A scoping review protocol on in vivo human plastic exposure and health impacts.

BACKGROUND: Global plastic production has increased exponentially since the 1960s, with more than 6300 million metric tons of plastic waste generated to date. Studies have found a range of human health outcomes associated with exposure to plastic chemicals. However, only a fraction of plastic chemicals used have been studied in vivo, and then often in animals, for acute toxicological effects. With many questions still unanswered about how long-term exposure to plastic impacts human health, there is an urgent need to map human in vivo research conducted to date, casting a broad net by searching terms for a comprehensive suite of plastic chemical exposures and the widest range of health domains. METHODS: This protocol describes a scoping review that will follow the recommended framework outlined in the 2017 Guidance for the Conduct of Joanna Briggs Institute (JBI) Scoping Reviews, to be reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. A literature search of primary clinical studies in English from 1960 onwards will be conducted in MEDLINE (Ovid) and EMBASE (Ovid) databases. References eligible for inclusion will be identified through a quality-controlled, multi-level screening process. Extracted data will be presented in diagrammatic and tabular form, with a narrative summary addressing the review questions. DISCUSSION: This scoping review will comprehensively map the primary research undertaken to date on plastic exposure and human health. Secondary outputs will include extensive databases on plastic chemicals and human health outcomes/impacts. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (OSF)-Standard Pre-Data Collection Registration, https://archive.org/details/osf-registrations-gbxps-v1 , https://doi.org/10.17605/OSF.IO/GBXPS.

Tetrazole as a Carboxylic Acid Isostere and the Synthesis of All Amine-Based Polyampholytes.

A new family of polyampholytes (PAMs) is described in which both the basic and acidic groups are based on nitrogen functional groups. Reversible addition-fragmentation chain transfer-prepared poly(pentafluorophenyl acrylate) is quantitatively modified sequentially with 3-picolylamine and 5-aminotetrazole, yielding the new well-defined statistical PAMs. Successful formation of the PAMs is confirmed via a combination of 19 F and 13 C NMR spectroscopy and FTIR. Aqueous electrophoresis indicates isoelectric points (pI) between 2.9 and 4.4 depending on copolymer composition. However, the pI is somewhat insensitive to the copolymer composition, a feature attributed to the similarity of the pKa s of the acid tetrazole species and the conjugate acid of the pyridyl repeat units.

Rh(I)(2,5-norbornadiene)(biphenyl)(tris(4-fluorophenyl)phosphine): Synthesis, Characterization, and Application as an Initiator in the Stereoregular (Co)Polymerization of Phenylacetylenes.

The synthesis of the Rh(I)-aryl complex, Rh(I)(nbd)(BiPh)(P(4-FC6H4)3) is reported and its efficacy as an initiator for the (co)polymerization of phenylacetylenes established. The X-ray crystal structure indicates that the complex adopts a slightly distorted square planar geometry whose purity and structure was also confirmed by elemental analysis and 1H, 13C, 31P, 19F, 103Rh, and 31P-103Rh{1H} HMQC NMR spectroscopy. We demonstrate that Rh(I)(nbd)(BiPh)(P(4-FC6H4)3) mediates the (co)polymerization of phenylacetylenes in a controlled fashion with initiation efficiencies as high as 0.98, as evidenced by the pseudo-first-order kinetic and number-average molecular weight versus conversion profiles. The ability to form well-defined AB diblock copolymers, in a stereoregular manner, by sequential monomer addition is verified in the block copolymerization of phenylacetylene with 4-fluorophenylacetylene with quantitative crossover efficiency, as determined by size exclusion chromatography.

Polymerizations Mediated by Well-Defined Rhodium Complexes.

This Minireview details the current state-of-the-art relating to (co)polymerizations mediated by well-defined RhI -ethynyl, vinyl, and aryl complexes. In particular, we focus on RhI species suitable for the (co)polymerization of phenylacetylenes, arylisocyanides, as well as propargyl esters and amides.

