wang, 2018). The ad-
sorption of organic co-contaminants onto MPs is usually positively
correlated to their water-octanol partition coefficient, i.e., log (Kow) (Li
et al., 2018; Wang et al., 2018). However, other factors, such as size,
shape, polarity, pH, and temperature, also influence the sorption kinetics
(Fu et al., 2021; Marchant et al., 2022). For example, in the case of POPs,
H. Kaur et al.
Fig. 1. Heat maps showing synergistic, antagonistic or no interaction between (a) Polymer type and contaminant class (b) Polymer size and contaminant class (c) Duration of
experiment and Polymer type and (d) Duration of experiment and contaminant class (the intensity of color is directly proportional to the number of studies; and the grey
colored boxes indicate the areas not studied). Syn, ant and add represent synergistic, antagonistic and additive effects, respectively.
the Freundlich isotherm model was a better fit for the sorption dynamics
and had little influence of environmental factors like salinity (Bakir et al.,
2014). Hydrophobic interactions have been reported as the dominant
type of bonding in the case of POPs (Wang et al., 2020a-e). In the case of
cyanotoxins like microcystin LR, the sorption was negatively correlated
with the particle size and had little effect due to pH and salinity
(Hyenstrand et al., 2001; Moura et al., 2022). Smaller-sized MPs showed
higher adsorption of the cyanotoxins (Moura et al., 2022). Depending
upon the sorption affinity and dynamics, changes in bioavailability of co-
contaminants take place, i.e., a contaminant that was earlier freely avail-
able in the surrounding medium now gets adsorbed onto MPs. This leads
to a decrease in its ambient concentration and hence a reduction in the
bioavailability of contaminant. Moreover, these will not be available for
toxicological interactions until desorption takes place. Thus, sorption-
desorption dynamics mediate the toxicity of MPs, co-contaminants, or
mixtures (Marchant et al., 2022).
Bioavailability refers to the fraction of a chemical available for biological
interactions within an organism or the fraction of a chemical in an environ-
mental matrix that may be absorbed or metabolized by living organisms. In
contrast, bioaccessibility refers to only that fraction of a contaminant avail-
able for assimilation. Besides the soil-plant-food chain as a route of contami-
nant transport, bioaccessibility also considers contamination routes, such as
inhalation, skin contact, and the direct ingestion of contaminated soil parti-
cles. While bioavailability refers to the amount of co-contaminant available
for the sorption-desorption process, bioaccessibility refers to the amount of
co-contaminant available for metabolism in the living organism after the
sorption process.
Biological effects of contaminants in an organism are a net outcome of
their bioavailability. The net effect of contaminants on different levels of bi-
ological organization reflects the bioavailable fraction of contaminants and
sensitivity of cells, organs, species, and population; bioavailability serves as
a promising tool in risk assessment. However, bioavailability remains a
complex concept because it results from a diverse interaction between con-
taminant, media and organism type, target organs, and metabolism.
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Science of the Total Environment 841 (2022) 156593
Consequently, evaluation methods of bioavailability have been developed
while considering physico-chemical properties of contaminants or media
(soil, water, air) or target organisms and the metabolic processes operating
in target organs.
In the case of MPs-sorbed contaminants, the bioavailability of contami-
nants is significantly governed by a series of mass transfer processes and
sorption-desorption dynamics, which are bound to differ due to environ-
mental factors such as pH, temperature and moisture, and properties of
the environmental matrix (Sleight et al., 2017). Environmental factors
also influence the behavior of organisms interacting with contaminated
MPs. Consequently, bioavailable fractions of a target contaminant are
assessed by (i) chemical assays (e.g., extraction methods), and (ii) biologi-
cal assays to monitor effects by exposing organisms to contaminated
water, soil or soil eluates. In either case, assessing exposure and measuring
effects remains critical.
Physico-chemical methods have been widely used to estimate the bio-
availability of different contaminants, but their application is limited when
contaminants are present in low concentrations. In such conditions, high-
performance liquid chromatography (HPLC), ultra-high-performance liquid
chromatography (UPLC), and gas chromatography (GC) have been highly ef-
ficient in detecting bioavailable contaminants in low concentrations (Li et al.,
2020a, 2020b, 2020c, 2020d, 2020e). However, physico-chemical methods
are mostly supplemented with biological assays. For example, ultra-high-
performance liquid chromatography and electrospray tandem mass spec-
trometry (UHPLC-MS) were supplemented with estimating uptake rate and
concentration bioaccumulated to detect the bioavailability variations BPA
in the presence of MPs (Chen et al., 2017). Liquid chromatography-mass spec-
trophotometry (LC-MS) and acute toxicity tests have also been used to mea-
sure bioavailable nonylphenol in contaminated MPs (Beiras et al., 2019).
Accumulated polychlorinated biphenyls (PCBs) were estimated along with
the solid-water distribution coefficient (Beckingham and Ghosh, 2017). Sim-
ilarly, bioaccumulated co-contaminants were estimated in different body
parts to measure their bioavailable concentrations (Chua et al., 2014;
Oliveira et al., 2018). In another case, the reduction in free carbon of
H. Kaur et al. Science of the Total Environment 841 (2022) 156593

polycyclic aromatic hydrocarbons (PAHs) supplemented with mortality and
body burden analysis was used to estimate PAHs' bioavailability on co-
exposure with MPs (Sørensen et al., 2020). As an indirect method, alterations
in biomarkers may also be sufficient for gauging the bioavailability of a well-
characterized contaminant in a model or target organism. For example,
changes in bioavailability were measured through changes in gene expression
of Cyp1a and vtg genes (Granby et al., 2018; Sleight et al., 2017). Mathemat-
ical models like the weight of evidence (WOE) models have also been em-
ployed for estimating hazard indices based on variations in values of
different biomarkers (Avio et al., 2015).
3.2.2. MPs - properties and characteristics
MPs vary in their chemical composition and physical properties,
i.e., size, shape, color, aging, etc. (Gunaalan et al., 2020). These properties
alter their interactions with co-contaminants, causing direct and indirect
toxicological concerns due to the mixtures.
3.2.2.1. Size of MPs. Size and exposed surface area drive the sorption pro-
cess of MPs with the co-contaminant (Ateia et al., 2020). Large-sized MPs
have a low surface area and thus lower number of sites available for adsorp-
tion of co-contaminants (Ašmonaitė et al., 2018). In contrast, small-sized

Fig. 2. Relative proportion of studies reporting synergistic/antagonistic/additive effects of mixture toxicity (MPs mixed with other contaminants) classified according to
a) MP size and type b) Co-contaminant's chemical nature and categories c) Target organism's habitat, classification and in vitro systems used d) experimental design's test
system and duration.

