Milan Marić

Leaching of the plasticizer di(2-ethylhexyl)phthalate (DEHP) from plastic containers and the question of human exposure

Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer to render poly(vinyl chloride) (PVC) soft and malleable. Plasticized PVC is used in hospital equipment, food wrapping, and numerous other commercial and industrial products. Unfortunately, plasticizers can migrate within the material and leach out of it over time, ending up in the environment and, frequently, the human body. DEHP has come under increased scrutiny as its breakdown products are believed to be endocrine disruptors and more toxic than DEHP itself. DEHP and its breakdown products have been identified as ubiquitous environmental contaminants, and daily human exposure is estimated to be in the microgram per kilogram level. The objective of this review is to summarize and comment on published sources of DEHP exposure and to give an overview of its environmental fate. Exposure through bottled water was examined specifically, as this concern is raised frequently, yet only little exposure to DEHP occurs through bottled water, and DEHP exposure is unlikely to stem from the packaging material itself. Packaged food was also examined and showed higher levels of DEHP contamination compared to bottled water. Exposure to DEHP also occurs in hospital environments, where DEHP leaches directly into liquids that passed through PVC/DEHP tubing and equipment. The latter exposure is at considerably higher levels compared to food and bottled water, specifically putting patients with chronic illnesses at risk. Overall, levels of DEHP in food and bottled water were below current tolerable daily intake (TDI) values. However, our understanding of the risks of DEHP exposure is still evolving. Given the prevalence of DEHP in our atmosphere and environment, and the uncertainty revolving around it, the precautionary principle would suggest its phaseout and replacement. Increased efforts to develop viable replacement compounds, which necessarily includes rigorous leaching, toxicity, and impact assessment studies, are needed before alternative plasticizers can be adopted as viable replacements.

Designing green plasticizers: Influence of molecular geometry on biodegradation and plasticization properties

The plasticizer di (2-ethylhexyl) phthalate (DEHP) and its metabolites are considered ubiquitous contaminants, which have a range of implications on the environment and human health. This work considered several alternative compounds with structural features similar to DEHP. This added to the understanding of why DEHP is so poorly biodegraded once it enters the environment. These alternative compounds were based on 2-ethylhexyl diesters of maleic acid (cis-isomer), fumaric acid (trans-isomer) and succinic acid (saturated analogue). The rates of biodegradation by the common soil bacterium Rhodococcus rhodocrous were shown to be dependent on the structure of the central unit derived from the diacid used to make the ester. The diacid components of DEHP and the maleate both had a cis orientation and they were the two that were slow to biodegrade. Plasticizing properties were also compared and, because the ester of the saturated succinic acid was degraded quickly and also had good plasticizing properties, it was concluded that the succinic esters of straight chain alcohols would make the best green plasticizers. The maleate ester had excellent plasticizing properties but this is mitigated by a significant resistance to biodegradation.

Nitroxide mediated controlled synthesis of glycidyl methacrylate-rich copolymers enabled by SG1-based alkoxyamines bearing succinimidyl ester groups

The controlled nitroxide-mediated copolymerization of glycidyl methacrylate (GMA) and styrene (S) with varying GMA molar feed fractions (fGMA,0 = 0.12–0.94) was accomplished by using a SG1-based alkoxyamine initiator bearing a N-succinimidyl ester group (NHS-BlocBuilder) in 50 wt% 1,4-dioxane solution at 90 °C. Copolymerizations indicated linear evolution of number average molecular weight Mn with respect to conversion up to approximately 50% and narrow molecular weight distributions with Mw/Mn = 1.22–1.44 and GMA incorporation into copolymer (FGMA) as high as 0.92. No additional SG1 free nitroxide was required to control polymerizations, even at high fGMA,0. Chain extensions of poly(GMA-ran-S) macroinitiators with S at 110 °C yielded a high fraction of block copolymer in most cases (except at the highest FGMA), as clear, monomodal shifts in Mn using gel permeation chromatography (GPC) were observed, thereby suggesting the poly(GMA-ran-S) macroinitiators were substantially “living”.

Designing green plasticizers: influence of alkyl chain length on biodegradation and plasticization properties of succinate based plasticizers.

Phthalate diesters such as di (2-ethylhexyl) phthalate (DEHP) are considered ubiquitous contaminants and are poorly biodegraded in the environment. Moreover, both the parent compound and stable metabolites such as mono (2-ethylhexyl) phthalate (MEHP) are linked to several negative impacts on the environment and human health. Earlier work established that saturated diester compounds, such as succinates, showed better biodegradation characteristics and comparable plasticizer properties compared to DEHP. In this work we examine the effect of alkyl chain length of succinate molecules on plasticizer and biodegradation properties. This included both the side chains (n-ethyl to n-octyl) as well as substituents on the middle part of the succinate molecule. We showed that the common soil bacterium Rhodococcus rhodocrous could rapidly break down all unsubstituted succinates, without the appearance of stable metabolites. Furthermore, the organisms used the plasticizer metabolites as carbon source. The introduction of a large cyclohexyl substituent on the succinate resulted in a poorer degradation rate. Glass Transition Temperature (Tg) measurements were performed to evaluate plasticizer properties and showed that longer side chains reduced the Tg more efficiently, while large cyclohexyl substituents on the succinate decreased this effect. However, all compounds performed better or equal to DEHP at reducing the Tg.