A (2-(naphthalen-2-yl)phenyl)rhodium(i) complex formed by a proposed intramolecular 1,4-ortho-to-ortho' Rh metal-atom migration and its efficacy as an initiator in the controlled stereospecific polymerisation of phenylacetylene.

The synthesis of a novel Rh(i)-aryl complex is detailed and its ability to serve as an initiator in the stereospecific polymerisation of phenylacetylene evaluated. Targeting the Rh(i) species, (2-phenylnaphthalen-1-yl)rhodium(i)(2,5-norbornadiene)tris(para-fluorophenylphosphine), Rh(nbd)(P(4-FC6H4)3)(2-PhNapth), following recrystallization we obtained the isomeric (2-(naphthalen-2-yl)phenyl)rhodium(i) complex, Rh(nbd)(P(4-FC6H4)3)(2-NapthPh), as determined by X-ray single-crystal structure analysis, and confirmed by X-ray powder diffraction. The isolation of the latter species was proposed to occur from the target (2-PhNapth) derivative via an intramolecular 1,4-Rh atom migration. This supposition was supported by density functional theory (DFT) calculations that indicated the isolated (2-NapthPh) derivative has lower energy (-19 kJ mol-1) than the targeted complex. The structure of the isolated (2-NapthPh) species was confirmed by multinuclear NMR spectroscopy including 2D 31P-103Rh{1H, 103Rh}, heteronuclear multiple-quantum correlation (HMQC) experiments; however, NMR analysis indicated the presence of a second, minor species in solution in an approximate 1 : 4 ratio with the 2-NapthPh complex. The minor species was identified as a second structural isomer, the 3-phenylnaphthyl derivative, proposed to be formed under a dynamic equilibrium with the 2-NapthPh derivative via a second 1,4-Rh atom migration. DFT calculations indicate that this 1,4-migration proceeds through a low-energy pathway involved in the oxidative addition of a C-H bond to Rh followed by a reductive elimination with the distribution of the products being thermodynamically controlled. The recrystallized Rh(nbd)(P(4-FC6H4)3)(2-NapthPh) complex was subsequently evaluated as an initiator in the polymerisation of phenylacetylene (PA); gratifyingly, the Rh(i) species was an active initiating species with the pseudo-first-order kinetic and molecular weight evolution vs time plots both linear implying a controlled polymerisation while yielding (co)polymers with low dispersities (D = Mw/Mn typically ≤1.25) and high cis-transoidal stereoregularity (>95%). Typical initiation efficiencies, while not quantitative (as judged by size exclusion chromatography), were nonetheless high at ca. 0.8. The presence of the minor 3-phenylnaphthyl species when in solution is proposed to be the cause of the observed non-quantitative initiation.

Reactive Conjugated Polymers: Synthesis, Modification, and Electrochemical Properties of Polypentafluorophenylacetylene (Co)Polymers.

(Co)Polymers containing pentafluorophenylacetylene (F5 PA) have been prepared for the first time mediated by [Rh(nbd)Cl]2 /NEt3 to give materials with properties typical of poly(phenylacetylene)s prepared with this catalyst/co-catalyst combination. It is demonstrated that the F5 PA repeat units in these new (co)polymers serve as convenient reactive species for post-polymerization modification with thiols via para-fluoro aromatic nucleophilic substitution reactions to give an entirely new family of novel thioether-functional polyene materials accompanied by absorption maxima shifts of up to 130 nm. Finally, the electrochemical properties of these new fluorinated polyene materials are briefly examined and the distinct difference in behavior of the F5 PA homopolymer versus polyphenylacetylene, copolymers, and functional derivatives is highlighted.

Stimulus-Responsive Nanoparticles and Associated (Reversible) Polymorphism via Polymerization Induced Self-assembly (PISA).

