Potential Effects of Persistent Organic Contaminants on Marine Biota: A Review on Recent Research

: Synthetic organic compounds belonging to different chemical classes and possessing diverse physicochemical properties are frequently present in marine environments. Microplastics, pharmaceuticals, pesticides, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are contained in the list of persistent organic pollutants (POPs) that have been detected in the global marine system. Numerous ecotoxicological studies have revealed the direct and indirect effects of anthropogenic toxicants on marine biota. The present review presents the research that has been conducted during the period from 1 January 2016 to 30 June 2021 concerning the lethal and sub-lethal impacts of selected organic-synthetic stressors on different plant and animal marine species, and summarizes the observed or predicted individual and combined effects after exposure to chemical mixtures of such contaminants. Future research needs dependent on the knowledge gaps that remain in the bibliography are also highlighted. short notes, editorial commentary, research articles, books and book chapters, etc., that were published from 1 January 2016 to 30 June 2021. Target pollutants were tested either individually or in mixture with other contaminants.


Introduction
A wide variety of anthropogenic synthetic compounds of organic nature that are used in terrestrial areas for several different purposes can penetrate the sea environment through different pathways and mechanisms ( Figure 1). Therefore, large inputs of various man-made synthetic substances launch into the oceans. Plastics, plastic-derived chemicals, pharmaceuticals, drugs, pesticides, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are only some examples contained in the list of persistent organic pollutants (POPs) that sometimes eventually reach the coastal and open-sea ecosystems even though they are considered toxic pollutants.
Those chemicals belong to different chemical classes and possess diverse physicochemical properties in terms of molecular size, hydrophobicity, ionic strength, polarity, volatility, and several other characteristics that determine the distribution, availability, and environmental persistence of their molecules in the marine ecosystems.
According to the relevant literature, numerous invisible and visible pollutants, either individual or contained in chemical mixtures, have the potential after their entrance into the ocean to travel for long distances and periods of time that are dependent on their persistence, bioavailability, mobility, and distribution into the different compartments of marine ecosystems (water column, sediment, and biota), and consequently cause impacts on a wide range of marine organisms many degrees of latitude and longitude away from their origin and their entrance to the sea system [1]. Several different classes of POPs have been detected in the global marine system during the last years [2][3][4][5][6]. For instance, the detection of microplastic pollution in seawater and marine organisms in samples taken from the Tropical Eastern Pacific and the Galápagos archipelago has been reported in a recently published research of Alfaro-Núñez et al. (2021) [2]. The occurrence and spatial distribution of 158 pharmaceuticals, drugs of abuse and related metabolites in offshore seawater have been examined by Alygizakis et al. (2016) [4]. Similarly, the presence of antifouling biocides in aquatic systems including marine ecosystems has been investigated and reported in a newly reported investigation of de Campos et al. (2021) [6].
Subsequently, during the last decades an intense and stable scientific interest focusing on the potential biological effects of those toxicants towards non-target aquatic organisms of different trophic levels is observed in the published data. Numerous studies in the field of ecotoxicology have revealed the direct and indirect effects of anthropogenic toxicants on marine biota either on individual population, or community, or entire ecosystem level.
The current chapter aims: (i) to present and discuss the research that has been conducted concerning the lethal and sub-lethal impacts of selected organic-synthetic stressors on different plant and animal marine species, (ii) to summarize the observed or predicted combined effects after exposure to chemical mixtures of such contaminants based on the data published from 2016, and (iii) to highlight the future research needs depending on the knowledge gaps that may remain in the relevant bibliography. Several different classes of POPs have been detected in the global marine system during the last years [2][3][4][5][6]. For instance, the detection of microplastic pollution in seawater and marine organisms in samples taken from the Tropical Eastern Pacific and the Galápagos archipelago has been reported in a recently published research of Alfaro-Núñez et al. (2021) [2]. The occurrence and spatial distribution of 158 pharmaceuticals, drugs of abuse and related metabolites in offshore seawater have been examined by Alygizakis et al. (2016) [4]. Similarly, the presence of antifouling biocides in aquatic systems including marine ecosystems has been investigated and reported in a newly reported investigation of de Campos et al. (2021) [6].
Subsequently, during the last decades an intense and stable scientific interest focusing on the potential biological effects of those toxicants towards non-target aquatic organisms of different trophic levels is observed in the published data. Numerous studies in the field of ecotoxicology have revealed the direct and indirect effects of anthropogenic toxicants on marine biota either on individual population, or community, or entire ecosystem level.
The current chapter aims: (i) to present and discuss the research that has been conducted concerning the lethal and sub-lethal impacts of selected organic-synthetic stressors on different plant and animal marine species, (ii) to summarize the observed or predicted combined effects after exposure to chemical mixtures of such contaminants based on the data published from 2016, and (iii) to highlight the future research needs depending on the knowledge gaps that may remain in the relevant bibliography.

Methods
The search was mainly conducted in the "Scopus Database", whereas the additional citations that were located by "Google Scholar", "SpringerLink", and "Open Access Journal Search Engine" were also added to the list of reviewed literature.
Several different combinations of keywords were used to collect both research and review papers from peer-reviewed journals published in the global scientific bibliography. Book chapters, conference papers, editorials, books, short surveys, notes, and letters were also included in the retrieved data. The specific search terms and keywords that were inserted in the "search" of the Scopus database included the name of each individual group of targeted POPs (either one of the categories microplastics, pharmaceuticals, pesticides, PCBs, or PAHs) and "marine toxicity", or "impacts on marine organisms", or "effects on marine biota", or "stress on marine organisms". In this point, it must be mentioned that only the studies that were published during the period from 1 January 2016 to 30 June 2021 were collected and reviewed, whereas the total number of found data was 4272 documents.
Afterward, the obtained data were characterized as relevant or irrelevant on the basis of the scope of each study as described and presented by their authors in the abstract. Irrelevant studies were excluded. Next, based on the further information of the accepted surveys as contained in the extended articles of the studies concerning the impacts of selected POPs towards marine organisms, the relevant studies were categorized into five main categories: (i) microplastics and plastic-derived organics, (ii) pharmaceuticals, (iii) pesticides, (iv) PCBs, and (v) PAHs. Each one of the aforementioned categories was further subdivided into three subgroups that were named (a) experimental, (b) nonexperimental/prediction models, and (c) reviews.

Review Results
According to the findings of the current review, a great number of publications have arisen by researchers in the last 5.5 years regarding the evaluation of the ecotoxicological impacts of five selected groups of persistent organic pollutants towards the exposed flora and fauna inhabitants of marine ecosystems that receive their inputs. Based on the gathered and categorized data, depicted in Figure 2, it is indicated that the majority of the studies (≈28%) is dealing with the group of pharmaceuticals, followed by pesticides/agrochemicals (≈24%), PAHs (≈21%), microplastics and plastic-derived chemicals (≈17%), and PCBs (≈10%). Overall relative frequency of reports of different chemical groups of POPs overviewed in present review regarding the evaluation of their potential toxicity on marine biota. The plotted data were obtained from "Scopus", "Google Scholar", "SpringerLink", and "Open Access Journal Search Engine". Overall means all kinds of data including research article, review, short notes, editorial commentary, research articles, books and book chapters, etc., that were published from 1 January 2016 to 30 June 2021. Target pollutants were tested either individually or in mixture with other contaminants. Figure 3 depicts the annual number of records published for each selected chemical group of reviewed pollutants in which a constantly growing number of studies regarding the effects of several types and sizes of microplastics (MPs), nanoplastics (NPs), and plasticderived chemicals is observed. Moreover, in this point, it must be underlined the fact that even if the survey for 2021 is restricted only to the first half of the year (from 1 January 2021 to 30 June 2021), a large number of retrieved data is observed, indicating the enlarged scientific interest in the ecotoxicological impacts of selected POPs.
were obtained from "Scopus", "Google Scholar", "SpringerLink", and "Open Access Journal Search Engine". Overall means all kinds of data including research article, review, short notes, editorial commentary, research articles, books and book chapters, etc., that were published from 1 January 2016 to 30 June 2021. Target pollutants were tested either individually or in mixture with other contaminants. Figure 3 depicts the annual number of records published for each selected chemical group of reviewed pollutants in which a constantly growing number of studies regarding the effects of several types and sizes of microplastics (MPs), nanoplastics (NPs), and plastic-derived chemicals is observed. Moreover, in this point, it must be underlined the fact that even if the survey for 2021 is restricted only to the first half of the year (from 1 January 2021 to 30 June 2021), a large number of retrieved data is observed, indicating the enlarged scientific interest in the ecotoxicological impacts of selected POPs. . Annual number of records published for each selected chemical group of POPs and potential effects on marine biota. The plotted data were obtained from "Scopus", "Google Scholar", "SpringerLink", and "Open Access Journal Search Engine". Overall means all kinds of data including research article, review, short notes, editorial commentary, research articles, books and book chapters, etc., that were published from 1 January 2016 to 30 June 2021. Target pollutants were tested either individually or in mixture with other contaminants.
In the next sections all the data overviewed in the literature since 2016 are summarized according to their chemical class.