5
H. Kaur et al.
MPs, having a high surface-to-volume ratio, have increased opportunities
for interaction with co-contaminants, increasing the toxic potential of mix-
tures (Guo et al., 2020; Ma et al., 2019). However, smaller-sized particles
may tend to aggregate at high concentrations, reducing the surface-to-
volume ratio and decreasing contaminants' sorption (Wang et al., 2019b;
Zhang et al., 2021b). The 171 studies classified based on the size range of
MPs (1–100 μm, >100 μm, 100–1000 nm, and 1–100 nm) showed syner-
gism as the most common outcome of its interaction with co-
contaminants followed by antagonistic and additive effects (Figs. 1 & 2a).
Although most mixture toxicity studies have focused on MPs (83 %), specif-
ically 1–100 μm (63 %), the recent studies show that NPs are far more toxic
than MPs (Kang et al., 2021; Tang et al., 2020a).
It is reported that small-sized NPs (50 nm) exerted an additive effect to
toxicity from phenanthrene, a co-contaminant, whereas MPs (10 μm) did
not have any significant effects (Ma et al., 2016). Several studies corrobo-
rated the varying influence of the size of MPs on mixture toxicity. It is
shown that although both MPs/NPs show synergistic impacts, the NPs
showed substantially higher accumulation and toxicity in a mixture with
POPs (González-Soto et al., 2019; Jeong et al., 2018). Smaller-sized MPs
(0.5 μm) caused greater DNA damage than larger-sized ones (4.5 μm)
(González-Soto et al., 2019). Exacerbated enlargement of liver and gonads
was observed in zebrafish when co-exposed with triphenyl phosphate and
46 nm Poly(styrene) - PS NPs, but it was comparatively lesser with 5.8
μm PS MPs (He et al., 2021). Moreover, NPs on exposure to benzo[a]pyrene
(B[a]P) and 17β-estradiol mixture showed higher toxicity as compared to
MPs (Tang et al., 2020a). Small-sized (100 nm) PS NPs had higher toxicity
on Chlamydomonas reinhardtii as compared to large-sized (5 μm) PS NPs
(Dong et al., 2021a). However, adsorption of nonylphenol increased with
the decrease in the particle size of MPs, resulting in lower combined toxicity
due to reduced bioavailability of co-pollutants (Yang et al., 2020b).
Also, 1 μm PS MPs and antibiotic roxithromycin showed a stronger syn-
ergistic effect on Daphnia as compared to 10 μm PS MPs (Zhang et al.,
2019a). In contrast with additive and antagonistic effects of size, the
NPs and MPs mixed with other contaminants lacked any significant
difference in their toxicity to lettuce, although toxicity due to co-
contaminants was enhanced in both the cases (Gao et al., 2021). How-
ever, in the case of phenanthrene it was seen that 150 μm PS MPs had
a greater toxic influence than 17 μm PS MPs (Zhang et al., 2021b).
Thus, besides size, other factors such as composition and surface modi-
fications of MPs also play major roles in facilitating the sorption of other
contaminants onto MPs (Zhang et al., 2021d).
3.2.2.2. Types of MP polymer. Marine ecosystems serve as a reservoir of di-
verse MPs and organic contaminants. PS, Poly(ethylene) - PE, Poly(propyl-
ene) - PP, and Poly(vinyl chloride) - PVC are the most common MPs found
in marine ecosystems (de Haan et al., 2019). Surface properties of MPs
change with their chemical composition and dictate the ultimate toxicity
as the sorption capacity varies with polymer types (Hüffer and Hofmann,
2016).
Due to large free volumes available in amorphous rubbery polymers, in-
cluding PE and PP, organic contaminants quickly diffuse and get absorbed
into these polymers (Hartmann et al., 2017). However, glassy polymers,
such as Poly(ethylene terephthalate) - PET, PS and PVC, absorb co-
contaminants poorly but efficiently with low diffusivity (Hüffer and
Hofmann, 2016; Li et al., 2020b). Being highly hydrophobic, PE, PP, and
PS have high affinities for high ring polyaromatic hydrocarbons (PAHs)
than low ring ones (Honda and Suzuki, 2020). Due to the slow diffusion of
pollutants in high-density plastics, PE and PVC sorb perfluorooctanesulfonate
(PFOS) and perfluorooctanesulfonamide (FOSA), significantly higher than PS
(Wang et al., 2015). Therefore, PE and PP act as nucleation particles in
aquatic ecosystems to concentrate the contaminants and cause more signifi-
cant health risks to marine organisms than PET and PVC (Agboola and
Benson, 2021; Rochman et al., 2013a, 2013b; Rochman et al., 2017). How-
ever, PS and PVC with highly condensed and cross-linked structures adsorb
other contaminants strongly and release them slowly (diffusion coefficient =
10−13–10−14 cm2 s−1) as compared with PE (diffusion coefficient = 10−10
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Science of the Total Environment 841 (2022) 156593
cm2 s−1) (Teuten et al., 2007), which can be a matter of concern in the
long run.
A wide variety of MPs occur in nature, but studies are limited to only a
few (Figs. 1 and 2a). PS and PE are the most widely studied MPs and
showed a comparatively greater number of synergistic interactions
(Figs. 1 and 2a). The mixture toxicity of MPs with triclosan followed the
order PE < PVC < PS indicating different hydrophobicity and adsorption ca-
pacity due to the difference in their composition influenced the combined
toxicity (Zhu et al., 2019). Poly(lactic acid) - PLA MPs increased the bio-
availability of Cadmium (Cd) more than PE MPs (Wang et al., 2020b).
Even the same polymer with varying functional modifications exerts differ-
ential toxicity. For example, carboxyl modified PS (PS-COOH) showed
higher toxicity than virgin PS due to anionic carboxyl groups (Kim et al.,
2017). In another study, the carboxyl modified, and non-functionalized
PS showed synergistic toxicity on algae Scenedesmus and zebrafish Danio
rerio (Liu et al., 2019) but the amine modification on PS (PS-NH2) caused
an antagonistic effect. With surface modifications MPs vary in surface
charge; for example, PS-NH2 confers net negative charge to MPs and is re-
sponsible for greater dispersibility due to electrostatic repulsion causing an-
tagonistic effects (Chen et al., 2020). Also, it was seen that antagonistic
interactions were more evident in PVC and PA (Figs. 1 and 2a). PVC MPs
were shown to alleviate Arsenic (As) toxicity in earthworm Metaphire
californica (Wang et al., 2019) and copper (Cu) nanoparticle toxicity in
microalgae Skeletonema costatum (Zhu et al., 2020) but had little effect on
Cd uptake in mussels Mytilus edulis (Li et al., 2020a). Interestingly, in the
case of aquatic plant Vallisneria natans, PVC MPs along with Cd inhibit
growth rate synergistically (Wang et al., 2021). Moreover, many studies fo-
cused on a red polymer type of unknown composition, limiting the predict-
ability of final research outcomes (Figs. 1 and 2a). Very few studies focused
on mixture toxicity of other polymer types, thus, demanding more research
attention.
3.2.2.3. Weathering, aging, and color of the polymer. As discussed earlier,
macroplastics fragment into MPs with time. This fragmentation and
weathering of MPs leads to decreased molecular weights, surface modifica-
tions, and altered morphology (Kalogerakis et al., 2017; ter Halle et al.,
2017). For example, PVC developed an uneven irregular surface with age,
exposing the hydroxyl group and aromatic C_C bond; such chemical
changes conferred the aged microcellular PVC (mPVC) higher growth inhi-
bition than virgin mPVC (Fu et al., 2019; Wang et al., 2021). An increase in
oxygen-containing functional groups, especially carboxyl groups, was also
seen (Hanun et al., 2021). Carbonyl index, specifying the degree of degra-
dation of the polymer, also increased with aging time (Liu et al., 2021c).
Biofilm formation on MPs further increased its surface area and enhanced
its potential to adsorb pollutants (Rummel et al., 2017). Also, aged MPs
caused significantly higher oxidative stress and triggered differential gene
expression than the non-aged ones (Cheng et al., 2020; Ho et al., 2020).
Moreover, it is suggested that salinity may increase the aging rate by generat-
ing more porous surfaces with an increased surface for adsorption (Hanun
et al., 2021). Aging of MPs increased the accumulation of antibiotic propran-
olol by 82.3 % in the brain of red tilapia (Oreochromis niloticusas) but allevi-
ated toxicity due to lipid peroxidation (Huang et al., 2021b). Prolonged
aging due to UV exposure further increased the specific surface area and
surface roughness of MPs (Wang et al., 2020e). Therefore, weathering or
aging affects the chemical composition of MPs and influences their toxicity
potential (Liu et al., 2020). Investigating accelerated weathering effects on
the chemical composition of MPs using ATR-FTIR would help identify the
chemical and physical properties of antifouling MPs.
The exposed surface area and toxic potential of MPs also vary with
shape. Most of the reviewed studies (90 %) investigated the toxicity of reg-
ular microbeads, ignoring other shapes like fibers, fragments, pellets, etc.
Moreover, the source of MPs i.e. whether they were virgin MPs or if they
were isolated from personal care products like facial scrubs (Chua et al.,
2014; Wardrop et al., 2016) or isolated from coastal areas and beaches
(Frias et al., 2013; Pannetier et al., 2019b) may also influence the results
of toxicity interaction due to differences in their surface area. Further, it
H. Kaur et al.
is quite possible that the color of the MPs may also influence their ultimate
toxicity. For example, polymer samples collected along the Portuguese
coast showed that aged yellow and black plastics pellets sorb PCB and
PAH in high concentrations than the colored and white ones. In contrast,
pesticide – Dichlorodiphenyltrichloroethane (DDT) concentration was sim-
ilar in black and white but higher in aged ones (Antunes et al., 2013; Frias
et al., 2010). Long residence time increased the sorption of contaminants
onto MPs surface, while degradation enhanced specific surface area that
further increased sorption (Liu et al., 2021c). However, high sorption of
other contaminants such as B[a]P on black colored plastics may be due to
pigments added to plastics or plant and animal pigments adhered to plastics
(Frias et al., 2013; Fries et al., 2013).
3.2.2.4. Concentration of MPs during exposure. The concentration of MPs,
i.e., the amount in which MPs are present, also influenced the toxicity of
the mixtures. For example, PS resin pellets with arsenic (As) showed a syn-
ergistic toxic effect at higher concentrations of MPs (0.2 g/L), whereas PS at
low concentrations (0.04–0.1 g/L) exerted an antagonistic toxic effect on
rice plants (Dong et al., 2020) and algae (Zhang et al., 2018). Similar results
were obtained in Daphnia and marine algae Tetraselmis chuii. A low concen-
tration of red fluorescent MPs (0.02 mg/L) and gold nanoparticles (0.2
mg/L) leads to antagonistic interaction, whereas a higher concentration
of these MPs (0.2 mg/L) leads to a synergistic interaction (Davarpanah
and Guilhermino, 2019; Pacheco et al., 2018). Low concentration of PE
MPs (2 μg/L) had an antagonistic effect on teratogenicity and lethality
caused by phenanthrene, but higher concentrations (20 and 200 μg/L)
had an additive effect on marine fish Oryzias melastigma (Li et al., 2020c).
These findings were corroborated in a terrestrial plant, Triticum seedlings;
when grown in soil contaminated with a mixture of phenanthrene and arti-
ficially aged low-density PE MPs, phenanthrene accumulation is reduced in
wheat tissues with a simultaneous increase in shoot height. However, shoot
height is significantly reduced at >5 % MPs (Liu et al., 2021a,b). Similarly,
in the aquatic plant Salvinia cucullata, a PSMPs and glyphosate mixture
showed synergism with the yellowing of leaves and increased oxidative
stress (malondialdehyde levels), at >15 + 20 mg/L (Yu et al., 2021). One
plausible explanation is that MPs at low concentrations serve as a sink for
co-contaminants by active adsorption. This phenomenon is responsible
for decreasing the co-contaminant bioavailability, whereas if present at
higher concentrations, MPs themselves may cause significant toxicity
masking the lowered toxicity of the co-contaminant (Lin et al., 2019; Shi
et al., 2021). Antithetically, MPs at 20 mg/L remain antagonistic to dibutyl
phthalate (DBP) induced toxicity, while at 5 mg/L fail to significantly im-
pact cumulative toxicity (Li et al., 2020d). It is suggested that the
aggregation-both homo-aggregation and hetero-aggregation led to a de-
crease in bioavailability of MPs and DBP, decreasing the cumulative toxic-
ity (Li et al., 2020d).
3.2.3. Surface contaminants - properties and characteristics
MPs facilitate the transfer of various co-contaminants to the organisms,
acting as ‘Trojan horses’ (Cole et al., 2011; Syberg et al., 2015). The co-
pollutants in the reviewed studies were classified as either organic, inor-
ganic, or organometallic based on their chemical structures. The various
co-pollutants showed differences in their impacts; for example, PS with in-
organic metal oxide nanoparticles exerts a synergistic effect, whereas with
organic PAH it causes an antagonistic effect (Singh et al., 2021).
Organic contaminants include PAH, POPs, pesticides, pharmaceuticals,
and plastic additives (Fig. 2b). 9 PAH, 7 POP, 10 pesticides, 21 pharmaceu-
ticals and 10 plastic additives (Table 1) have been analyzed for mixture tox-
icity exposure to different target organisms. Majority of these studies
showed synergistic interaction. Antagonistic interactions of MPs with pesti-
cides and POPs have also been reported in a few studies (Figs. 1 and 2b),
and have been attributed to an initial decrease in bioavailability of co-
pollutants due to their adsorption onto MPs (Bartonitz et al., 2020;
Bringer et al., 2021; Dolar et al., 2021; Garrido et al., 2019; Liu et al.,
2021a,b). PAHs are the most widely studied organic pollutants (Fig. 2b).
Bisphenol A (BPA), which serves as a precursor of plastics and dibutyl
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Science of the Total Environment 841 (2022) 156593
phthalate (DBP), a plasticizer, has also been widely investigated while
assessing the mixture toxicity (Chen et al., 2017; Dong et al., 2021b; Li
et al., 2020e; Tang et al., 2020b; Wang et al., 2020c). As an additive, BPA
enhances plastic products' durability, elasticity, and transparency, and it
has been reported in aqueous and terrestrial environments and organ-
isms/animals. BPA causes several developmental and reproductive abnor-
malities, but its toxic effects are amplified when present with MPs (Chen
et al., 2017; Mathieu-Denoncourt et al., 2015). Along with the structure,
the net outcome of mixture toxicity may also vary with the concentration
of co-contaminants. For example, MPs (10 mg/L) with low DBP concentra-
tion (0–1 mg/L) produced an antagonistic effect, whereas, with high DBP
concentration (3.5–8.5 mg/L), the resultant toxicity was synergistic (Li
et al., 2020d).
MPs dispersion in different environmental compartments is unknown to
a large degree. However, transport and fate models and sorption/desorp-
tion isotherms have been used to estimate and predict the dispersion of
MPs in air, groundwater, freshwater, stormwater, and sea. However, hydro-
logic models need to be calibrated, whereas soil models still need due atten-
tion, although dispersion in the soil is slower. Polymer properties, such as
its crystallinity, elasticity, and hydrophobicity, govern the MPs dispersion
in the environment. Besides physical characteristics of MPs (density,
shape, and size), environmental processes, such as aeolian, hydrologic
and fluvial processes, significantly affect dispersion. Dispersion of MPs in
aquatic ecosystems is also influenced by physico-chemical properties of
water, especially pH and salinity, besides coexisting estrogens.
Metals, heavy metals, and nanoparticles mainly represent inorganic co-
pollutants (Figs. 1 and 2b). Metallic ions have a high adsorption capacity for
MPs, which is further increased by surfactant films (Lee et al., 2021).
Twelve metals and heavy metals along with 6 nanoparticles have been stud-
ied. Differential toxicity was observed even in the same class of co-
pollutants. The presence of MPs led to an increase in the bioavailability of
Zn and Cd (Zhou et al., 2020) in earthworms, but the risk was insignificant
in the case of Zn as it is an essential metal and was thus regulated by the
metabolic processes (Hodson et al., 2017). Similarly, no significant effect
of cadmium was observed in mollusk Mytilus sp. when co-exposed with
PVC MPs (Li et al., 2020a). However, cadmium toxicity was alleviated by
PSNPs in the wheat plant (Lian et al., 2020). Even in the case of inorganic
co-pollutants, synergistic interactions dominated.
The third category includes organometallic compounds like triphenyltin
and tributyltin. Only 3 studies assessing their impact on mixture toxicity
were available (Yi et al., 2019b, 2019a; Yoon et al., 2021). More attention
needs to be given to these compounds to understand their toxicity interac-
tion better.
3.2.4. Test organisms - characteristics
The choice of the test organism has a significant impact on the net out-
come of mixture toxicity. In reviewed toxicity assays, most studies used
aquatic organisms (138 studies) with nearly equal representation of fresh-
water (69 studies) and marine organisms (60 studies) (Fig. 2c). Although
mixing MPs with other contaminants is primarily a common feature of
aquatic ecosystems, the growing evidence from agroecosystems (Khalid
et al., 2020; Ya et al., 2021) emphasizes on analyzing terrestrial ecosys-
tems/organisms. The 171 studies involved diverse test organisms
(Figs. 2c and 3) most of which were animals, followed by algae and
flowering plants. 12 algal species and 5 plant species were investigated.
Among animals, chordates (102 studies) formed the dominant group, repre-
sented primarily by 16 species of fish, followed by 13 species of mollusks
and 11 species of arthropods (Table 1). 4 annelids, 2 nematodes, and a ro-
tifer were also studied.
Mostly small aquatic animals, known for their sensitivity to environ-
mental change, such as Daphnia magna (Ma et al., 2016; Yin et al., 2020),
Caenorhabditis elegans (Dong et al., 2018; Qu et al., 2019b), copepods (Li
et al., 2020e; Syberg et al., 2017), zooplanktons (Almeda et al., 2021;
Rehse et al., 2018) and bivalves (Bringer et al., 2021; Parra et al., 2021)
were considered. Antagonistic interaction was better pronounced in
small-sized organisms, especially arthropods (Chua et al., 2014; Rehse
H. Kaur et al. Science of the Total Environment 841 (2022) 156593