Polymerization-induced self-assembly (PISA) is an extremely versatile method for the in situ preparation of soft-matter nanoparticles of defined size and morphologies at high concentrations, suitable for large-scale production. Recently, certain PISA-prepared nanoparticles have been shown to exhibit reversible polymorphism ("shape-shifting"), typically between micellar, worm-like, and vesicular phases (order-order transitions), in response to external stimuli including temperature, pH, electrolytes, and chemical modification. This review summarises the literature to date and describes molecular requirements for the design of stimulus-responsive nano-objects. Reversible pH-responsive behavior is rationalised in terms of increased solvation of reversibly ionized groups. Temperature-triggered order-order transitions, conversely, do not rely on inherently thermo-responsive polymers, but are explained based on interfacial LCST or UCST behavior that affects the volume fractions of the core and stabilizer blocks. Irreversible morphology transitions, on the other hand, can result from chemical post-modification of reactive PISA-made particles. Emerging applications and future research directions of this "smart" nanoparticle behavior are reviewed.

RAFT dispersion polymerization of 3-phenylpropyl methacrylate with poly[2-(dimethylamino)ethyl methacrylate] macro-CTAs in ethanol and associated thermoreversible polymorphism.

The direct synthesis of methacrylic-based soft polymeric nanoparticles via reversible addition-fragmentation chain transfer dispersion polymerization (RAFTDP) is described. The use of poly[2-(dimethylamino)ethyl methacrylate]s, of varying average degree of polymerization (X¯n), as the stabilizing blocks for the RAFTDP of 3-phenylpropyl methacrylate (PPMA) in ethanol at 70 °C, at various total solids contents, yielded the full spectrum of self-assembled nanoparticles (spherical and worm aggregates and polymersomes). We also demonstrate that nanoparticle morphology can be tuned simply by controlling temperature. This is especially evident in the case of worm aggregates undergoing a thermoreversible transition to spherical species - a process that is accompanied by a macroscopic degelation-gelation process.

Mechano-responsive polymer solutions based on CO2 supersaturation: shaking-induced phase transitions and self-assembly or dissociation of polymeric nanoparticles.

Mechanical stimulation of supersaturated aqueous CO2 solutions is accompanied by a pH increase within seconds. In solutions of tailored homo- and AB diblock copolymers this is exploited to induce micelle formation, or, taking advantage of an aqueous upper critical solution temperature transition, nanoparticle disassembly.

Novel α,α-bischolesteryl functional (co)polymers: RAFT radical polymerization synthesis and preliminary solution characterization.

Well-defined poly[pentafluorophenyl (meth)acrylate] (PPFP(M)A) homopolymers are prepared by RAFT radical polymerization mediated by a novel chain transfer agent containing two cholesteryl groups in the R-group fragment. Subsequent reaction with a series of small-molecule amines in the presence of an appropriate Michael acceptor for ω-group end-capping yields a library of novel bischolesteryl functional hydrophilic homopolymers. Two examples of statistical copolymers are also prepared including a biologically relevant sugar derivative. Specific examples of these homopolymers are examined with respect to their ability to self assemble in aqueous media-a process driven entirely by the cholesteryl end groups. In all instances evaluated, and under the preparation conditions examined, the homopolymers aggregate clearly forming polymersomes spanning an impressive size range.

Combining ring-opening metathesis polymerization and thiol-ene coupling chemistries: facile access to novel functional linear and nonlinear macromolecules.

The aim of this article is to highlight recent examples in which two powerful synthetic tools, namely ring-opening metathesis polymerization (ROMP) and thiol-ene (including the thiol-Michael variant) click chemistry have been combined to facilitate the preparation of novel functional materials of varying topology.

Amidine functionality as a stimulus-responsive building block.

This mini-review describes basic features and applications of small molecules and macromolecules containing amidine, and to a lesser extent, guanidine functional groups. The emphasis in this article is on the exploitation of such functionality as species that are capable of reversibly binding carbon dioxide in the presence of water, a process that also commonly involves a hydrophobic-to-hydrophilic transition. The review is not intended to be exhaustive but rather serves to highlight this one particular feature and demonstrate its application in areas ranging from reversible emulsion stabilization, purification and reversible self-assembly of polymeric nanoparticles.