Microplastics, Nanoplastics and Plastic-Derived Chemicals
A great variety of synthetic organic polymers such as polystyrene (PS), polyethylene terephthalate (PET), polymethylmethacrylate (PMMA), polyethylene (PE), polypropylene (PP), polyvinylchloride (PVC), polytetrafluoroethylene (PTFE), and others are known by the term plastics, and are associated with specific applications and consumer products. Furthermore, a wide diversity of plastic-derived chemicals such as bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) can be present in coastal waters as well as in the open sea.
Several polymers are currently used world-wide due to their unique properties, including: (i) chemical stability and long durability, (ii) low weight, and (iii) ease to be shaped, transformed, and manufactured. Though there exist advantages regarding the convenience and practicability in their use and numerous applications, their principal  . Annual number of records published for each selected chemical group of POPs and potential effects on marine biota. The plotted data were obtained from "Scopus", "Google Scholar", "SpringerLink", and "Open Access Journal Search Engine". Overall means all kinds of data including research article, review, short notes, editorial commentary, research articles, books and book chapters, etc., that were published from 1 January 2016 to 30 June 2021. Target pollutants were tested either individually or in mixture with other contaminants.
In the next sections all the data overviewed in the literature since 2016 are summarized according to their chemical class.

Microplastics, Nanoplastics and Plastic-Derived Chemicals
A great variety of synthetic organic polymers such as polystyrene (PS), polyethylene terephthalate (PET), polymethylmethacrylate (PMMA), polyethylene (PE), polypropylene (PP), polyvinylchloride (PVC), polytetrafluoroethylene (PTFE), and others are known by the term plastics, and are associated with specific applications and consumer products. Furthermore, a wide diversity of plastic-derived chemicals such as bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) can be present in coastal waters as well as in the open sea.
Several polymers are currently used world-wide due to their unique properties, including: (i) chemical stability and long durability, (ii) low weight, and (iii) ease to be shaped, transformed, and manufactured. Though there exist advantages regarding the convenience and practicability in their use and numerous applications, their principal drawbacks are that these materials are very resistant to chemical and biological degradation and thus exhibit long persistence into the environment.
Large amounts of plastic waste penetrate sea systems after their direct or indirect release into the marine and estuarine ecosystems, and afterward they are dispersed throughout the global ocean, and hence defined as plastic litter [7,8]. According to the recent Water 2021, 13, 2488 5 of 35 review of Gonçalves and Bebianno (2021) most of the plastic debris found in the marine environment originates from land-based sources [8], while the environmental behavior, distribution, and fate of MPs and NPs are strongly dependent on the affinity and stability of their formed aggregates. In the review work of Ajith et al. (2020), among the most frequently detected polymers in the marine environments low-density polyethylene (LDPE), high-density polyethylene (HDPE), PP, PS, PET, and PVC are included, while also present are several polymers such as acrylic, nylon, polyurethanes, polycarbonate, polylactic acid, and other biodegradable plastics [7].
It has been reported that approximately 8 million tons of plastics are being dumped into the sea annually [9]. The survey of Boucher and Friot (2017) revealed the microplastic debris contribution by certain geographical areas, namely Southeast Asia (15.9%), North America (17.2%), and Africa and Middle East (8.7%) [10].
Even though a precise, accurate and united definition of MPs and NPs has not yet been established in the literature, as scientists are still disputing [11], the majority of the authors have defined MPs as the particles of synthetic polymers with sizes <5 mm or <1000 µm to >0.1 µm or 1 µm to 1 mm [12], while NPs are the pieces of plastics with a size <20 µm or <0.1 µm or <1 µm or <100 nm or <1000 nm [13]. Those materials can be further divided into primary and secondary MPs and NPs. Primary MPs and NPs are the particles that launch into the environmental compartments in their original small size (within the corresponding size scale described above), whilst secondary MPs and NPs are those particles that are formed as a consequence of macro/microplastic degradation of larger plastic materials [8]. Barreto et al. (2015) [14] surveyed the behavior of colloidal gold nanoparticles in different ionic strength media and highlighted the fact that nanoparticles when contained in saltwater are expected to aggregate/agglomerate and consequently, differences in terms of decreased bioavailability with increased concentration due to aggregation must be taken into account.
The toxic effects of MPs and NPs on different marine biota has been demonstrated by numerous researchers during the last 5.5 years, and a rising research interest can be observed in investigating the toxicity of those group of emerging pollutants towards various marine organisms, as illustrated in Figure 3. Based on the found and reviewed data it is shown that a great variety of marine plant and animal species have been employed to evaluate the toxicological effects of MPs, NPs, and plastic-derived chemicals such as bisphenol A (BPA), di-(2-ethylhexyl) phthalate (DEHP), polybrominated diphenyl ethers (PBDEs) and others (Table 1).
Various species of marine bacterium have been exposed to small size polymers of different types and sizes and under different experimental conditions (concentration, duration, etc.). The toxicities of PS-NPs and PS-nano beads (PS-NH 2 , 50 nm and PS-beads, 55 nm, respectively) towards the marine bacterium Halomonas alkaliphila was investigated by Sun et al. (2018) [15]. The results indicated that in the presence of polymers, particles with size 50 nm at concentrations between 20-320 µg mL −1 after 2 h exposure affected the bacterium and resulted in inhibition of growth rate, decreased chlorophyll content, and increased oxidative damage of the exposed microorganisms [15]. Moreover, according to the same study, compared to PS-nano beads, PS-NH 2 induced higher oxidative stress on the exposed bacterial species [15].
Marine bacterium strains Marinobacter adhearens, Oceanobacter kriegii, Cobetia marina, Marinobacter algicola, Pseudoalteromonas carrageenovora, and Phaeobacter inhibins were used by Okshevsky et al. (2020), and the formation of biofilm by the selected marine bacteria when exposed to PS NPs was impacted by concentration and surface functionalization of polymer NPs in a species-specific manner [16]. It was observed that whereas PS-COOH increased the amount of biofilm formed by several species, on the contrary, amidine-functionalized NPs decreased the amount of biofilm of the tested bacteria with the exception of Oceanobacter kriegii. In addition, it was suggested that the aggregation dynamics of bacteria and NPs were strongly impacted by the surface properties and concentration of the NPs [16].  The presence of plain and aminated PS microplastics (1000 mg L −1 ) could additively increase the toxic effects of nano-TiO 2 (3, 6, and 9 mg L −1 ) in comparison to the carboxylated PS microplastics (1000 mg L −1 ), which antagonistically decreased the toxic effects of nano-TiO 2 after a 72-h incubation.
Thiagarajan et al., 2019a [32] Chlorella pyrenoidosa (Microalgae) Combined effect of PS plastics and triphenyltin chloride The algal surface could adsorb microplastics and disturb the membrane transport and could cause detrimental damage to the membrane structure.
In general, many published reports have investigated and reported the effects of MPs and NPs on several microalgae and microcrustacean species belonging to these two low trophic levels that are both at the bottom of the food chain of marine environments, as prey and predator, correspondingly. In addition, the combined toxicity of microplastics and various nanomaterials on those marine species has been assessed, such as gold nanoparticles [31] and nano-TiO 2 particles [18,32,[40][41][42][43]. Furthermore, the toxicity of amine-modified iron oxide-doped polystyrene microplastics and carboxyl-modified polystyrene microplastics has been evaluated [28].
The toxic mechanisms of MPs and NPs affecting the exposed microalgae and microcrustacean species has been elucidated in several cases, and among them growth inhibition [27], effect of photosynthesis by blocking the light transport and access [44], disturbance of the membrane structure and transport [33], metabolism disorders [27], DNA damage [27], genotoxic effect [27], and oxidative stress [27,44] are included.
According to a recent survey of Hou et al. (2019) that reviewed the scientific literature on toxic effects of TiO 2 -NPs on different organisms, the toxicity mechanism on multiple taxa of microorganisms including plants, algae, invertebrates, and vertebrates can be outlined in three features: (i) the generation of reactive oxygen species (ROS) after the penetration of electron-hole pairs; (ii) the formation of NP-cell bonds through electrostatic nature interactions (that are favored by the large surface area of TiO 2 -NPs) that cause the destruction of the cell wall structure and lipid peroxidation of the cell membrane; and finally (iii) the connection of TiO 2 -NP with the biological macromolecules and intracellular organelles [43].
Overall, the studies regarding the impacts of MPs and NPs on microorganisms at the bottom of the food chain, such as microalgae, rotifers, and polychaetes, have demonstrated particle and species-specific responses [45]. For instance, Venâncio et al. (2019) [37] reported that organisms that have the role of primary and secondary consumers as zooplankton members, such as Brachionus plicatilis (rotifers), can be more sensitive to PMMA-NPs (size 40 nm; 96 h; at concentrations 4.7-75.0 mg L −1 ) exposure than organisms that are producers, such as the microalgae Tetraselmis chuii and Nannochloropsis gaditana [37]. Manfra et al. (2017) [46] showed that with Brachionus plicatilis, after its short exposure (24-48 h) to PS-COOH (size 40 nm) and PS-NH 2 (size 50 nm) at concentration levels that ranged between 0.5 and 50 mg L −1 , high mortality due to PS-NH 2 was observed, whereas on the contrary no acute toxicity due to the PS-COOH was illustrated [46]. The results of a survey conducted by Jeong and Choi (2019) [47] revealed that with marine rotifer Brachionus koreanus, when exposed at a concentration of 10 µg L −1 to two different sizes of PS-NPs (500 and 6000 nm, and 50 nm, respectively), it was suggested that the molecular initiating event was ROS formation [47]. Even though data on the ecotoxicological effects of MPs and NPs on rotifers are scarce [37,46,47], the reviewed literature herein indicates that in general the toxicity that is observed, such as oxidative stress, induced damage to lipid membranes, accumulation, and mortality, is dependent on both type and size of polymers.
Based on the reviewed data within the current study, PS-NH 2 comparatively possess a more toxic effect on echinoderms than PS-COOH, as seen and described above in bacteria, algae and rotifers [8,36,48,49]. For example, it has been reported by Bergami et al. (2019) [49] that PS-NPs affected the innate immune system of the Antarctic sea urchin Sterechinus neumayeri, while amino-modified PS-NPs affected signaling pathways of the sea urchin Paracentrotus lividus embryos, according to Pinsino et al. (2017)] [48].