Table 1
List of co-contaminants and test organisms used in toxicity assays.
Pesticide Pharmaceuticals POP

Pyrene Paraquat Gemfibrozil Sulfamethoxazole PCB

Benzo(a)pyrene Dimethoate Furosemide Triclosan PBDE
Fluoranthene Glyphosate Fluoxetine Carbamazepine DDT
Phenanthrene Chlorpyrifos Metformin Florfenicol PFOS
17α-ethinylestradiol Chlortoluran Acetaminophen Cefalexin PFOA
17β-estradiol Atrazine Sertraline Procainamide PFOSA
9 Nitroanthracene Deltamethrin Tetracycline Doxycycline F-53B
Complex PAH mixture Dufulin Ciprofloxacin Venlafaxine
3Nitrobenzanthrone Triphenyltin Ibuprofen Roxithromycin
Tributyltin Triclocarban Propranolol

Nanoparticles Heavy metals Additives Others

Copper Copper Bis-2-ethylhexyl phthalate Nonylphenol

Gold Silver Bisphenol A(BPA) Microcystin LR
Silver Zinc flame retardants Ammonium
Zinc oxide Nickel Dibutyl phalate (DBP) Natural acidic organic polymer
Copper oxide Mercury Phathalate esters
Titanium dioxide Chromium Benzophenone 3
Arsenic Tetrabromobisphenol A
Lead Triphenyl phosphate
Gold Butylated hydroxyanisole
Manganese

Arthropoda Mollusca Annelida Plantae Algae

Allorchestes compressa Corbicula fluminea
Artemia sp. Lymnaea stagnalis
Daphnia magna Chlamys farreri
Nephrops norvegicus Crassostrea brasiliana
Acartia tonsa Crassostrea gigas
Acartia clausi Mactra veneriformis
Porcellio scaber Mytilus coruscus
Calanus hyperboreus Mytilus edulis
Gammarus roeseli Mytilus galloprovincialis
Tigriopus japonicus Perna canaliculus
Drosophila Ruditapes philippinarum
Scrobicularia plana
Arenicola marina Oryza sativa Microcystis aeruginosa
Lumbricus terrestris Lactuca sativa Chlamydomonas reinhardtii
Metaphire californica Triticum sp. Ochromonas Danica
Eisenia fetida Zea mays Scenedesmus obliquus
Enchytraeus crypticus Vallisneria Tetraselmis chuii
Salvinia cucullate Chlorella pyrenoidosa
Daucus carota Dunaliella salina
Phaeodactylum tricornutum
Skeletonema costatum
Raphidocelis subcapitata
Chlorella vulgaris

Pisces Rotifera Nematoda Bacteria

Clarias gariepinus Misgurnus anguillicaudatus Brachionus koreanus Meiobenthic nematode Thermophilic bacteria
Ctenopharyngodon idella Oncorhynchus mykiss Caenorhabditis elegans Escherichia coli
Cyprinus carpio Oreochromis niloticus Mammalia Aves In vitro system
Danio rerio Oryzias latipes Mus musculus Fulmarus glacialis Fish gut model
Dicentrarchus labrax Oryzias melastigma Seabird Human gut model
Hippocampus kuda Pomatoschistus microps Fish cell line
Lates calcarifer Prochilodus lineatus Human cell line
Melanotaenia fluviatilis Symphysodon aequifasciatu

et al., 2018) and algae (Fu et al., 2019; Garrido et al., 2019; Zhang et al.,
2018) owing to their high susceptibility to toxic chemicals like pharmaceu-
ticals, POPs and PAHs (Fig. 3). Among the higher organisms, small-sized
zebrafish was widely used as choice species in toxicity assays (Yang et al.,
2020a; Zhao et al., 2020) in addition to those which are mostly consumed
as commercial seafood, such as Asian seabass, Lates calcarifer (Guven
et al., 2018), European seabass, Dicentrarchus labrax (Barboza et al.,
2018b, 2018c) and Norway lobster, Nephrops norvegicus (Devriese et al.,
2017). Moreover, the life stage of the target organism also plays a major
role in deciding the toxicity outcome. Juveniles are more sensitive to the ef-
fect of chemicals like PAH and POP, and thus the initial decrease in the bio-
availability due to their sorption onto MPs produced an antagonistic
response (Beiras et al., 2019; Miranda et al., 2019; Santos et al., 2021b;
Sleight et al., 2017; Zhang et al., 2021a–d). Thus, MPs serve as a vehicle
for different contaminants in aquatic organisms and modulate the toxicity
potential of co-contaminants, such as POP and PAHs.
Most studies used in vivo toxicity assays, which have limited ecological
significance because they are conducted in controlled laboratory conditions
whereby organisms spend little energy searching for food and maintaining
homeostasis, making the results difficult to interpret in the natural environ-
ment. Microcosm, mesocosm, and field studies have high ecological
significance while predicting ecotoxicological impact (Wakkaf et al.,
2020) (Fig. 2d). A field study investigated the impact of ingested MPs
from the stomach of a bird, northern fulmar, to assess correlations with tis-
sue POP concentrations (Herzke et al., 2016) but found little effect of MP's
presence. Nevertheless, such studies are limited in number and therefore re-
quire more attention. Although few studies on cell lines were available,
most of them showed synergistic toxicity (Almeida et al., 2019; Bussolaro
et al., 2019; Huang et al., 2021a; Pannetier et al., 2019b; Wang et al.,
2020c). No significant effect of MPs was witnessed when the modelling
study was carried out using the single-compartment model - OMEGA (Opti-
mal Modelling for EcotoxicoloGical Applications) (Bakir et al., 2016). In
vitro studies using fish and human gut models concluded that MPs could in-
troduce labile contaminants like heavy metals into the organisms and thus
provide an additional route of exposure (Khan et al., 2017; Liao and Yang,
2020).
3.2.5. Environmental factors
Since environmental factors like the temperature, pH, salinity, and or-
ganic matter affect sorption-desorption kinetics between adsorbent (MPs)
and adsorbate (other contaminants), these factors determine mixture prop-
erties, including their bioavailability and toxicity (Wang et al., 2020f). Still,