Metabolites from the biodegradation of 1,6-hexanediol dibenzoate, a potential green plasticizer, by Rhodococcus rhodochrous

Metabolites from the biodegradation of a potential plasticizer 1,6-hexanediol dibenzoate in the presence of n-hexadecane as a co-substrate by the common soil organism Rhodococcus rhodochrous were identified using GC/MS and Fourier transform mass spectroscopy (FTMS) techniques. Trimethylsilylation of compounds from the biodegradation broth permitted detection of the following metabolites: 1-hexadecyl benzoate, 6-benzoyloxyhexanoic acid, 4-benzoyloxybutanoic acid, 6-benzoyloxyhexan-1-ol and benzoic acid. The presence of these metabolites was confirmed by repeating the biodegradation with 1,6-hexanediol di[(2)H(5)]benzoate, by measurement of their exact masses in FTMS and by comparison with available authentic materials. The results show that biodegradation of 1,6-hexanediol dibenzoate by R. rhodochrous does not lead to the accumulation of persistent metabolites as has been reported for commercial dibenzoate plasticizers.

Mechanisms of biodegradation of dibenzoate plasticizers

Biodegradation mechanisms were elucidated for three dibenzoate plasticizers: diethylene glycol dibenzoate (D(EG)DB), dipropylene glycol dibenzoate (D(PG)DB), both of which are commercially available, and 1,6-hexanediol dibenzoate, a potential green plasticizer. Degradation studies were done using Rhodococcus rhodochrous in the presence of pure alkanes as a co-substrate. As expected, the first degradation step for all of these systems was the hydrolysis of one ester bond with the release of benzoic acid and a monoester. Subsequent biodegradation of the monobenzoates of diethylene glycol (D(EG)MB) and dipropylene glycol (D(PG)MB) was very slow, leading to significant accumulation of these monoesters. In contrast, 1,6-hexanediol monobenzoate was quickly degraded and characterization of the metabolites indicated that the biodegradation proceeded by way of the oxidation of the alcohol group to generate 6-(benzoyloxy) hexanoic acid followed by beta-oxidation steps. This pathway was blocked for D(EG)MB and D(PG)MB by the presence of an ether function. The use of a pure hydrocarbon as a co-substrate resulted in the formation of another class of metabolites; namely the esters of the alcohols formed by the oxidation of the alkanes and the benzoic acid released by hydrolysis of the original diesters. These metabolites were biodegraded without the accumulation of any intermediates.

Designing greener plasticizers: Effects of alkyl chain length and branching on the biodegradation of maleate based plasticizers.

The ubiquitous presence of the plasticizer di (2-ethylhexyl) phthalate (DEHP) in the environment is of concern due to negative biological effects associated with it and its metabolites. In particular, the metabolite mono (2-ethylhexyl) phthalate (MEHP) is a potential endocrine disruptor. Earlier work had identified the diester di (2-ethylhexyl) maleate (DEHM) as a potential greener candidate plasticizer to replace DEHP, yet its biodegradation rate was reported to be slow. In this study, we modified the side chains of maleate diesters to be linear (i.e., unbranched) alkyl chains that varied in length from ethyl to n-octyl. The plasticization efficiency of these compounds blended into PVC at 29 wt.% increased with the overall length of the molecule, but all compounds performed as well as or better than comparable samples with DEHP. Tests conducted with the equally long DEHM and dihexyl maleate (DHM) showed that branching has no effect on glass transition temperature (Tg) reduction efficiency. Biodegradation experiments with the common soil bacterium Rhodococcus rhodocrous in the presence of the plasticizer showed acceptable hydrolysis rates of maleates with unbranched side chains, while the branched DEHM showed almost no degradation. The addition of hexadecane as auxiliary carbon source improved hydrolysis rates. Temporary buildup of the respective monoester of the compounds were observed, but only in the case of the longest molecule, dioctyl maleate (DOM), did this buildup lead to growth inhibition of the bacteria. Maleates with linear side chains, if designed and tested properly, show promise as potential candidate plasticizers as replacements for DEHP.