The impacts of PS-NPs on the ability of the polychaeta Hediste diversicolor were assessed by Silva et al. (2000a and2000b) [50,51] and the results of their study revealed the effects on burrowing behavior and regenerative capacity [50,51].
Marine crustaceans such as planktonic and benthic organisms are useful and important test organisms used in the bioassays concerning the toxicity and impacts of plastics in marine ecosystems. These organisms possess both the role of primary and secondary consumers and thus are considered as the connectors between the primary producers and the higher level consumers, hence are responsible for the corresponding energetic fluxes (trophic transfers) within the food web. Effects of MPs and NPs on several crustaceans have been assessed, such as brine shrimp Artemia franciscana [36,52], nauplii of the acorn barnacle Amphibalanus amphitrite [53,54], and Antarctic krill juveniles, Euphausia superba [55]. Effects of PS-COOH (40 nm) and PS-NH 2 (50 nm) particles on the expression of two genes, cathepsin L-associated protein (clap) and cathepsin B (cstb), which are connected to the growth of Artemia franciscana, were reported after their exposure to 0.5-10 µg mL −1 for 24 and 48 h [36]. Moreover, according to the same researchers, the results of the growth inhibition test (72 h) and a long-term sub-lethal test (14 d) revealed that tested pollutants were retained inside the gut lumen and thus had been accumulated. PS-COOH particles were less toxic than PS-NH 2 , once again [52]. Accumulation of PS particles was also observed in the case of Amphibalanus amphitrite simultaneously with other effects such as the impact on the organism's swimming speed and mobility inhibition observed by Gambardella et al. (2017) [53]. Similar observations for bioaccumulated particles of polymers were reported for the same crustacean, A. amphitrite, after its exposure to PMMA (45 nm; 5-25 µg mL −1 ; 24 h) [54].
Unquestionably, bivalves have been characterized as excellent sentinel organisms for ecotoxicological evaluations and bioindicators not only due to their wide geographical distribution but also due to their ability to accumulate several chemicals that are present in their ecosystem through their filter-feeding mechanism [8]. Interestingly, in a recently published survey of Hamm et al. (2021) [20], who exposed juvenile Mytilus spp. to environmentally realistic doses of irregularly shaped PVC particles (from 15 to 1,500,000 particles/individual/week calibrated in the size range 11-60 µm) and regularly shaped PS beads (from 15 to 15,000 particles/individual/week, 40 µm) over 42 weeks, the negative effects of the tested microplastics on mussel performance (in terms of on clearance rate, byssus production, growth rate, superoxide dismutase activity, malondialdehyde concentrations, and the condition index) emerged late in the experiment and were rather weak [20].
The impacts of the cationic polystyrene nanoparticles (amino-modified PS-NH 2 ) on early embryo development of Mediterranean mussel, Mytilus galloprovincialis, and more specifically the effects on shell formation, were investigated by Balbi et al. (2018). Based on their published results, the studied emerging pollutants were shown to affect gene expression profiles during early embryo development, because decreased mineralization and shell size was observed at a concentration of 0.150 mg L −1 ( ∼ =EC 50 ) with malformed D-veligers, whereas higher concentrations (in the range of 5-20 mg L −1 ) resulted in high embryotoxicity/developmental arrest [56].
In the study of González-Fernández et al. (2018) [57] regarding the cellular responses of Pacific oyster (Crassostrea gigas), it was reported that in gametes exposed in vitro to PS-NPs, tested NPs (PS-COOH and PS-NH 2 , 100 nm; 0.1-100 mg L −1 ) attached to both oocytes and spermatozoa, and cellular impacts on spermatozoa were observed. Furthermore, PS-COOH exposure generated a dose-response increase in ROS production in spermatozoa, while the higher impact of PS-COOH suggested an influence of particle surface properties [57]. In a more recent investigation conducted by   [19] on the Pacific oyster, Crassostrea gigas, they discovered that the sub-chronic exposure to HDPE MPs alone or in combination with the pesticide chlortoluron significantly affected valve activity and daily growth of the tested bivalve [19].
The presence of MPs and NPs in the gastrointestinal system of several fish species has been exhibited by a number of researchers, the majority of which seems to agree with the recommendation that the detected MPs are either ingested accidentally (because fishes are habituated to ingest various indigestible particles such as sand, fish scales, and shells of smaller invertebrates) or have been transferred through the food chain from lower to higher trophic levels [7,58]. The findings of the present review revealed that most of the available literature data have focused on the effects of MPs and NPs on freshwater fish species [59][60][61][62][63][64], whereas the corresponding research regarding the impacts on marine fish species are fewer [45,[65][66][67][68][69]. Common bluegill (Lepomis macrochirus) [65], Atlantic salmon [65], European seabass (Dicentrarchus labrax) [66,69], rainbow trout (Oncorhynchus mykiss) [67], gilthead seabream (Sparus aurata) [45,69], and marine fish Dicentrarchus labrax [68] are some of the fish species on which the potentially toxic effects of exposure to several and different types and sizes of MPs and NPs has been scrutinized.
Based on the findings of Mallik et al. (2021) [9] who summarized the scientific data on ecotoxicological and physiological risks of MPs on fish and their possible sources, routes, bioavailability, trophic transfer, and consequences, it was concluded that the ingested MPs could cause severe health implications, including improper gill functioning, immunosuppression, reduced feeding intensity and compromised reproducibility. Several review studies have also been conducted in the same period to investigate the mobility and bioaccumulation of chemical stable MPs and NPs into aquatic biota via the food chain from primary producers to top predators [3,[70][71][72][73][74][75][76][77]. According to the aforementioned review of Mallik et al. (2021), the ingestion of plastic debris by fishes can either directly cause lethal effects and mortality (due to choking and internal injuries) or sub-lethal damages via intestinal alterations and injuries that may reduce nutrient intake. Disruption of various metabolic processes, such as fat metabolism, immune system, and hepatic stress, induced different physiological changes, such as behavioral changes and reduced ability to sense predators, are also some possible consequences of direct or indirect ingestion of MPs and NPs in the gastrointestinal tract of fish [9].
An important indicator that has been recognized as adequate in assessing the toxic impacts of small size plastic pollutants in exposed fish on a molecular scale is fish cell lines and the infection of them with the pancreatic necrosis virus [65][66][67]. The use of this tool enables scientists to avoid the employment of animals in their experimental sections as proposed by the Directive 2010/63 EU of the European Union [8]. For instance, Almeida et al. (2019) [69] surveyed how PS-NPs could alter the cytotoxicity of human pharmaceuticals on marine fish cell lines of the sea bream Sparus aurata and the seabass Dicentrarchus labrax, and reported that 100 nm PS plastics may alter oxidative status and biotransformation of the exposed species. Specifically, a slight decrease (25%) in the viability of cell lines of the S. aurata and the D. labrax at lowest concentrations was observed, starting at 0.001 up to 10 mg L −1 , to assess effects on viability and activity of catalase and glutathione S-transferases [69]. Brandts et al. (2021) reported that short-term exposure of the seabream S. aurata to PMMA (size 45 nm; concentration range 0-10 mg mL −1 ; 24 and 96 h) resulted in upregulation of the mRNA levels of essential lipid metabolism-related genes that controlled the increase in plasma cholesterol and triglycerides [45]. The increase in abundance of mRNA transcript, as well as the impairment of the fish's immune system, was also described by the same authors [68] in their previous study regarding the seabass D. labrax after their exposure to the same NP and size (PMMA; 45 nm; 0-20 mg/L; 96 h). PS disturbed the pentose phosphate pathway and nucleotide metabolism in the liver of the marine medaka (Oryzias melastigmas), suppressed hepatic organic acids in the tricarboxylic acid cycle and glycolysis and most monosaccharides and amino acids in the liver, and induced accumulation of hepatic fatty acids, fatty acid methyl, and ethyl esters, while the PS size affected hepatic metabolism and PS accumulation [78]. The conclusions of the study conducted by Gonçalves and Bebianno (2021) [8] have shown that small particles of synthetic polymers of several types and sizes can disrupt the immune system of fish, induce oxidative stress, compromise lipid metabolism and cause cell viability to decline.
In a recent study, Ajith et al. (2020) [7] revealed that even though microplastics are undeniably one of the most crucial and urgent environmental threats that are detected in almost all the marine habitats and biota of the world, only a low number of countries have performed research regarding their distribution in the marine environment (44 countries, equal to 22.9% of the overall 192 countries of the world). The same authors observed that the research investigating their impacts on organisms have mostly targeted fish (38%), while on the contrary surveys on other highly affected organisms such as turtles (1%) were not well documented [7].
Moreover, it has been well documented in the relevant bibliography that various organic and inorganic compounds such as PCBs and PAHs, which are among the most reported adsorbates found in MPs [79], as well as pharmaceuticals [80,81], pesticides [26,82], heavy metals [83] and other contaminants, are widely present in the sea environment [84]. The affinity of coexisting pollutants towards MPs and NPs is dependent on several different parameters, such as the type of both pollutant and polymer, the size of plastic pieces (MPs or NPs), the type and energy of chemical intermolecular forces of interaction (van der Waals, hydrogen bonding, π-π interaction, etc.), and the gradual changes in their chemical bonds over time (ageing) [84]. Usually, after their ingestion, the contaminants adsorbed onto plastics are desorbed in the intestine of organisms (especially benthic invertebrates, fish, deep ocean biota, and larger mammals) and their translocation follows to the circulatory system, tissues, intestinal epithelia, liver, and other organs.
The combined effects of MPs-or NPs-pollutants complexes has been assessed in a number of studies [26,[85][86][87][88][89][90][91][92][93][94][95]. A recent study by Bellas et al. (2020) [26] revealed that even though PE-MPs did not induce any toxic impact in sub-lethal fitness responses (such as fecundity, feeding, and egg viability) of exposed Acartia tonsa individuals, the tested MPs increased the toxicity of the organophosphorus pesticide chlorpyrifos on the widely distributed calanoid copepods in planktonic communities [26]. Similarly, synergistic impacts of MPs and some PAHs have been reported in the bibliography on some marine organisms [91][92][93][94][95], among which Mediterranean mussels Mytilus galloprovincialis [91,95] and the blue mussel Mytilus edulis [93] are included. However, more research in this direction in the future must be performed with more realistic scenarios of more compounds simultaneously present in the tested cocktails of chemicals.