8
H. Kaur et al.
Fig. 3. Heat maps reporting synergistic antagonistic or no-interaction effects between (a) Test system and contaminant type and (b) Test system and polymer type (Note: The
intensity of color is directly proportional to the number of studies, and the grey colored boxes indicate the areas not studied. Syn, ant, and add represent synergistic,
antagonistic, and additive effects, respectively).
very few studies focused on analyzing these parameters while determining
MPs interaction with co-contaminants and their impact on subsequent tox-
icity.
The pH of the environment can influence whether the co-contaminant
will adsorb onto MPs, reducing the former's concentration in the surround-
ing environment or if it will get desorbed, thereby increasing its concentra-
tion, bioavailability, and ecotoxic potential. For example, metal sorption
increased with increasing pH (Ahechti et al., 2020), reducing the environ-
mental impact at high pH. Also, the effect of pH was more significant on
electrostatic interactions of PS and PE (adsorbent) with PFOS (adsorbate)
but not with the neutral FOSA (Wang et al., 2015). In a microcosm study,
acid rain and MPs showed additive toxic effects on garden cress Lepidium
sativum seedlings (Pignattelli et al., 2021). Also, exposure to contaminated
soil with a mixture of ZnO nanoparticles and MPs (PE MPs and PLA MPs)
increased the soil pH, altering the nutrient translocation to the plants and
mycorrhizal fungi (Yang et al., 2021).
Temperature is also a determinant of the mixture toxicity of MPs and or-
ganic contaminants. For example, log KPE-W of PAHs (B[a]P, chrysene,
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Science of the Total Environment 841 (2022) 156593
fluoranthene, phenanthrene, pyrene) increased with change in temperature
from 18 to 24 °C but decreased slightly at 30 °C having a major influence on
its mixture toxicity with MPs (Kolomijeca et al., 2020). Another study
showed that co-exposure to antibiotic cefalexin and MPs caused higher tox-
icity due to lipid peroxidation when the temperature was increased from 20
°C to 25 °C (Fonte et al., 2016). Similarly, increasing temperature favored
the synergistic toxicity of MPs with ammonium and reduced Daphnids sur-
vivability (Serra et al., 2020). However, the role of temperature in the
partitioning of chlorobenzene, PAHs, PCBs, and DDT on plastics remains
questionable (Lohmann, 2012). Although temperature and pH were re-
ported as the most important factors driving MP-contaminants interactions,
these factors have been under-investigated as determinants of mixture tox-
icity.
Salinity affects the partitioning of contaminants by neutralizing the sur-
face charge of MPs and lowering the effect of electrostatic interactions dur-
ing sorption, leading to salting out of contaminants from MPs (Liu et al.,
2019). With increasing salinity up to ~34 %, the PCBs sorption was en-
hanced (Velzeboer et al., 2014), but another study showed that increasing
H. Kaur et al.
salinity (from 10 to 35 %) resulted in the aggregation of NPs, which re-
duced the sites for adsorption (Wu et al., 2019). PFOS failed to sorb on PS
particles in pure water, whereas the sorption was effective in highly saline
conditions (Wang et al., 2015). However, salinity increased PFOS sorption
on PE but not FOSA (Wang et al., 2015). Since marine and freshwater eco-
systems differ mainly in salinity, the impact of salinity on the nature of in-
teraction needs more attention. Moreover, it becomes pertinent to
understand salinity-induced partitioning of MPs and co-contaminants in en-
vironmental compartments because highly saline industrial effluent will
promote the adsorption of co-contaminants onto MPs. Also, the low saline
physiological conditions of living organisms will cause the desorption of
contaminants from MPs surface, triggering many toxic effects (Velzeboer
et al., 2014; Wu et al., 2019). Although synergistic interaction of MPs
with PAHs and POPs has been reported in marine and freshwater habitats,
it was more pronounced in marine organisms (Fig. 4). However, synergistic
effects of PS-MPs were notable in freshwater organisms as compared with
marine ones suggesting a major influence of pH and salinity on sorption-
desorption processes and thus the ecotoxicity (Fig. 4).
Organic matter also dictates the toxicity outcome. It was shown to facil-
itate Cu adsorption on MPs followed by its accumulation in the gut and liver
of zebrafish, resulting in oxidative stress and increased cumulative toxicity
(Qiao et al., 2019). Another study also showed increased toxicity and oxida-
tive stress when a natural acidic organic polymer (NAOP), fumic, and
humic acid were combined with PS-COOH, whereas decreased oxidative
stress in PS-NH2 MPs (Liu et al., 2019).
Earlier exposure to environmental contaminants also affects the toxicity
outcome. The juveniles of common goby (Pomatoschistus microps), which
were taken from the Minho River estuary, were less sensitive to exposure
Fig. 4. Heat maps reporting synergistic antagonistic or no-interaction effects
between (a) Habitat and Contaminant class, and (b) Habitat and Polymer type
(Note: the intensity of color is directly proportional to the number of studies, and
grey colored boxes indicate the areas not investigated).
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Science of the Total Environment 841 (2022) 156593
to PE microspheres and chromium as compared to those taken from the
Lima river estuary of the Iberian peninsula in Europe for the same dose
and duration of exposure (Luís et al., 2015). Similarly, great pond snail
Lymnaea stagnalis was shown to be resilient to the effects of both, Poly
(amide) PA MPs and POP mixture and PS MPs and Cu co-exposure
(Horton et al., 2020; Weber et al., 2021).
Duration of combined exposure is another factor determining the syner-
gistic or antagonistic effects of mixtures (Figs. 1 and 2d). In the acute toxic-
ity studies, synergistic and antagonistic effects were reported in nearly
equal proportion (Figs. 1 and 2d). However, with the increase in the dura-
tion of toxicity assays, the synergistic effects dominated, and ambiguity in
toxicity outcomes decreased. For example, PCBs bioavailability increased
after 40 days of co-exposure with PE-MPs and led to a synergistic toxic ef-
fect on European Seabass (Granby et al., 2018). The toxicity of MPs
mixed with silver (Ag) ions to E. coli remained antagonistic during the ini-
tial 24 h of assays but turned into synergistic after 48 h of exposure (Sun
et al., 2020). No significant effect of PS-MPs was observed on co-exposure
with pesticides dimethoate and deltamethrin in a 72 h study on Daphnids
(Horton et al., 2018). Similarly, no effect of MPs was observed in 48 h co-
exposure study with 4-nonylphenol on sea urchin larvae (Beiras and Tato,
2019). A 96 h study on Daphnia also showed antagonistic interaction with
Bisphenol A and PA MPs on account of the decreased body burden of the
former. Accumulation of PAH phenanthrene increased with the duration
of exposure in zebrafish (Xu et al., 2021). Even with reduced accumulation,
the same effect was observed with 9-Nitroanthracene (Zhang et al., 2021a–
d). PS-MPs mixed with pharmaceuticals, such as triclosan, methyl triclosan,
and triclocarban lacked any effect on cumulative toxicity to neonates in the
initial 48 h. However, after 21 days of co-exposure, it turned into a synergis-
tic effect (Yin et al., 2020), indicating that the duration of co-exposure is
one of the most important factors dictating combined toxicity (Fig. 1). Sim-
ilar results were obtained in Daphnia where little or no effects of MPs with
glyphosate were observed in the initial 48 h but increased with the duration
of co-exposure up to 168 h (Zocchi and Sommaruga, 2019). Loach
(Misgurnus anguillicaudatus) exposed to MPs, and antidepressant
venlafaxine showed increased bioaccumulation of the latter after 40 days
of combined treatment (Qu et al., 2019a). The synergistic effect of MPs
when co-exposed with heavy metals on enzyme activities increased with
the duration of co-exposure in seahorse, Hippocampus kuda (Jinhui et al.,
2019). Another long-term exposure study spanning 90 days showed a syn-
ergistic effect of organophosphorus flame retardants with MPs on mice
(Deng et al., 2018). Therefore, biosorption/desorption dynamics of co-
contaminant vary with the exposure time that ultimately governs the syner-
gistic/antagonistic effect of contaminant mixtures. MPs tend to adsorb co-
pollutants during the initial phase of co-exposure, whereas depending on
the co-pollutant, the desorption leads to an increase in toxicity.
3.3. Perspective on global health concern due to MPs-contaminants mixture
Three possible pathways of interactions between MPs and co-
contaminants have been visualized, and their implications on exposure to
and effects on living organisms have been proposed (Menéndez-Pedriza
and Jaumot, 2020). First, living organisms already have a high body load
of contaminants ingest MPs, which is relevant while evaluating the impact
of clean MP ingestion by humans (Aljerf and AlHamwi, 2018). Many stud-
ies showed that ingestion of clean plastic in diet might reduce bioaccumu-
lation of other contaminants. However, the contaminant sequestering
potential of MPs varies with plastic-type. For example, 10 % poly(ethane)
in the diet reduces the body burden of pollutants by 20 % due to high sorp-
tion capacity (Gouin et al., 2011), whereas feeding PE MPs to rainbow fish
did not affect PCBs burden (Rummel et al., 2016). Examining ingestion of
clean MPs by humans from bottled mineral water or packaged food and
its effect on the body burden of pollutants would be a paradigm shift in im-
proving human health. However, following the precautionary principle, it
might be advisable to prevent intake of any persistent and xenobiotic con-
taminant at any concentration, even if suggested as beneficial for any pur-
pose. Moreover, it is even suggested that MPs mixture may lead to
H. Kaur et al.
physical toxicity, especially skin irritation in addition to the chemical toxic-
ity that causes respiratory, cardiovascular, and digestive disorders
(Atugoda et al., 2021; Carbery et al., 2018).
The second pathway includes uptake of contaminant-loaded MPs in the
body by organisms lacking any prior exposure. In several studies, organisms
feeding on MPs loaded with pollutants show increasing bioconcentration
and bioaccumulation of pollutants (Granby et al., 2018; Sheng et al.,
2021). Such cases become relevant in countries or cities where
(i) industries release untreated effluents that carry both primary MPs and
a high concentration of contaminants or (ii) industrialization has just
begun, and the human population is not yet exposed to pollutants. In
most developing counties, environmental regulations either ignore testing
specific pollutants while discharging industrial effluents in the environ-
ment or lack strict implementation (Onydinma et al., 2021). Consequently,
human exposure to MP-loaded with co-contaminants is expected to be very
high, and physiological conditions of the gut accelerate desorption and
bioconcentration of chemical contaminants (Liao and Yang, 2020). For ex-
ample, feeding seabass with MPs carrying pollutants reduces its ability to
remove pollutants significantly compared with when the feed carries pol-
lutants alone (Granby et al., 2018). In addition, tissues and organs show dif-
ferential bioaccumulation of MPs; for example, the presence of NPs
enhances BPA bioaccumulation in the head and viscera of zebrafish,
while BPA concentrations in gills and muscles remain insignificant (Chen
et al., 2017). In mollusks, the gills were more sensitive to MPs and pharma-
ceutical carbamazepine and PAH fluoranthene than the digestive gland