RAFT polymerization and thiol chemistry: a complementary pairing for implementing modern macromolecular design.

Reversible addition fragmentation chain transfer (RAFT) polymerization is one of the most extensively studied reversible deactivation radical polymerization methods for the production of well-defined polymers. After polymerization, the RAFT agent end-group can easily be converted into a thiol, opening manifold opportunities for thiol modification reactions. This review is focused both on the introduction of functional end-groups using well-established methods, such as thiol-ene chemistry, as well as on creating bio-cleavable disulfide linkages via disulfide exchange reactions. We demonstrate that thiol modification is a highly attractive and efficient chemistry for modifying RAFT polymers.

Combining RAFT radical polymerization and click/highly efficient coupling chemistries: a powerful strategy for the preparation of novel materials.

This paper highlights the powerful combination of reversible addition-fragmentation chain transfer (RAFT) radical polymerization and various click/coupling chemistries. This is not an exhaustive review but rather an overview demonstrating the impressive possibilities that the "marriage" of these two synthetic approaches offers in modern macromolecular design and synthesis.

Thiol-click chemistry: a multifaceted toolbox for small molecule and polymer synthesis.

The merits of thiol-click chemistry and its potential for making new forays into chemical synthesis and materials applications are described. Since thiols react to high yields under benign conditions with a vast range of chemical species, their utility extends to a large number of applications in the chemical, biological, physical, materials and engineering fields. This critical review provides insight into emerging venues for application as well as new mechanistic understanding of this exceptional chemistry in its many forms (81 references).

Improved molecular weight control in ring-opening metathesis polymerization (ROMP) reactions with ru-based olefin metathesis catalysts using N donors and acid: a kinetic and mechanistic investigation.

The effect of the addition of H(3)PO(4) on the ROMP activity of cyclooctene (COE) with first- [Cl(2)(PCy(3))(2)Ru=CHPh] and second-generation [(H(2)IMes)Cl(2)(PCy(3))Ru=CHPh] Grubbs' catalysts 1 and 4 (Cy=cyclohexyl, Ph=phenyl, Mes=2,4,6-trimethylphenyl (mesityl)), their inhibited mixtures with 1-methylimidazole (MIM), as well as their isolated bis-N,N'-dimethylaminopyridine (DMAP) derivatives [Cl(2)(PCy(3))(DMAP)(2)Ru=CHPh)] (5 b) and [Cl(2)(H(2)IMes)(DMAP)(2)Ru=CHPh] (7 b) (DMAP=dimethylaminopyridine), a novel catalyst, has been investigated. The studies include the determination of their initiation rates, as well as a determination of the molecular weights and molecular weight distributions of the polymers obtained with these catalysts and catalyst mixtures from the exo-7-oxanorbornene derivative 11. The structure of catalyst 7 b was confirmed by means of X-ray diffraction. All N-donor-bearing catalysts or N-donor-containing catalyst mixtures not only exhibited elevated activity in the presence of acid, but also increased initiation rates. Using the reversible inhibition/activation protocol with MIM and H(3)PO(4) enabled us to conduct controlled ROMP with catalyst 4 producing the isolated exo-7-oxanorbornene-based polymer 12 with predetermined molecular weights and narrow molecular weight distributions. This effect was based on fast and efficient catalyst initiation in contrast to the parent catalyst 4. Hexacoordinate complex 5 b also experienced a dramatic increase in initiation rates upon acid-addition and the ROMP reactions became well-controlled in contrast to the acid-free reaction. In contrast, complex 7 b performs well-controlled ROMP in the absence of acid, whereas the polymerization of the same monomer becomes less controlled in the presence of H(3)PO(4). The closer evaluation of catalysts 5 b and 7 b demonstrated that their initiation rates exhibit a linear dependency on the substrate concentration in contrast to catalysts 1 and 4. As a consequence, their initiation rates are determined by an associative step, not a dissociative step as seen for catalysts 1 and 4. A feasible associative metathesis initiation mechanism is proposed.