Pharmaceuticals
Pharmaceuticals, also identified as drugs or medicines, are chemical substances that are used for the treatment, diagnosis, or prevention of a specific disease. Among these chemical substances several classes of human and veterinary pharmaceuticals are included, such as antibiotics, anti-inflammatory drugs, antidepressants, antineoplastic or anticancer drugs or immunomodulating agents, and several other different groups that are discovered, developed, produced, and marketed to patients in order to cure, vaccinate or alleviate the symptoms of a wide variety of human and animal illnesses. During the past years and up to today, remarkable increasing research and development in the processes of discovering and designing new pharmaceuticals has been achieved, and has resulted in a wide range of medicines utilized all over the world.
For instance, more than 250 registered antibiotic drugs, subdivided mainly into six different classes, including macrolide, β-lactam, tetracyclines, fluoroquinolones, sulfonamide, and diaminopyrimidine, are currently available in the global market of pharmaceuticals. As a consequence, residues of pharmaceuticals can be found and detected in several water bodies around the world. Due to their increasing consumption, combined with their incomplete removal in wastewater treatment plants, their detected concentrations in the aquatic environment can range from ng L −1 to µg L −1 [96]. According to the relevant data, the occurrence and spatial distribution of several pharmaceuticals and related metabolites have been observed in a variety of aqueous environmental samples of wastewater, surface water, groundwater, drinking water, and transitional systems such as estuaries and coastal systems (offshore seawater) [4,5,97,98].
The effects induced by pharmaceuticals on non-target aquatic organisms are dependent on many factors, among which the sensitivity of the exposed organism, the type of pharmaceutical, the exposure concentration, and the duration of exposure are the most important that are reported in the reviewed literature. In general, factors related to experimental designs and biological materials are applied to determine the results obtained after an ecotoxicological assessment experiment.
Some of the studies reviewed herein were selected to be presented in summary regarding the experimental information (tested pharmaceutical and target marine organism) and the main findings and highlights are reported in Table 2.
Matozzo et al., 2016a [103] The bivalves were exposed to 100, 200 and 400 mg L −1 for 1, 3 and 7 days, and the effects on the THC, the diameter and volume of the haemocytes, haemocyte proliferation, LDH activity in cell-free haemolymph, the haemolymph pH, and the formation of micronuclei were evaluated.