(Brandts et al., 2018; Magara et al., 2018). Moreover, seafood contami-
nated with MPs acts as an additional route of exposure and poses serious
concerns for human health (Danopoulos et al., 2020; Smith et al., 2018;
Thiele et al., 2021; Vital et al., 2021). This is especially true for organisms
eaten whole, like the fish and the bivalve mollusks (Dawson et al., 2021).
Even in cases where the whole organism is not eaten, MPs contamination
in the edible parts needs to be analyzed (Daniel et al., 2021). These obser-
vations draw attention to undertake an assessment of mixture toxicity in
human tissues and organs and evaluate the associated health risks.
Third pathway includes living organisms already having a high load of
MPs and further ingesting pollutant-loaded MPs, which is likely to be prev-
alent in most third world countries hosting dirty industries and serving the
developed countries for the last few decades (Rawat et al., 2016). In devel-
oping countries, partially treated or untreated industrial effluents are being
released into the environment due to a lack of infrastructure accompanied
by ill-drafted or poorly implemented environmental policies. In addition,
occupational hazards to industrial workers are very high due to poor infra-
structure and lack of safety conditions. Furthermore, most studies have
shown that MPs in industrial wastewater discharged into water bodies
(Enfrin et al., 2019) pose high risks to humans, especially in Asian and
African countries where peri-urban communities often use waterbodies as
a source of drinking water for themselves and their livestock. The impact
of mixture toxicity on human health appears to be far greater than expected
in the emerging economies, such as India, China, and Bangladesh, serving
as the global hub of polluting industries and carry the world's highest bur-
den of disease and suffering from the highest number of pollution-related
deaths (Fuller et al., 2022). However, these emerging toxicants have still
not received due attention, especially in human cell lines studies and pro-
spective research on populations living in the vicinity of these industrial
sites is still needed.
Ingestion of MPs loaded with contaminants further increases bioaccu-
mulation of co-contaminants in living organisms, even in highly polluted
settings. For example, plastic ingestion and bioaccumulation of
polybrominated diphenyl ethers (PBDEs) in fish were positively correlated
with enhanced accumulation of lower chlorinated PCB congeners
(Besseling et al., 2013). Similarly, MPs were found not only to serve as a
source of PBDEs but also to be a cause of enhanced bioaccumulation in ab-
dominal adipose tissue in seabirds (Tanaka et al., 2013). However, a few
studies reported the lack of an increase in silver (Ag) uptake with PE inges-
tion in zebrafish (Khan et al., 2015). Similarly, no relationship was found
between the ingestion of MP sorbed with hydrophobic organic compounds
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such as PCB, BPA and alkylphenols and their bioaccumulation in arthro-
pods (Devriese et al., 2017). Such ambiguity appears to be a result of im-
mense variability in experimental conditions.
In the environment, MPs are also expected to enhance the bioavailabil-
ity and bioaccessibility of emerging pollutants like pharmaceuticals and
flame-retardants (Yu et al., 2020b) despite being present at significantly
low concentrations. For example, Benzophenone-3, which is used as a UV
stabilizer in personal care products, was more bioavailable and showed syn-
ergistic effects with PE pellets on Daphnia magna (Na et al., 2021). Although
research on mixture toxicity has looked at the toxic effects of drugs adhered
to MPs, most studies have tested the effects of antibiotics with some studies
on pain-relieving drugs such as acetaminophen or ibuprofen (Wang et al.,
2020a–f), anti-diabetic medicines, including metformin (Almeida et al.,
2019), cardiac drugs such as procainamide or propranolol (Prata et al.,
2018). Furthermore, most studies have assessed toxicity in fish, and
mollusks (Guo et al., 2021; Han et al., 2021; Nobre et al., 2020; Webb
et al., 2020), arthropods and algae giving less attention to effects on higher
animals.
Most of the early studies proposed MPs as a source of organic and inor-
ganic pollutants in aquatic ecosystems, interacting with co-pollutants and
triggering toxicity in freshwater and marine organisms. However, recent
studies project these assumptions far from reality because MPs are gener-
ally present in extremely low concentrations; therefore, MPs might not be
a significant competitor of dissolved organic matter for sequestering and
partitioning co-contaminants. Although recent studies reported significant
sequestration of co-contaminants on MPs, prospective long-term studies
on populations residing in hotpots of MPs contamination would help estab-
lish a link between MPs mixture and its adverse impacts on human health
and wildlife.
3.4. Ecological relevance of mixture toxicity studies
Toxicity studies on contaminated MPs were evaluated for ecological rel-
evance based on the level of ecological hierarchy investigated in the study,
i.e., molecular, cellular, organ, organismic, and population (Fig. 5a). Most
toxicity studies investigated one (56) or two (75) ecological levels; how-
ever, only a few studies evaluated three (29) or four (10) levels, with the
least number of studies analyzing five levels. A decreasing order from or-
ganismic (123) > cellular (108) > molecular (52), >organ toxicity (28)
was followed in toxicity studies reviewed. Only 32 studies assessed toxicity
at the population level, whereas studies on community or higher levels are
completely lacking, signifying little ecological relevance of toxicity studies
carried out so far (Fig. 5a).
Pollutant toxicity varies with ecological level; for example, PS combined
with decabromodiphenyl ether (BDE-209) lacks any impact on a molecular
level but causes high toxicity at the cellular level (Xia et al., 2020). Simi-
larly, MPs and PAH F-53B mixture in zebrafish exert an antagonistic re-
sponse at organismic levels while causing synergistic oxidative damage at
cellular levels (Yang et al., 2020a). Another study on adult zebrafish with
MPs and B[a]P showed synergistic toxicity at the cellular level but antago-
nistic at the population level (Batel et al., 2018). Similarly, heavy metals
(Cd, Pb, Zn) and PS NPs cause synergistic toxicity at molecular and organ-
ismic levels but negligible effects at the population level in brackish water
medaka (Yan et al., 2020). To sum up, the current evaluation provides an
ecological perspective for future investigations on mixture toxicity.
3.4.1. Molecular toxicity
Molecular toxicity involves changes in the biomarkers at the subcellular
level. These include alteration of gene expression, damage or breakage of
DNA, and micronuclei formation (Fig. 5b).
The genes primarily altered by MPs toxicity include oxidative stress and
inflammation-related genes, detoxification-related genes, neurotoxicity
and immunotoxicity-related genes, reproductive function-related genes,
etc. (Table 2). MPs have been suggested as an oxidative stressor causing
changes in gene expression of antioxidant defense enzymes - superoxide
dismutases, catalases, glutathione S-transferases, etc. (Dong et al., 2018;
H. Kaur et al.
Fig. 5. (a) Bar diagram showing the relative proportion of studies using assays at different levels of biological organization in 171 mixture toxicity studies with their ecological
relevance, and (b) List of assays and their endpoints under the different class of toxicity assays and their ecological relevance conducted in 171studies (Note: The arrowhead
indicates increasing ecological relevance of the assay).
Li et al., 2022; Paul-Pont et al., 2016). In the case of MPs co-exposure with
heavy metals and pharmaceuticals, enrichment of metal and antibiotic re-
sistance genes was observed (Liu et al., 2022; Ma et al., 2020b, 2020a).
Therefore, MPs biofilms serve as an ideal site for promoting the evolution
of microbial communities tolerant to diverse contaminants via genetic ex-
change. Co-exposure of MPs with antibiotics may also generate stress, evi-
denced by the upregulation of heat shock proteins (hsp70) (Cheng et al.,
2020). Changes in gene expression of these heat shock proteins also sig-
nifies disturbances in the homeostatic mechanism (Gu et al., 2020).
Metallothioneins (mt1 and mt2) and cytochrome P450 (cyp1a) genes are
commonly involved in the detoxification of metals and other xenobiotics,
respectively (Cormier et al., 2019; Lu et al., 2018; Santos et al., 2021b,
2021a). Compromised reproductive success can be witnessed with PAH
phenanthrene through a decrease in gene transcription of reproductive hor-
mones - a gonadotropin-releasing hormone, GnRH, and fushi tarazu-factor,
ftz-f1 (Karami et al., 2016). POP contaminated MPs also caused endocrine
disruption evident from decreased expression of choriogenin (Chg H), vitel-
logenin (Vtg I), and estrogen receptor genes (Erα) (Rochman et al., 2014).
An early indication of neurotoxicity during co-exposure with BPA was sig-
naled with changes in gene expression of acetylcholinesterase (AChE), my-
elin basic protein (mbp), α1-tubulin and mesencephalic astrocyte-derived
neurotrophic factor (manf) (Chen et al., 2017).
Molecular toxicity also includes testing for genotoxicity. It is usually
measured in terms of DNA damage through the Comet assay. Clam
Scrobicularia plana exposed to MPs and B[a]P showed significant breaks
in DNA strands, whereas treatments with PFOS failed to cause any DNA
damage (O'Donovan et al., 2018). Increased DNA damage in hepatocytes
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Science of the Total Environment 841 (2022) 156593
and erythrocytes was seen in teleost Prochilodus lineatus with PE MPs and
copper (Roda et al., 2020), whereas an additive effect was observed in scal-
lops after exposure to PS MPs with BDE-209 (Xia et al., 2020) and PS NPs
with zinc oxide nanoparticles (Estrela et al., 2021b). An increase in the fre-
quency of micronuclei appearance after treatment with pyrene-
contaminated PS MPs is another indication for molecular toxicity (Avio
et al., 2015). It was also reported in Mediterranean Mussels,Mytilus
galloprovincialis exposed to B[a]P contaminated MPs (Pittura et al., 2018).
Toxicity assays at the sub-cellular level have the lowest ecological rele-
vance because sub-cellular changes may or may not have implications at
the population level. Also, linking sub-cellular changes with any change
at population level is a challenge due to the very long time it might take
to manifest these sub-cellular changes at the population level. Although
the sensitivity of endpoints at the sub-cellular level varies and it requires
testing at multiple endpoints to ensure reliable results (Brandts et al.,
2018; Cheng et al., 2020), sub-cellular assays form a basis for toxicity test-
ing at a higher level of biological organization (Rawat et al., 2016) because
alterations at sub-cellular level provide an early indication of toxicity
(Granby et al., 2018).
3.4.2. Cellular toxicity
Cellular toxicity can be measured through both, in vivo and in vitro cel-
lular assays and has been given considerable attention (105 studies)
(Fig. 5a). Analysis of cytotoxicity includes parameters like cell viability,
cell composition and phagocytosis, lipid peroxidation (LPO), chlorophyll
damage, glucose, triglycerides, Adenosine triphosphate (ATP) and choles-
terol levels, oxidative stress or reactive oxygen species (ROS) production;
 Table 2
Details of studies on contaminated MPs and key results at different level of biological organization.
Biological Microplastic Co-contaminant Test organism Effect Reference
H. Kaur et al.