Statistical terpolymers with thermo-responsive fluorescence response in an ionic liquid: effects of solvatophilicity on LCST phase separation and reversibility

Well-defined terpolymers of benzyl methacrylate (BzMA) and 9-(4-vinylbenzyl)-9H-carbazole (VBK) with either methyl methacrylate (MMA) or oligo(ethylene glycol)methacrylate (OEGMA) were synthesized to study their LCST-type phase behavior (due to BzMA) and fluorescence properties (due to VBK) in a hydrophobic ionic liquid IL, 1-ethyl-3-methylimidazolium bis(trifluoromethane sulfone)imide ([C2mim][NTf2]) as a function of solvatophilicity and the difference in terpolymer chain mobility (via glass transition differences due to using MMA versus OEGMA). Specifically, MMA and OEGMA provided solvatophilic groups (the ester in MMA or ethylene glycol units in OEGMA) to the terpolymers and their composition was varied to study the effect of solvatophilicity on the terpolymer phase separation and re-dissolution processes in the IL. The concentration of solvatophilic groups in the terpolymer was not only shown to affect phase separation temperature significantly, but also demonstrated to be crucial in driving the re-dissolution process. A minimum concentration of solvatophilic groups to facilitate reversible phase separation was in the range of 20–30 mol% for both terpolymer systems. Solution concentration (1–10 wt%) also showed significant effects on phase separation temperature but lower concentration did not guarantee improved re-dissolution. Phase separation temperature was also demonstrated to be inversely proportional to the polymer molecular weight (7.3–22.5 kg mol−1). Finally, the reversibility of phase separation and fluorescence responses in terpolymers with sufficient solvatophilicity was confirmed to be consistent by multiple heating/cooling cycles.

Amphiphilic core-shell nanoparticles with dimer fatty acid-based aliphatic polyester core and zwitterionic poly(sulfobetaine) shell for controlled delivery of curcumin

ABSTRACT Multifunctional nanocarriers are gaining increasing research interest as polymeric platforms for targeted drug delivery in cancer therapy and diagnosis. In this work, preparation and characterization of surfactant-free polyester nanoparticles (NPs) from a bio-based poly(butylene sebacate-co-butylene dilinoleate)s, poly(butylene sebacate) (PBSE)/poly(butylene dilinoleate) (PBDL), using nanoprecipitation, is reported. The polymeric nanoparticles (sizes narrowly distributed in a range less than 100 nm) were loaded with curcumin (CURC) with an encapsulation efficiency of 98% and drug loading (DL) content of 5–10% wtdrug/wtpolymer. The CURC-loaded nanoparticles were efficiently coated with a novel poly(sulfobetaine)-type zwitterionic polymer synthesized by nitroxide-mediated polymerization and postpolymerization functionalization step. Free and CURC formulated into noncoated and poly(sulfobetaine)-type zwitterionic polymer-coated nanoparticles were further investigated for cytotoxicity and antioxidant activity in a panel of human cell lines and rat liver microsomes, respectively. Formulated into coated NPs, CURC has superior cytotoxic and antioxidant activity versus the free drug and CURC incorporated in noncoated NPs. In addition, cell viability experiments of nonloaded nanoparticles, both coated and noncoated, demonstrated that developed nanoparticles are nontoxic, making them potentially suitable candidates for systemic passive targeting in cancer therapy, namely for treatment of solid tumors exhibiting high tumor accumulation of NPs due to enhanced permeability and retention effect. Polyzwitterion-coated nanoparticles exhibited slower drug release compared with the noncoated ones (half as much after 24 h) presumably due to the presence of the polymer shell around nanoparticles associated with a wider diffusion layer around the particles. GRAPHICAL ABSTRACT

Poly(styrene- alt -maleic anhydride)- block -poly(methacrylate- ran -styrene) block copolymers with tunable mechanical properties by nitroxide mediated controlled radical polymerization

Poly(styrene-alt-maleic anhydride)-block-poly(methacrylate-ran-styrene) block copolymers were synthesized from low dispersity (Mw/Mn=1.24) and perfectly alternating poly(styrene-alt-maleic anhydride) macroinitiators, by nitroxide mediated controlled radical polymerization (NMP), using various methacrylate-rich mixtures: methyl methacrylate/styrene (MMA/S), ethyl methacrylate/styrene (EMMA/S), n-butyl methacrylate/styrene (BMA/S) and benzyl methacrylate/styrene (BzMA/S). Some irreversible termination was present during the chain extension from the macroinitiator, resulting in some bimodality in the molecular weight distribution of the final block copolymer (≈2% to ≈25% dead chains) which is common for methacrylate/styrene copolymerizations by NMP. The resulting final block copolymers were determined to be methacrylate-rich (molar ratio XMA/S ≈3.3 to 5.5) by 1H NMR and the resulting glass transition temperature (Tg) of the chain-extended segments were found to be similar to the coresponding pure poly(methacrylate)s. NMP allows the controlled placement of functional maleic anhydride containing segments within a block copolymer with tunable mechanical properties by simple substitution of methacrylate monomer used in synthesis.