Pharmaceuticals Tested Species Main Findings Reference
Mytilus galloprovincialis (Bivalve, mussel) Assessment of in vivo and ex vivo toxicity at levels up to 1000 ng L −1 for 14 days. In vivo exposure to cyclophosphamide provoked oxidative stress and oxidative damage in tissues. DNA damage reported in mussels exposed over 14 days to drug. Cytotoxicity registered in mussels hemocytes. Likely metabolic activation of tested pharmaceutical in mussels and prompt of its mode of action. Exposure concentration and time dependent sulfomethoxazole accumulation presented in mussels. Antioxidant defense was initiated in vital tissues of exposed marine mussels. Gill was more sensitive under the antibiotic induced stresses compared to digestive gland. Gene expression was more sensitive than responses at protein level. Expression of GSTs gene revealed its potential role in the metabolism of pharmaceutical and ROS elimination.
Chen et al., 2021 [113]  The pharmaceutical could be up-taken by fish through both water and diet. Both warming and acidification decreased its uptake in liver, while uptake in brain was favored under warming conditions. Its elimination in liver was impaired by warming and acidification. According to the gathered data in the current review, it is observed that most of the research has been devoted to assessing the impacts and threats of pharmaceuticals on marine bivalves that are in classes of mollusks that have not only ecological value but socio-economic benefits as well, as edible species [98]. Thus, several species of marine mussels and clams have been studied within the conducted research in order to evaluate the interactive effects of pharmaceutical products. Among the large variety of tested species Mytilus galloprovincialis, Mytilus edulis, Mytilus coruscus, Ruditapes philippinarum, Ruditapes decussatus, Scrobicularia plana and several others are included [96,98,[103][104][105][106][107][108][109][110][111][112][113][114][115][124][125][126].
Based on the published results of the relative studies, within the wide list of the reported effects triggered by pharmaceuticals on marine bivalves, alterations related to organisms' oxidative status such as the induction of antioxidant and biotransformation enzyme activities [96,103,104,109], and the occurrence of cellular damages are encompassed. More specifically, individual and sub-individual impacts have been induced and observed by the authors regarding tissue, cellular and molecular levels of biological organization [8]. Lipid peroxidation of cellular membranes of marine mussel Mytillus galloprovincialis was observed by Capolupo et al. (2016) after its exposure to caffeine [106], and to marine clams Ruditapes decussatus and Ruditapes philippinarum by Aguirre-Martínez et al. (2016) after 14-day exposure to caffeine, ibuprofen, carbamazepine, and novobiocin (0.1, 1, 5, 10, 15, and 50 µg L −1 ) [107]. Induced changes have been observed in oxidative stress-related enzymatic activities, including catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione-S-transferase in mussels' tissues after their exposure to a broad spectrum of pharmaceuticals [96,103,104,109].
It is worth noticing that according to a recent study conducted by Costa et al. (2020) [112] investigating the effects of climate change-related factors (temperature and ocean pH) on two clam species to diclofenac (a non-steroidal anti-inflammatory drug), the results showed that both tested species (Ruditapes philippinarum and Ruditapes decussatus) displayed particular mechanisms to face stress related to warming and ocean acidification (20 • C, pH 7.7; control: 17 • C, pH 8.1). However, the predicted climate change related to warming and ocean acidification (20 • C, pH 7.7; control: 17 • C, pH 8.1) may not enhance the effects of diclofenac in studied clams in a species-dependent manner [112]. This observation is in accordance with the acquired results of a more recent study conducted by Almeida et al. (2021) [98] investigating the combined impacts of ocean warming and antiepileptic and antihistaminic pharmaceuticals (carbamazepine and cetirizine) in the edible marine clam Ruditapes philippinarum. Published data highlighted that ocean warming can activate the defense mechanisms of the tested bivalves and reduce their metabolic capacity (lower lipid peroxidation and protein carbonylation levels, higher reduced to oxidized glutathione ratio), especially when both drugs were combined [98].
On the contrary, fewer data exist in the scientific literature regarding the ecological risk of pharmaceuticals to fish species [99][100][101]. Despite their scarcity, ecotoxicological studies have revealed various biochemical disturbances in fish exposed to human and veterinary drugs (e.g., induced catalytic activity of cytochrome P450), such as oxidative stress, genotoxicity, and neurotoxicity [99][100][101].
Furthermore, findings of the current review showed that when compared to other classes of pharmaceuticals, the antibiotics have received the most attention up to date, especially if the comparison is done with the anticancer or antineoplastic group of pharmaceuticals, for which a limited amount of information exists [127].
Moreover, in studies conducted with marine and estuarine species, few have demonstrated that temperature rise and ocean acidification scenario will exert changes from the molecular level to ecosystem functioning [98,112,124] and might change the marine organisms' sensitivity to drugs or alter pharmaceuticals' toxicity. For example, in a study by  evaluating the chronic toxicity of carbamazepine (1 mg L −1 ) and cetirizine (0.6 mg L −1 ) on the clam Ruditapes philippinarum, for 28 days under control and low pH conditions (pH 7.8 and 7.5, respectively) the transcription of several genes related to neurotransmission, immunity, and biomineralization was revealed by low pH values [124]. More studies should investigate the combined effects of both pharmaceutical drugs and climate-related changes as stressors on marine invertebrates.