organization
level
analzyed

Molecular PS NPs-100 nm Phthalate esters Human alveolar cell line – A549 Upregulation of gene expression of proinflammatory cytokines-IL6, IL8, TNFα at high Shi et al., 2021
concentration of NPs, downregulation at low concentration
PS NPs-50 nm Gold ions Zebrafish (Danio rerio) embryos Upregulation of gene expression of proinflammatory cytokines-IL6, IL8 Lee et al., 2019
PS, PS-NH2, Triphenyl phosphate Medaka (Oryzias melastigma) MPs normalized gene expression of inflammatory, eye development and photoreception genes Zhang et al.,
PS-COOH 1 μm larvae 2021a–d
PS NP-108 nm Titanium dioxide nanoparticles Nematode Caenorhabditis elegans Upregulation of oxidative stress related genes-sod2, sod3, skn1 Dong et al., 2018
PE 125–250 μm PCB and PBDE mixture European seabass (Dicentrarchus Downregulation of detoxification related genes-cyp1a1, gstα Granby et al., 2018
labrax)
PS −5 μm Cadmium Zebrafish (Danio rerio) adult Upregulation of metal detoxification related genes and inflammatory response related genes-mt1, mt2, tnfα, il1b Lu et al., 2018
and ifng1–2, downregulation of oxidative stress related genes-sod1, sod2, nfe212
PA, PVC-30 μm Tetracycline Enchytraeus crypticus Increase in antibiotic resistance genes Ma et al., 2020a,
microbiome 2020b
PE 3 mm PCB and PBDE mixture Japanese medaka (Oryzias Downregulation of estrogen receptor related genes Rochman et al., 2014
latipes)
PE 11–13 μm Benzo[a]pyrene (BaP) and Clam Scrobicularia plana Increased DNA damage with BaP, No significant effect with PFOS O'Donovan et al., 2018
Perfluorooctane Sulfonic acid (PFOS)
PE <100 μm PAH pyrene Mussels Mytilus Increased micronuclei frequency during co-exposure Avio et al., 2015
galloprovincialis
Cellular PS, PA, PE150μm, 13 Nonylphenol Microalgae Chlorella pyrenoidosa Increased activity of antioxidant enzymes-SOD, CAT, MDA, LPO and ROS production Yang et al., 2020b
μm, PA-13 μm
PS −500 nm, 30 Sertraline Mollusk Tegillarca granosa Reduced total haemocyte count, phagocytosis, pyruvate kinase activity and increased MDA caspase 3 activity Shi et al., 2020
μm
PS-20 μm, 65 nm Butylated hydroxyanisole (BHA) Zebrafish (Danio rerio) adult Alteration of thyroid hormones - decrease in T3 and increase in T4 Zhao et al., 2020