Sequential phosphine-catalyzed, nucleophilic thiol-ene/radical-mediated thiol-yne reactions and the facile orthogonal synthesis of polyfunctional materials.

The first example of highly efficient sequential thiol-ene/thiol-yne reactions conducted in an orthogonal manner is presented and its broad application in the synthesis of polyfunctional materials demonstrated. The anionic chain mechanism of the phosphine-mediated thiol-ene reaction is highlighted, as is the radical-mediated thiol-yne reaction. Kinetic data for a model reaction are presented, followed by a discussion of the synthesis of a range of materials with diverse functionality, including an example of potential biomedical significance.

RAFT synthesis and stimulus-induced self-assembly in water of copolymers based on the biocompatible monomer 2-(methacryloyloxy)ethyl phosphorylcholine.

Reversible addition-fragmentation chain transfer (RAFT) radical polymerization, mediated by 4-cyanopentanoic acid dithiobenzoate and 4,4'-azobis(4-cyanovaleric acid) (V-501) in water at 70 degrees C, of biocompatible 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) yields a macro-chain transfer agent (CTA) that was employed in the synthesis of a range of stimulus-responsive AB diblock copolymers in protic media. Well-defined block copolymers of varying molar composition, with narrow molecular weight distributions (M(w)/M(n) = 1.10-1.24) were prepared with N,N-diethylacrylamide (DEAm), 4-vinylbenzoic acid (VBZ), N-(3-sulfopropyl)-N-methacryloyloxyethyl-N,N-dimethylammonium betaine (DMAPS), and the newly synthesized N,N-di-n-propylbenzylvinylamine (DnPBVA) in either methanol, 2,2,2-trifluoroethanol, or aqueous media. When a combination of (1)H NMR spectroscopy and dynamic light scattering is used, it is shown that all block copolymers are capable of existing as molecularly dissolved chains in aqueous media with average hydrodynamic diameters of approximately 6-7 nm provided the aqueous environment is appropriately tuned. Similarly, these unimers can be induced to undergo self-assembly in the same aqueous environment provided the correct external stimulus (change in temperature, pH, or electrolyte concentration) is applied. In such instances, aggregates with average sizes in the range of approximately 22-180 nm are formed and are most likely due to the formation of polymeric micelles and vesicles. Such self-assembly is also completely reversible. Removal, or reversal, of the applied stimulus results in the reorganization to the unimeric state.

Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine alpha-hydroxylating monooxygenase (PHM).

Peptidyl alpha-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of alpha-amidated peptide hormones in mammals and insects. PHM is a potential target for the development of inhibitors as drugs for the treatment of human disease and as insecticides for the management of insect pests. We show here that relatively simple ground state analogs of the PHM substrate hippuric acid (C(6)H(5)-CO-NH-CH(2)-COOH) inhibit the enzyme with K(i) values as low as 0.5microM. Substitution of sulfur atom(s) into the hippuric acid analog increases the affinity of PHM for the inhibitor. Replacement of the acetylglycine moiety, -CO-NH-CH(2)-COOH with an S-(thioacetyl)thioglycolic acid moiety, -CS-S-CH(2)-COOH, yields compounds with the highest PHM affinity. Both S-(2-phenylthioacetyl)thioglycolate and S-(4-ethylthiobenzoyl)thioglycolic acid inhibit the proliferation of cultured human prostate cancer cells at concentrations >100-fold excess of their respective K(i) values. Comparison of K(i) values between mammalian PHM and insect PHM shows differences in potency suggesting that a PHM-based insecticide with limited human toxicity can be developed.

Convergent synthesis of 3-arm star polymers from RAFT-prepared poly(N,N-diethylacrylamide) via a thiol-ene click reaction.

A novel convergent route to 3-arm star polymers is described that takes advantage of RAFT-synthesized homopolymers serving as masked macromolecular terminal thiol-containing materials capable of undergoing thiol-ene click reactions.