PAHs and PCBs
PAHs, also known as polyaromatic hydrocarbons, are chemical compounds that consist of two or more aromatic rings fused in linear, angular, or clustered arrangements, and are a group of unsaturated organic substances that exhibit high values of molecular weights and low water solubility. Their occurrence in the ocean and marine ecosystems is attributed to both anthropogenic sources (pyrogenic and petrogenic PAHs) as much as to natural sources from oil regeneration processes [128].
Petroleum hydrocarbons pollution is the most common culprit of marine pollution due to leakage from oil refineries or petrochemical factories, accidental spillage from tankers, or/and through atmospheric fallout or waterway-transport from the land, leading to a streak of negative effects for the marine environment. Petroleum is a complex mixture that consists of several different organic substances, among which PAHs, monoaromatic hydrocarbons, aliphatic hydrocarbons, and naphthenic acids are included [129][130][131][132].
Based on their molecular weight values, PAHs can be divided into two major categories: (i) those that are composed of less than four aromatic rings (two or three fused benzene rings), such as phenanthrene, naphthalene, fluorene, acenaphthene, and acenaphthylene, which are known as low molecular weight (LMW) PAHs and are more water-soluble; and (ii) those with four or more fused benzene rings, such as chrysene, pyrene, benzo[a]pyrene, dibenz[a,h]anthracene and several others, which are referred to as high molecular weight (HMW) PAHs and which are generally more hydrophobic substances (as they have higher values of the logarithmic form of octanol-water partition constants (log K ow ) than LMW PAHs and thus are more readily distributed into organic matter, higher sorption tendency onto organic particles compared to LMW PAHs, lower vapor pressures and Henry's constants). Consequently, a wide variety of benthic organisms can potentially be exposed to PAHs compounds either by being dissolved in the overlying water or alternatively diluted in pore water, or by direct contact with the sea bottom where they are adsorbed.
Overall, this group of POPs is considered as chemical stable compounds with great environmental persistence. Because of their potentially negative ecological health effects, human toxicity, and carcinogenicity, a list of 16 specific PAHs have been prioritized by the U.S. Environmental Protection Agency (USEPA) that are regulated in aquatic and terrestrial ecosystems. Maximum contaminant levels have been established for them in drinking water, whereas according to the relevant toxicological data benzo[a]pyrene is considered to have the highest cancer risk, and furthermore, 7 of these 16 PAHs may cause cancer in humans.
In Table 3 some selected studies reviewed herein are presented in summary regarding the experimental information (tested PAHs and target marine organism) and the main findings and highlights are shown.    As it has been well established in the literature, marine microalgae are the primary producers of marine ecosystems that have often been used for the evaluation of environmental effects and toxicity of a wide range of chemical pollutants due to several different advantages, among which their small size, rapid growth and reproduction, and great sensitivity are included [130]. For all of the aforementioned reasons, the scientific research focusing on the impacts of oil pollution on these organisms (that are the base of the marine food chain) is a field that has been extensively researched worldwide in the scientific community [131]. Especially due to the characteristic of PAHs to be subjected under low biodegradation, combined with their ability to be bioaccumulated through the marine food webs, makes the effects on phytoplanktonic species of those pollutants more important for the fate and magnification capacity of PAHs in higher trophic levels [132].
Polychlorinated biphenyls (PCBs) are compounds that were widely produced in the industrialized countries during the 20th century that were used as dielectric fluid in electric transformers and capacitors, plasticizers, etc. PCBs currently are substances of particular concern since their continuous detection in various environmental compartments such as fatty tissues and sediments became known.
According to the found and reviewed bibliography herein, marine microalgal bioassays have been conducted with sediments or sediment extracts containing PAHs, although for some microalgal species an induced inhibition of algal growth and a decrease of biomass and Chlorophyll-a (Chl-a) content has been observed, such as in Dunaliella tertiolecta, Isochrysis galbana, and Phaeodactylum tricornutum, for which inhibitions of microalgal growth were observed for fractions of aromatics with log K ow 5-6, esterase activity and cell membrane integrity [130]. However, for some other microalgal species, contradictory results were reported since those species tolerated PAHs and therefore resisted the toxic effects of the same toxicants through accumulating and biodegrading mechanisms [131,140,141]. For instance, Bretherton et al. (2020) [141] reported that whereas growth and photosynthetic response of microalgal species Micromonas pusilla, and Prorocentrum minimum was sensitive to oil and dispersant exposure, three other tested microalgal species Tetraselmis astigmatica, Ochromona sp., and Heterocapsa pygmaea were resistant under the same exposure conditions. Furthermore, cell size was reported to be the most important factor in determining the biomass response to oil, whereas motility/mixotrophy was the more important parameter in the dispersed oil [141].
Similarly, large algae, such as species of diatoms, have been observed to possess the capacity to tolerate PAHs exposure. For example, in a study conducted by Melliti Ben Garali et al. (2021) [131], the diatoms Pseudo-nitzschia mannii and Pseudo-nitzschia hasleana that were isolated from a PAH contaminated marine environment not only maintained their growth in non-axenic cultures (in the presence of 15 PAHs in mixture up to concentration level of 120 µg L −1 and 144-h exposure) but increased the cell biovolume as well, and the greater increase was revealed to occur for P. mannii [131]. Other PAHs tolerating diatoms species are Skeletonema costatum, Phaeodactylum tricornutum, Chaetoceros sp., and Nitzschia sp. [142][143][144][145].
Even though the majority of researchers have mainly focused on the carcinogenic toxicity of PAHs on organisms, the more recent surveys have revealed the toxic effects of those pollutants on marine biota, including endocrine disruptions and tissue-specific toxicity of exposed aquatic animals. Among the most commonly observed disturbances and various harmful effects on marine organisms (including fish, benthic organisms, and invertebrates), developmental toxicity (heart developmental anatomy on cardiotoxicitybased adverse outcome pathways, ocular development, etc.), genotoxicity, immunotoxicity, oxidative stress, and endocrine disruptions have been reported [146][147][148][149]. More specifically, the impacts of petroleum-derived pollutants and PAHs on fish development and the wide diversity of health implications have been studied and reviewed by a number of researchers [146,150,151]. Moreover, the differential toxicokinetics of PAHs in embryos of Atlantic haddock and cod have been exhibited by Sørensen et al. (2017) [152]. Toxicity to immune system functions, inflammatory responses, and estrogen and androgen metabolic pathways on male tilapia by benzo(a)pyrene exposure was reported by Colli-Dula et al. Several invertebrates such as wharf roach Ligia sp. [159] and blue crab Portunus segnis from the Persian Gulf [160] have been studied regarding accumulation and pollution surveys for the biomonitoring of PAHs [146].
Aquatic fauna including marine reptiles are susceptible to LMW-PAHs, which are chemical compounds with the tendency to remain in the water and thus be bioavailable for biological uptake [161]. According to a recent review by   [161] regarding the impacts of petroleum toxicity in marine reptiles, and specifically marine turtles and iguanas, and focusing on research data related to physiology and fitness toxicological effects, it was stated that these organisms play a key role in the balance of trophic webs due to their ectothermic nature that enables them to have slow metabolisms and therefore makes them sensitive to xenobiotics [161]. Multiple routes of exposure have been reported for marine turtles, such as inhalation of air from the sea surface layer that contains vaporized PAHs, while after diving, consumption of contaminated prey (e.g., invertebrates, mollusks) can lead to the bioconcentration of PAH toxicants, therefore Lepidochelys kempii (Kemp's ridleys) and loggerhead turtles are at higher risk of exposure to PAHs than the Chelonia mydas (herbivorous green turtle) [162].
Based on the reported data, the most common effects of petroleum and crude oil on marine reptiles (turtles and iguanas) include: (i) modifications of skin function, immune responses, energy metabolism, respiration, and diving patterns of adult turtles, (ii) hatchling deformities in exposed eggs, altered incubation duration, and decreased embryonic survival, (iii) decrease of body mass and modification of clinical pathology parameters, and (iv) increased corticosterone levels in marine iguanas and wipe out of gut bacteria [163][164][165][166][167][168].
Peer-reviewed literature on the chronic and catastrophic petroleum spillage and conventional crude oil on marine mammals has been conducted by   [169], and based on the reviewed findings the observed effects include: (i) genotoxicity, (ii) modulations of immune function and/or organ weight, (iii) hematological injury, (iv) neurotoxicity, (v) metabolic and clinical abnormalities, (vi) lung disease, (vii) eye irritation, (viii) decreased reproductive success, (ix) behavioral impacts, (x) population-level declines, and (xi) mortality [169]. Both polluted seawater and marine sediments are marine mammals' habitats for potential exposure to PAH because apart from their incidental ingestion at the sea surface (air-water interface), concentrated quantities of sinking PAHs adsorbed onto organic sediment particles can be found as well. Direct contact and inhalation through blowholes, nasal turbinates, and air-filtering cilia are some of the ways through which marine mammals can be contaminated, whereas when absorbed into the circulation of marine mammals those compounds can attack the liver, blood-forming tissues, and nervous system. Persistent lung disease and impaired stress response [170], immunotoxic effects [171,172], bacterial pneumonia, adrenal dysfunction, DNA damages, lethargy, reduced reproductive success, and mortality have been observed and reported in marine cetaceans, such as bottlenose dolphins [169,170,173,174]. Metabolic stress and hypothermia, which most commonly result in death, are the effects on marine fissipeds [169].
Finally, it is worth mentioning that according to the reviewed data, during the last 5.5 years the synergistic impacts of some specific PAHs and MPs on some marine organisms have been investigated, and among the several other published studies are included the cases of anthracene or phenanthrene with PE (2 and 20 mg g −1 marine sediment) where decreased effects on the bacterial community were reported by Kleinteich et al. (2018) [94]. This is in accordance with the results of Li et al. (2020) [30], who reported decreased early developmental toxicity of phenanthrene on Oryzias melastigma (marine medaka) with the co-presence of a low level of PE-MPs. Similarly, González-Soto et al. (2019) [91] observed increased effects of MPs-benzo[a]pyrene compared to MPs alone in hemocyte viability and catalase activity and in digestive gland structure of exposed mussels Mytilus galloprovincialis, while size-dependent impacts of MP were revealed on DNA damage and cell-type composition of digestive tubules. The synergistic immunotoxic impact of benzo[a]pyrene on bivalve species Tegillarca granosa was generally aggravated by smaller MPs (500 nm) and mitigated by larger ones (30 mm) [92]. Another case of a study investigating the synergistic effects of PAHs and MPs is the study of Magara et al. (2019) [93], who surveyed the impacts of combined exposures of fluoranthene and polyethylene or polyhydroxybutyrate (which is an eco-friendly substitute to plastic and more biodegradable) MPs on oxidative stress biomarkers in the blue mussel (Mytilus edulis). Based on the acquired results of co-exposure and incubation treatments, it was suggested that there was an apparent absence of combined effects [93].