13
Red MPs 1–5 μm Doxycycline and Procainamide Microalgae Tetraselmis chuii Reduction in chlorophyll content Prata et al., 2018
PE MPs 23 μm Di-n-butyl phthalate (DBP) Lettuce Reduced chlorophyll content and increased activity of antioxidant enzymes-SOD, Gao et al., 2019
CAT, GSH-Px, APX, MDHAR, DHAR, and GR
PS 0.05, 0.5, 6 μm BDE-47, triclosan Rotifer Brachionus koreanus Increased ROS, MDA decreased activity of p-glycoprotein and multidrug resistance protein calcein Jeong et al., 2018
PS 30 μm PAH mixture Blood clam Tegillarca granosa Decreased haemocyte viability and phagocytic activity Sun et al., 2021a
Organ PE 45–53 μm Phthalate esters Male mice Increased intestinal inflammation Deng et al., 2021
system PS 46 nm, 5.8 μm Triphenyl phosphate Zebrafish (Danio rerio) adult Enlargement of liver and gonads He et al., 2021
PS 2–6 μm PAH fluoranthene Mussels Mytilus Histopathological lesions in gills, gonads and digestive tract Paul-Pont et al.,
2016
PE 125–250 μm POP mixture Zebrafish (Danio rerio) Increased vacuolisation in liver Rainieri et al., 2018
PS 21–466 μm Chlorpyrifos Rainbow trout (Oncorhynchus Altered histopathology and histomorphometry of gills, gut and skin Karbalaei et al., 2021
mykiss) juvenile
Red MP 1-5 μm Copper Zebrafish (Danio rerio) embryos Epithelial detachment in brain Santos et al., 2020
PE 23 μm Di-n-butyl phthalate (DBP) Lettuce Decrease in root growth parameters - length, root hair, root diameter Gao et al., 2021
Organismic PVC 230 μm POP and PAH mixture Lugworm Arenicola marina Decrease in feeding and survival rate Browne et al., 2013
PE 7–250 μm Triclosan Acartia tonsa Increase in mortality Syberg et al., 2017
PA 13–19 μm PBDEs Pond snail Lymnaea stagnalis Alteration in the microbiome structure Horton et al., 2020
Red MP 1–5 μm Mercury Fish Dicentrarchus labrax Decrease in swimming speed and resistance time Barboza et al., 2018c
juvenile
MPs 40–50 μm Dufulin (pesticide) Earthworm (Eisenia fetida) Increased bioccumulation of co-exposed pesticide Sun et al., 2021b
PE, PLA 100–154 μm Cadmium Maize plant Increased bioavailibilty of cadmium in soil, little effects on plant at low conc., decreased plant growth at higher conc. Wang et al., 2020b
PS 20 nm Silver nanoparticles Algae Chlamydomonas reinhardtii Decrease in levels of growth parameters Huang et al., 2019
and Ochromonas danica.
Population PE 2–10 μm Chlorpyrifos (pesticide) Copepod Acartia tonsa Decreased egg production and egg hatching Bellas and Gil, 2020
PS 0.05 μm Crude oil Rotifer Brachionus koreanus Delayed reproduction Jeong et al., 2021
PS 70 nm Microcystin LR Zebrafish (Danio rerio) Accumulation of MPs in F1 larvae, increased malformations and decreased hatching rate Zuo et al., 2021
PP, PS 600 μm Benzo(a)pyrene Japanese medaka (Oryzias Decreased hatching and increased malformations Pannetier et al., 2019b
latipes)
PS 101 nm Microcystin LR Nematode Caenorhabditis Decreased brood size Qu et al., 2019b
elegans
Science of the Total Environment 841 (2022) 156593
H. Kaur et al.
enzyme activities: acetylcholinesterase (AChE), glutathione S-transferase
(GST), ethoxyresorufin-O-deethylase (EROD), superoxide dismutase
(SOD), catalase (CAT), and lactate dehydrogenase (LDH) (Table 2).
Antioxidant enzymes like SOD and CAT form the first line of defense
against oxidative burst (Winston and Di Giulio, 1991). In C. pyrenoidosa
algal cells, oxidative stress, seen as the enzymatic expression of MDA,
SOD, and CAT, was alleviated when NPs were present along with
nonylphenol (Yang et al., 2020b). However, MPs with selective serotonin
reuptake inhibitor (SSRI) sertraline showed synergistic cytotoxic effects in
blood clam, T. granosa affecting the lipid metabolism and causing increased
oxidative stress in terms of increased levels of ROS, LPO, Adenosine triphos-
phate (ATP), cortisol, and pyruvate kinase (PK) (Shi et al., 2020). The de-
toxification process was also altered, resulting in increased levels of the
neurotransmitters - acetylcholine (ACh) and γ-aminobutyric acid (GABA),
which caused immunomodulation (Shi et al., 2020). Antagonism in the ac-
tivity of enzyme cholinesterase (Che), Glutathione S-transferases (GST) and
LPO levels were observed in bivalve Corbicula fluminea on co-exposure to
MPs and mercury (Oliveira et al., 2018).
Moreover, the enzyme activities showed organ specificity. For example,
SOD, CAT, GST, glutathione peroxidase (GPx), and glutathione reductase
(GR) activities showed an additive effect in gills, but synergism along
with the additional impact on the liver of juvenile Dicentrarchus labrax
(Barboza et al., 2018a). Similarly, the synergistic interaction of MPs and
Cd was seen in gills and gonads, but an additive effect was observed in
the digestive gland (Parra et al., 2021). LPO and AChE activities were
also increased on co-exposure with mercury signaling neurotoxicity and ox-
idative damage (Barboza et al., 2018b). In marine mussels, increased bio-
availability and cytotoxicity of pollutants have been demonstrated using a
wide range of cellular markers, such as antioxidant enzymes including
CAT, glutathione peroxidases, reductases and transferases, acyl-CoA oxi-
dase (AOX), LPO, total oxyradical scavenging capacity (TOSC), a latency
period of lysosome (LP), and lipofuscin and the frequency of neutral lipids
(Avio et al., 2015).
Exposure to a mixture of pesticide paraquat and MPs increased activities
of aspartate aminotransferase (AST) and alanine aminotransferase (ALT),
LDH and creatine phosphokinase (CPK) (Nematdoost Haghi and Banaee,
2017). However, gamma-glutamyl transferase (GGT) activity and the con-
centration of plasma glucose, creatinine, total protein, albumin, and globu-
lin were decreased, signifying functional imbalance in the organs. After co-
exposure to MPs and cadmium (Cd) in European bass Symphysodon
aequifasciatus, innate immune responses were triggered evident by the ex-
acerbated levels of enzymes lysozyme, acid phosphatase, and alkaline phos-
phatase (Wen et al., 2018). Zebrafish showed developmental deformities
and altered levels of thyroid hormones triiodothyronine (T3), thyroxine
(T4), and thyroid-stimulating hormone (TSH) after co-exposure to MPs
and butylated hydroxyanisole (BHA) (Zhao et al., 2020).
In algae and plants, decreased chlorophyll content is taken as a measure
of cellular toxicity (Gao et al., 2019). Reduced chlorophyll content in ma-
rine alga (Tetraselmis chuii) confirmed the synergistic toxicity due to co-
exposure of MPs with local anesthetic and antibiotic, procainamide, and
doxycycline, respectively (Prata et al., 2018). When co-exposed to PE MPs
and DBP, decreased photosynthetic rate, stomatal conductance, and tran-
spiration rate were observed in lettuce (Gao et al., 2019). Similarly, MPs
and heavy metals reduced chlorophyll contents in the microalga Chlorella
vulgaris (Tunali et al., 2020). Antithetically, an antagonistic effect was ob-
served in Chlorella pyrenoidosa and Microcystis aeruginosa when challenged
with MPs co-mixed with ibuprofen and Pb, respectively (Wang et al.,
2020a–f; Wang et al., 2021b). Freshwater alga Raphidocelis subcapitata ex-
perienced negligible toxicity due to PS-COOH NPs and Cu (Bellingeri
et al., 2019), but an antagonistic effect was observed in microalgae
Skeletonema costatum and microalgae Dunaliella salina when in combination
with antibiotic tetracycline and ZnO particles respectively (Feng et al.,
2020; Gunasekaran et al., 2020).
The expression of selected biomarkers also provides a mechanical in-
sight into the underlying cellular toxicity pathways. For example, induction
of multi xenobiotic resistance (MXR) caused by P-glycoproteins (P-gps) and
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Science of the Total Environment 841 (2022) 156593
multidrug resistance proteins (MRPs) is suggested as the probable underly-
ing mechanism of NPs-induced synergistic toxicity in rotifers (Jeong et al.,
2018). It is also suggested that the phagocytic activity of cells may be ham-
pered due to alteration in NFκB signaling pathway, which in turn may also
hinder the hematopoiesis (Sun et al., 2021a). Understanding such responses
may help mitigate toxicity, but these have not been given due importance.
3.4.3. Organ level toxicity
Organ toxicity provides better insights into bioconcentration and bioac-
cumulation of co-contaminants and the level of energy reserves in target or-
gans, such as the liver, gills, and stomach (Fig. 5b). Comparatively, fewer
studies exist on organ toxicity as the differentiation into organ systems ex-
ists only in higher animals.
Different species show differential organ toxicity due to the accumula-
tion of contaminants and MPs. In common goby Pomatoschistus microps,
pyrene metabolites accumulated in the bile (Oliveira et al., 2013), whereas
virgin and contaminated MPs accumulated in gills, hemolymph, and diges-
tive glands (Avio et al., 2015). Accumulation of MPs in gills and digestive
glands of mussel, Mytilus sp. corroborated the MP vector effect for mercury
(Rivera-Hernández et al., 2019). Severe histopathological lesions like he-
mocyte infiltration and the presence of ceroids were observed in digestive
glands, gills, and intestine of mussels Mytilus sp. due to co-exposure to fluo-
ranthene and PS MPs (Paul-Pont et al., 2016). PE MPs and phthalate esters
caused increased inflammation of the intestine and changes in gut mi-
crobiota (Deng et al., 2020a). Increased vacuolization was observed in
the livers of zebrafish fed with contaminated MPs (Rainieri et al.,
2018). Maximum histopathological alterations in gills and gut were ob-
served in rainbow trout when they were co-exposed to MPs and pesti-
cide chlorpyrifos (Karbalaei et al., 2021). The toxic response varies
even within the same organism. Severe hyperplasia was observed in
the gills of African catfish, Clarias gariepinus, upon exposure to
phenanthrene-loaded PE-MP, but the liver showed no significant effects
(Karami et al., 2016). Depletion of liver glycogen reserves was also re-
ported with exposure to POPs contaminated MPs (Rochman et al.,
2013a, 2013b). When mixed with MPs, silver (Ag) is seen to be
partitioned more in the intestine (Khan et al., 2015). Differential accu-
mulation of MPs and co-contaminants in organs drastically impacts me-
tabolism and organ dysfunction, causing various disorders and diseases
(Deng et al., 2020b).
3.4.4. Organismic toxicity
Among different ecological hierarchies, organismic toxicity has been
most widely investigated for MPs exposure (123 studies) (Fig. 5a). The tox-
icity has been analyzed in growth rate, morphological malformations, fillet
quality, behavioral responses such as uptake and clearance rate, and feed-
ing rate (Fig. 5b). In plants, other parameters investigated were photosyn-
thesis rate, transpiration rate, root-leaf biomass, and bioaccessibility of
the contaminants (Table 2).
Ingestion of contaminated MPs causes pseudosatiety (Guzzetti et al.,
2018). For example, in lugworm Arenicola marina, it decreased feeding
and survival (Browne et al., 2013). However, exposure to MPs with phar-
maceutical florfenicol inhibited feeding in bivalve Corbicula fluminea
(Guilhermino et al., 2018). In snails, combined exposure to PBDE and
MPs altered microbiome structure, while body weight remained un-
changed, indicating resilience to these toxicants. Increased bioaccumula-
tion of antibiotic roxithromycin was observed in fish red tilapia after co-
exposure to PS-MPs (Zhang et al., 2019b). PE MPs did not affect the
bioaccumulation of petroleum hydrocarbons but had a synergistic effect
on reducing the feeding activity in arctic zooplankton (Almeda et al.,
2021). Similarly, no significant impact of PE MP on bioaccumulation of
mercury in manila clam Ruditapes philippinarum was observed (Sıkdokur
et al., 2020). In earthworms, increased bioaccumulation of pesticide
dufulin was observed when co-exposed with MPs (Sun et al., 2021b). In ma-
rine microalgae, Tetraselmis chuii, pharmaceuticals (procainamide and
doxycycline) and MPs showed a synergistic toxic effect on growth parame-
ters (Prata et al., 2018). However, Cu and MPs showed an additive effect on
H. Kaur et al.
T. chuii (Davarpanah and Guilhermino, 2015). A synergistic adverse effect
of PSNPs and silver nanoparticles-AgNPs was seen on growth rates of
freshwater algae Chlamydomonas reinhardtii and Ochromonas danica
(Huang et al., 2019). Mostly organismic toxicity is evaluated as mortal-
ity because it is fast, reproducible, and easy to record. However, the eco-
logical relevance of organismic toxicity remains low because organisms
continuously adapt to some stress levels after a long exposure (Oliveira
et al., 2013; Rawat et al., 2016). Synergism between MPs with pesticide
chlorpyrifos and triclosan leads to high mortality in marine copepod
Acartia tonsa (Bellas and Gil, 2020; Syberg et al., 2017). In green algae
Chlorella pyrenoidosa, co-exposure to PS MPs and triphenyltin chloride
or dibutyl-phthalate alters morphology and increases mortality (Li
et al., 2020a; Yi et al., 2019a). PS NPs increased cadmium (Cd) toxicity
in Drosophila, a decreased survival and locomotor activity (Zhang et al.,
2020).
Organismic toxicity as behavioral changes, including swimming speed
and locomotion, has also been reported in fish. With co-exposure to PAH-
pyrene and MPs, tropical fish (Lates calcarifer) exhibited decreased swim-
ming speed, which impaired predatory performance (Guven et al., 2018).