Pesticides
Pesticides, also known as agrochemicals or plant protection products, are chemical compounds that are designed to be used as plant protection products. They are applied in the field for the protection of plants against pests, weeds, and several diseases that affect and decrease the quantity and quality of agricultural crop products. Globally, approximately 3.5 million tons of pesticides are used each year, mainly for agricultural and secondly for non-agricultural and urban purposes [175]. Therefore, an expansive range of synthetic organic pesticides belonging to different chemical classes, possessing diverse physicochemical properties, and targeting multiple and dissimilar pests are available on the market.
Based on several different criteria, pesticides can be subdivided into many categories. For instance, on the basis of their chemical structure, the groups of anilides, amides, organophosphates, organothiophosphates, carbamates, benzothiazoles, triazines, neonicotinoids, organochlorines, and many other chemical classes are determined. On the basis of the target organism against which they are applied, the classes of acaricides, fungicides, herbicides, insecticides, nematicides, and plant growth regulators are included, among many others. Finally, according to the World Health Organization (WHO) pesticides are classified into five classes based on the risk and hazard towards non-target organisms and ecosystems: extremely hazardous (Class Ia), highly hazardous (Class Ib), moderately hazardous (Class II), slightly hazardous (Class III), and unlikely to present acute hazard (Class U) [176].
After their introduction, predominantly into the terrestrial environment, they can enter aquatic environmental bodies through alternative pathways such as diffuse processes, surface runoff, leaching, erosion, spray-drift, and atmospheric deposition after their volatilization. The distribution of pesticides between soil, water, air, and biota matrices determines their bioavailability and their environmental fate. Consequently, non-target organisms are often susceptible to pesticides due to the conserved nature of biochemical pathways across taxa, even though they are designed and marketed to target pest species [175].
Furthermore, to this point it must be mentioned that several xenobiotics such as pesticides that are applied in terrestrial agriculture, are simultaneously contained in the plant materials that are used for the replacement of marine ingredients in the feeds supplied in fish farms and can be introduced in the marine environment, affecting not only fishes but also other marine organisms [177]. According to the relevant literature, insecticides and herbicides are two groups of pesticides that are most frequently detected in river catchments, coastal waters, and in intertidal and subtidal marine environments.
The wide variety of effects observed in non-target species exposed to pesticides include detrimental impacts to biota with photosynthetic symbionts (e.g., marine microalgae Rhodomonas salina [178], diatoms Phaeodactylum tricornutum [179] and Chaetoceros muelleri [180], tropical marine cnidarian, sea anemones Exaiptasia pallida and symbiotic zooxanthellae microalga Symbiodinium spp. [181], Cassiopea maremetens medusae [182]), but also disruptions to non-photosynthetic animals such as reduced growth and reproduction rates of invertebrates (e.g., sea urchin Paracentrotus lividus [183]) and vertebrates (Pacific oyster Crassostrea gigas [184] and Sheepshead minnow Cyprinodon variegatus [185]), disruptions of nerve impulses which can ultimately lead to paralysis and death of invertebrates, and several sub-lethal effects on physiological or metabolic endpoints that are usually measured during the exposure treatments and provide unambiguous information about responses to pesticide exposure [175,186,187]. Table 4 illustrates summarized information gathered in selected recent and reviewed studies regarding the evaluation of pesticide toxicity on marine plant and animal species during the period from 1 January 2016 to 30 June 2021. Table 4. Selected studies evaluating the toxicity of pesticides on marine plant and animal species.

Pesticide(s) Tested Species Main Findings Reference
Glyphosate formulation (Roundup) Natural communities of marine microphytobenthos The tests indicated that microphytobenthic communities were relatively resistant to herbicide. The species richness of the communities probably enabled them to rebuild effectively. Sensitive species were replaced by those more tolerant of glyphosate. Only at the highest glyphosate concentration (8.5 g·dm −3 ) tested was a strong negative effect noted that limited community abundance and eliminated some of the organisms. The dominant diatoms in the communities were replaced by intensively developing cyanobacteria, which ultimately comprised nearly 60% of all the cells observed in the communities. No susceptibility trend for any species tested, or inherent toxicity trend for any chemical was seen. Toxicological parameters indicate that recommended treatment concentrations may result in non-target organism toxicity. No susceptibility trend for any species, or inherent toxicity trend for any chemical, although DM tended to be the most toxic and HP the least toxic to the majority of species (macroalgae, echinoderms, bivalves, crustaceans and fish).

Moeris et al.,
2021 [191] Warfarin sodium Pelodiscus sinensiss (Oftshell turtles), Trachemys scripta elegans (Red-eared slider turtles) Green sea turtles metabolized warfarin very slowly. Intravenous administration of warfarin caused prothrombin time prolongation in sea turtles. Vitamin K epoxide reductase was inhibited in turtles. In vitro assay revealed interspecific differences in warfarin metabolism among different turtle species. Yamamura et al., 2021 [192] Metazachlor Prorocentrum minimum (Dinoflagellate, marine phototrophs) Metazachlor significantly decreased cell growth and pigment levels, and damaged chloroplast integrity, malfunctioning photosynthesis in P. minimum to lead to cell death. Treatment with melolachlor increased photosynthesis genes expression, destroying the chloroplast structure. Antioxidant PmGST induced by tested pesticide with ROS production, but PmKatG was not different.

Glyphosate-based Roundup
Phaeodactylum tricornutum (Marine diatom) High concentrations decreased cell density. Furthermore, inhibition of photosynthetic activity was not only caused by the impairment of electron transport in the thylakoids, but also by a decrease of antioxidant capacity and increased lipid peroxidation. Pigment composition and fatty acid profiles proved to be efficient biomarkers for the highest glyphosate-based herbicide concentrations.

Paracentrotus lividus (Sea urchin)
The effects on larval development, growth and metabolism were assessed during 48 h of exposure from the time of egg fertilization. The results confirm that AMPA and its parent compound, glyphosate have similar toxicity, as observed in other marine invertebrates. However, interestingly, the Roundup formulation seemed to be less toxic than the glyphosate alone.
Asnicar et al., 2020 [183] Atrazine and Chlorpyrifos Aurelia aurita (Jellyfish) The chronic exposure to current Australian water quality guideline values of atrazine and chlorpyrifos, either individually or in combination, has no effect on the survival or metabolome content of Aurelia aurita polyps.

Artemia salina (Marine crustaceans)
A. salina cyst exposure to low doses of cholinergic pesticides affects hatching and larvae viability. Larval survival changes, and decreased AChE activity were observed. Gambardella et al., 2018 [195] Atrazine (individual and combined effects of mixtures with Carbamazepine, and Bisphenol A) Perna viridis (Marine bivalves, Green mussels) 3 of the 10 biomarkers tested on green mussels (genotoxicity, inhibition of AchE, and EROD) responded after exposure to atrazine at environmentally relevant doses or below, and confirmed the potency of this herbicide to marine bivalves. Exposure tests using mixtures of atrazine, carbamazepine and Bisphenol-A also revealed that these 3 substances were generally acting in an additive manner on the selected biomarkers, at environmental doses, with some exceptions (antagonism and/or synergy) at low and high concentrations.  [186] focusing on the neurotoxic effects of several emerging pollutants in marine invertebrates, it is reported that even if studies on pollutants' neurotoxic effects are still few, marine invertebrates are used in ecotoxicological studies as model systems regarding the impacts of xenobiotics such as pesticides on the nervous system. Organochlorines, organophosphates, and carbamates are three classes of pesticides that are known for their neurotoxic effects on marine organisms, invertebrates, and vertebrates [186,187]. Although the use of many organochlorinated pesticides which are chlorinated hydrocarbon derivatives has been banned in developed countries due to their high toxicity and long environmental persistence, they are used in other non-developed countries. On the contrary, the substitutes of organochlorine pesticides currently used are both organophosphates, which are synthetic compounds containing at least one phosphate ester group, and carbamates, which are derived from carbamic acid, and are considered as less hazardous and more (bio)degradable compounds. They target the cholinergic system of exposed organisms, and their mode of action is based on their ability to inhibit the acetylcholinesterase (AchE) activity via binding the enzyme active site in an irreversible manner.
Sea urchin embryos and larvae have been employed in the toxicity assessment tests conducted to evaluate the neurotoxicity of pesticides on marine echinoderms. For example, Zhang et al. (2017) [197] observed ubiquitous disruptions of all the neurotransmitter pathways leading to adverse effects on larval morphogenesis of sea urchin Hemicentrotus pulcherrimus after the exposure to different concentrations (0.01, 0.10, and 1.00 mg L −1 ) of the organophosphorus insecticide monocrotophos. Moreover, monocrotophos induced disruptions in the expression of the netrin patterns during embryogenesis, which is a chemotropic axon guidance cue, and changes in its receptor neogenin during early development of the same species (Hemicentrotus pulcherrimus), and are revealed in the bibliography [197].
According to the recently published research of El Ayari et al. (2020) [194], the detoxifying effect of Polygonum equisetiforme extracts against dichlorvos induced oxidative stress and neurotoxicity in the commercial clam Ruditapes decussatus. Acquired results showed that even at the lower tested exposure level (0.05 mg L −1 ) and exposure for two days oxidative stress was induced which resulted in the reduction of AChE activity, whereas the greatest toxic effects were observed at 0.25 mg L −1 when significant changes of the several biochemical markers analyzed were reported to be caused [194].
Among the various different toxic effects induced by atrazine, either tested alone or in mixtures with bisphenol A (plasticizer) and carbamazepine (pharmaceutical) on green mussels, Juhel et al. (2017) [196] evaluated Perna viridis and found changes in mussel immune functions, significant alterations of DNA damage biomarkers, detoxification enzyme Ethoxyresorufin-O-Deethylase, severe inhibition of haemolymph AChE activity, increase of the total number of haemocytes, and a decrease in their phagocytic activity [196].
The impacts of chlorpyrifos on the crustacean Litopenaeus vannamei were investigated by Duarte-Restrepo et al. (2020) [198], and after the exposure of adult shrimp to sub-lethal concentration levels of chlorpyrifos (0.7 and 1.3 µg/L) for 96 h, significant alterations in the lipid oxidation levels, antioxidant enzymes activities, and AChE activity were revealed. After the exposure of Artemia salina (cyst stage) to a variety of pesticides (chlorpyrifos oxon, diazinon, and carbaryl) at concentration levels 10 −11 -10 −5 M (similar to those found in a contaminated coastal environment), for long exposure times (72, 96, and 192 h), significant alterations in the hatching speed and larval survival were observed, according to the published work of Gambardella et al. (2018) [195]. Moreover, decreased ChE activity at 96 h in the protocerebrum, a brain segment that is associated with vision, were revealed in the same survey.

Conclusions
Numerous toxic and persistent organic molecules can be found in the marine environment, interact with their surroundings, and cause diverse lethal and sub-lethal effects on marine biota and marine ecosystems. The present review presents the recent research that has been conducted during the period from 1 January 2016 to 30 June 2021 concerning the toxicity of selected chemical groups of POPs, and more specifically: (i) microplastics, nanoplastics, and plastic-derived chemicals, (ii) pharmaceutical drugs, (iii) PAHs and PCBs, and (iv) pesticides.
According to the findings of the current review, a wide interest is observed to arise within the scientific community regarding PCBs, PAHs, pesticides, pharmaceuticals, MPs, NPs, and other plastic-derived chemicals and their potential effects on an extended variety of marine species. Based on the gathered and reviewed data herein that were retrieved from "Scopus", "Google Scholar", "SpringerLink", and "Open Access Journal Search Engine", an undiminished scientific interest is revealed that is focused on the impacts of POPs on many marine organisms, both invertebrates and vertebrates, which may take part in the human food chain and, along with environmental pollution, can potentially provoke harmful and hazardous impacts to human health.
The retrieved bibliographic data after their classification into the relevant categories revealed that, in recent years, the majority of the studies (≈28%) are dealing with pharmaceuticals, followed by pesticides/agrochemicals (≈24%), PAHs (≈21%), microplastics and plastic-derived chemicals (≈17%), and PCBs (≈10%). A constantly growing number of studies regarding the effects of several types and sizes of MPs, NPs, and plastic-derived chemicals was also observed.
Acquired results showed that during the last 5.5 years several research studies have focused on the induced and responding mechanisms of the antioxidant system in multiple tissues of marine mussels (especially the edible species Mytilus galloprovincialis) after exposure to all the selected toxicants (MPs, NPs, pharmaceuticals, PAHs, PCBs, and pesticides). Therefore, these sessile, sensitive, and globally distributed organisms can be characterized as excellent bioindicators to a wide variety of environmental POPs stressors. Their crucial ecological role, due to their unique filter-feeding lifestyle, makes them susceptible to waterborne contaminants.
It must be highlighted the fact that even though a large number of published data exist on the impacts of selected anthropogenic toxicants on different species of marine organisms, the concentration levels used in the conducted studies evaluating the ecotoxicological and physiological risks due to the exposure of marine biota species to several POPs need to be environmentally relevant, so that acquired data can be harmonized. It will therefore be possible to clearly compare the effects of those toxicants in marine biota.
Furthermore, although the synergistic impacts of some specific POPs that belong to different groups, such as PAHs and MPs or pesticides and MPs, on some marine organisms have already been investigated, corresponding surveys regarding a variety of combinations and new mixtures of toxicants that can penetrate the sea system and contaminate global oceans should be conducted in the future. Moreover, clearly further work is required to elucidate the combined effects on marine and estuarine species and simultaneous climaterelated changes (temperature rise and ocean acidification scenario) and chemical POPs stress that might change the marine organisms' sensitivity towards them.