Another fish, Dicentrarchus labrax, showed erratic swimming and rapid fa-
tigue with co-exposure to MPs and mercury (Barboza et al., 2018b). How-
ever, no significant effects of co-exposure of PSNPs with zinc oxide
nanoparticles on behavioral and locomotor responses were observed
(Estrela et al., 2021a). Since behavioral responses are an early warning
sign of toxicity at a higher level of ecological organization, they should be
seriously considered (Syberg et al., 2015). Another study showed the tro-
phic transfer of MPs with sorbed POPs from Artemia nauplii to zebrafish,
warranting research attention to toxicity endpoints at a higher level of bio-
logical organization.
3.4.5. Population level
Despite having high ecological relevance, ecotoxicity assessment at the
population level is the least investigated (31 studies) (Fig. 5a). Copepods,
nematodes, and fish have often been used as test organisms to demonstrate
variations in population traits (Table 2), such as egg production, hatching
rate, abnormalities in gonads and germ cells, deformities in embryo and lar-
vae, brood size, and offspring viability (Fig. 5b).
In copepod Acartia tonsa, egg production is severely impacted due to the
combined treatment of MPs and pesticide chlorpyrifos (Bellas and Gil,
2020). Brood size decreased in Caenorhabditis elegans after prolonged expo-
sure to MPs and cyanobacterial toxins (Qu et al., 2019b). PSNPs with crude
oil fraction synergistically delayed reproduction and caused multigenera-
tional deformities in rotifer Brachionus koreanus (Jeong et al., 2021). Low
hatchability and high deformities in marine medaka (Oryzias melastigma)
were reported only at high MPs concentration due to synergism between
MPs and phenanthrene, while the trend was reversed at low MPs con-
centration (Li et al., 2020c). It is suggested that MPs decrease phenan-
threne toxicity at low concentrations by reducing its bioavailability.
Furthermore, the hatching may be delayed due to blockage of channels
and spiracles on eggshells leading to oxygen reduction and nutrient up-
take (Cong et al., 2017). Co-exposure to microcystin-LR and PSNPs
caused a reduction in the growth of F1 larvae (Zuo et al., 2021). With
co-exposure to butylated hydroxyanisole (BHA) and MPs, a decreased
hatching rate and increased malformations were observed (Zhao et al.,
2020). Exacerbated effect of insecticide deltamethrin was observed on
brood number in Daphnia during co-exposure with PE MPs (Felten
et al., 2020). PS MPs increased the toxicity of gold metal ions in
zebrafish embryos (Lee et al., 2019). High embryo mortality (81 %)
and increased hatching defects were observed when embryos and
prolarvae of Japanese fish medaka were treated with MPs contaminated
with B[a]P (Pannetier et al., 2019a). Reduced bioavailable concentra-
tion of co-contaminant was suggested as the basis of antagonism in tox-
icity caused by PAH mixture and Cd respectively with MPs to zebrafish
larvae and embryo. (Cheng et al., 2021; Trevisan et al., 2019). However,
it is imperative to shift our focus towards highly ecological relevant
assays to predict the ultimate adverse outcome pathways.
15
Science of the Total Environment 841 (2022) 156593
4. Research gaps and discussion
Over half of the studies on toxicity from contaminated MPs are from
China, although developed countries like the USA dump a comparable
amount of plastic waste in the environment (Jambeck et al., 2015). Also,
mixture toxicity from industrial effluent appears to be significantly higher
than expected in developing counties, such as India, Bangladesh,
Pakistan, Vietnam, and Indonesia. The developing countries with a rapidly
growing textile industry bear a high burden of disease attributed to pollu-
tion, which is not yet accounted for. Although India has taken initiatives
to examine the environmental challenges of textile industries, other
South-East Asian countries also need to address the issue to ensure sustain-
ability. Estimating contaminated MPs and the contaminant load onto their
surface and complementing prospective studies on the human population
residing in the vicinity of polluted sites would help determine the real im-
pacts of contaminated MPs on human health. Also, extensive studies on
human cell lines from target tissues would help to understand better mix-
ture toxicity and organ dysfunction and disorders in humans.
As vehicles of organic and inorganic toxicants, MPs act as a source of li-
pophilic pollutants with the potential to bioaccumulate and biomagnify
after entering the food chain (Syberg et al., 2015). However, the mixture
toxicity has been mostly studied in laboratories and not in open fields so
far (Fig. 2d). Using an unrealistically high concentration of contaminants
in lab studies has questioned the possible synergistic or antagonistic inter-
actions between MPs and other contaminants and their relevance in field
settings. Moreover, plastic concentration detected in the environment is sig-
nificantly less than those needed for MPs to outcompete the organic matter
to partition POPs in water. Furthermore, 89 % of studies reviewed used
only one contaminant while ascertaining the net effect of interactions be-
tween MPs with other contaminants. However, MPs are exposed to a cock-
tail of organic and inorganic contaminants in the environment, which are
also likely to compete for binding with MPs. Studies analyzing mixture tox-
icity need a shift in focus from labs to fields to estimate contaminated MPs
at spatio-temporal scale, determine the adsorption rate of contaminants
onto MPs surface and predict their environmental impacts. Further, meso-
and macrocosm studies in a controlled environment would be instrumental
in analyzing the real toxic effects of MPs adhered with other contaminants.
Due to the low environmental concentration of contaminants and MPs,
adsorption is more likely to prevail. Although the impact of chemical prop-
erties of MPs and co-contaminants has been well investigated, only a few
studies (3 %) have analyzed the effect of environmental factors, such as
pH, temperature, salinity, nutrients, organic matter, and microbes, on inter-
actions between MPs and other contaminants. Focused research on MPs de-
bris of different sizes and relative abundance of co-contaminants in natural
water bodies would provide realistic estimates of their ecotoxic potential.
Because of the micro- and nano-size of plastics, locating and analyzing a
single particle in the environment or tissues of living organisms, even with
fluorescent tags, is an arduous task. Although it is challenging to identify
the factors and their possible interactions governing the likely outcome, an-
alyzing the total proteome, transcriptome, and metabolome would help ad-
dress this task. Most studies used MPs beads, giving a little attention to
other shapes like fibrils. However, almost half of the global textile industry
is clustered in Southeast Asian countries; therefore, analyzing the mixture
toxicity of MPs fibrils would be a step forward for environmental manage-
ment and policy development to reduce the disproportionately high
pollution-associated global disease burden in ~25 % of the world popula-
tion. In fact, due to fast fashion and ever-increasing production of low-
quality clothes in the global south and consumption mainly in the global
north, textile-originated fibrils are expected to spread in developing coun-
tries at a high pace. Therefore, analyzing textile fibrils in mixture toxicity
needs focus globally.
Mixture toxicity research has primarily focused on PS (55 %) followed
by PE (26 %), commonly found in marine debris (26 %), ignoring other
types of MPs. Although textile effluent primarily contains PE (78 %), PA
(9 %), PP (7 %), and acrylic (5 %), these polymers have not received due
attention in mixture toxicity research. Field studies on the prevalence of
H. Kaur et al.
plastic beads have shown increasing acrylic, PE, PP, PA, and polyester con-
centrations in surface waters of the northeast Atlantic Ocean. Furthermore,
a couple of studies were on commercial red polymers of unknown compo-
sition, putting a question mark on the ecological relevance of these studies.
To ensure homogeneous dispersion of MPs, several studies use an ultra-
sonic bath or surfactants like Tween 20. Using such treatments might re-
duce the ecological significance of the results while relating to toxicity
from secondary MPs prevalent in nature; however, such studies are still rel-
evant because surfactants are part of textile effluents besides MPs. Most tox-
icity studies were conducted in in vivo laboratory conditions, apart from 5
in vitro studies, 4 mesocosm studies, and only 1 field-based study. More
studies using microcosm and mesocosm, and in fields are required to
obtain realistic estimates of ecotoxicological effects obtained when MPs
interact with other organic and inorganic contaminants (Fig. 6).
Acute toxicity tests with lethal endpoints or growth inhibition have
been most commonly used, ignoring the long-term impacts of the interac-
tions on the population or community (Fig. 6). Research on proteomics,
transcriptomics, and metabolomics for correlating epigenetic and genetic
triggers would be required to establish associations between exposure to
the mixture and the onset of pathogenesis in humans and wildlife. Combin-
ing the data from laboratory- and field-based studies, ecologically relevant
toxicity assays, and the role of environmental factors in modelling would
help predict the ultimate fate of contaminated MPs and their adverse conse-
quences.
5. Conclusions and perspective
Evidence from controlled and field studies shows MPs as emerging
ecotoxicants both individually and in mixtures with co-contaminants.
Sorption-desorption dynamics between MPs and other contaminants dic-
tates the bioavailability and bioaccessibility of the latter and results in addi-
tive, synergistic, neutral or antagonistic toxic effect. Various factors such as
properties of MPs, properties of co-contaminants, size, and life stage of test
organism, along with abiotic factors like pH and salinity, influence the sorp-
tion dynamics of co-contaminants onto MPs. Nevertheless, in most cases,
MPs increase the pollution potential of co-contaminants by serving as the
vehicle for their long-range transfer. An even better insight into sorption-
desorption mechanisms between MPs and co-contaminants is required to
reveal the hidden threats due to mixture toxicity. An in-depth and
Fig. 6. Research gaps and recommendations for future studies.
16
Science of the Total Environment 841 (2022) 156593
exhaustive analysis of simultaneous exposure to multivariant stressors is re-
quired to assess their cumulative outcome and predict their environmental
fate. Moreover, these studies need to be carried out primarily in areas of
high plastic production and disposal and major industrial areas where
chances of the co-availability of MPs and other contaminants are high. Bio-
accumulation and trophic transfer of MPs mixture with co-contaminants
need to be paid attention to find an association between human and ecosys-
tem health. Although the toxicity of contaminated MPs has started receiv-
ing attention globally, its ecological relevance is limited because most
studies do not include toxic impacts at different ecological hierarchies. Mul-
tifactorial design experiments using native species of plants, microbes, and
animals in the field-, micro-, and mesocosm would help reveal associated
risks and develop site-specific remediation methods. The insights offered
in the current review would help develop a framework for environmentally
relevant research that can be compared and generalized to provide realistic
estimates of risks associated with MPs or its mixture with co-contaminants.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.scitotenv.2022.156593.
CRediT authorship contribution statement
Harveen Kaur: Conceptualization, Data curation, Formal analysis, Vali-
dation, Visualization, Writing – original draft, Writing – review & editing;
Deepak Rawat: Data curation, Validation, Visualization; Pankaj Poria:
Data curation, Validation, Visualization; Udita Sharma: Data curation; Vali-
dation; Visualization; Yann Gilbert: Visualization, Writing – review &
editing; Abdul Samath Ethayathulla: Visualization, Writing – review &
editing; Ludovic F. Dumée: Formal analysis, Validation, Visualization, Writ-
ing – review & editing; Radhey Shyam Sharma: Conceptualization; Formal
analysis; Funding acquisition; Resources; Writing – review & editing;
Vandana Mishra: Conceptualization; Formal analysis; Funding acquisition;
Methodology; Project administration; Resources; Supervision; Validation; Vi-
sualization; Roles/Writing – original draft; Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial inter-
ests or personal relationships that could have appeared to influence the
work reported in this paper.
H. Kaur et al.
Acknowledgement
VM and RSS thank the Institute of Eminence (IoE), University of Delhi
(UoD) for Faculty Research Grant-Projects Grants (Ref. No./IoE/2021/
12/FRP dated 29/10/2021). RSS thanks Department of Environment, Govt.
of India for grants to the IoE, UoD. HK, PP, and US, acknowledge UGC-JRF
for Ph.D. program. Partial financial support from Khalifa University
through project RC2-2019-007 is gratefully acknowledged. YG is supported
by NIH grant/award numbers: P20 GM104357 and R01DE029803.
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