Structural alerts for the excess toxicity of acrylates, methacrylates, and propiolates derived from their short-term and long-term bacterial toxicity

For eight acrylates, three methacrylates, and three propiolates as three subclasses of α,β-unsaturated esters, short-term and long-term bacterial toxicity with Vibrio fischeri was determined in terms of EC(50) (effective concentration 50%) values for the 30-min bioluminescence and 24-h growth inhibition. To this end, experimental exposure concentrations were corrected for volatilization through a thermodynamic model based on Henry's law constant of the compounds. Moreover, toxicity enhancements T(e) as the ratio of narcosis-predicted over actual EC(50) were determined and discussed in terms of underlying mechanisms of reaction of the electrophiles with endogenous nucleophiles such as glutathione (GSH) and proteins. Overall, log EC(50) [M] ranges from -2.28 to -3.70 (30 min) and from -2.80 to -5.28 (24 h), respectively, indicating a significantly larger sensitivity of the growth inhibition bioassay for the reactive toxicity of these Michael acceptors. The latter is also reflected in the observed toxicity enhancements, where log T(e) > 1 was obtained for only 5 of 14 30-min EC(50) values but for 11 of 13 24-h EC(50) values. Moreover, the average long-term to short-term difference in log T(e) is 1 unit for the acrylates and 0.7 units for both methacrylates and propiolates. Methacrylates exert narcosis-level toxicity except for the methyl derivative in the long-term assay. The log EC(50) (24 h) of a subset of 10 mostly excess-toxic acrylates and a propiolate correlates with their logarithmic rate constants of reaction with GSH, log k(GSH), significantly more than with log K(ow) (r(2) 0.76 vs 0.47), yielding a respective regression rms of 0.34 log units. For allyl and propargyl acrylate as well as propargyl methacrylate, the observed excess toxicity is likely caused by initial enzymatic hydrolysis and subsequent oxidation of the α,β-unsaturated alcohols to the respective carbonyls. The latter shows that in the context of nonanimal testing schemes such as for REACH, the metabolic capacity of in vitro screens requires attention.     

Toxicity profiles of four metals and 17 xenobiotics in the human hepatoma cell line HepG2 and the protozoa Tetrahymena pyriformis—A comparison

We performed an interspecies comparison for the human hepatoma cell line HepG2 and the eukaryotic single cell organism Tetrahymena pyriformis (T. pyriformis) for 17 xenobiotics with diverse structures and four metals. The cytotoxicity was assessed by four different cell viability assays (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide reduction (MTT), neutral red uptake (NRU), resazurin dye (AlamarBlue), 5‐carboxyfluorescein diacetate acetoxymethyl ester (CFDA‐AM)) for the HepG2 and by cell count and MTT for T. pyriformis. For HepG2 cells, the results revealed interassay variations depending on the compound. The highest assay conformity was found for the metal Hg²⁺ and the fungicide prochloraz. The AlamarBlue assay was the most sensitive assay according to low‐effect concentrations. By contrast, the NRU assay was comprised of more frequent whole concentration response relationships and was more susceptible to EC₅₀. For T. pyriformis the EC₅₀ values of the two applied assays displayed a high conformity (R² = 0.97). Comparing the EC₅₀ values obtained by the MTT assay for the two cell models, a direct correlation was absent for the xenobiotics and only present for the metals (Cd²⁺, Cu²⁺, and Ni²⁺). Moreover, the protozoa T. pyriformis displayed a 20 times higher sensitivity than the cell line. The highest interspecies difference of three log degrees was obtained for the polycyclic aromatic hydrocarbon fluoranthene. In addition, a correlation of the EC₅₀ values and octanol‐water partition coefficient (log K_OW) of the xenobiotics was performed. No correlation was found for HepG2, and a weak one for T. pyriformis. Interestingly, the interspecies difference of logarithmized EC₅₀ correlated positive with the log K_OW (R² = 0.65). In conclusion, to obtain reliable evidence for human cytotoxicity, more than one viability/cytotoxicity assay had to be applied for cell lines. Second, the human hepatoma cell line was less affected by the organic compounds than the eukaryotic single‐cell organism and was also less dependent on the log K_OW of the xenobiotic. © 2009 Wiley Periodicals, Inc. Environ Toxicol 26: 171–186, 2011.     

Assessment of microcystin distribution and biomagnification in tissues of aquatic food web compartments from a shallow lake and evaluation of potential risks to public health

The objectives of this study were: (1) to examine the distribution and bioaccumulation of microcystins in the main components of the food web (phytoplankton, zooplankton, crayfish, shrimp, mussel, snail, fish, frog) of Lake Pamvotis (NW Greece), (2) to investigate the possibility of microcystin biomagnification and (3) to evaluate the potential threat of the contaminated aquatic organisms to human health. Significant microcystin concentrations were detected in all the aquatic organisms during two different periods, with the higher concentrations observed in phytoplankton and the lower in fish species and frogs. This is the first study reporting microcystin accumulation in the body of the freshwater shrimp Atyaephyra desmsaresti, in the brain of the fish species common carp (Cyprinus carpio) and in the skin of the frog Rana epirotica. Although there was no evidence for microcystin biomagnification, the fact that microcystins were found in lake water and in the tissues of aquatic organisms, suggests that serious risks to animal and public health are possible to occur. In addition, it is likely to be unsafe to consume aquatic species harvested in Lake Pamvotis due to the high-concentrations of accumulated microcystins.     

A review of the toxicological and environmental hazards and risks of tetrahydrofuran

Abstract

We present in this paper a review of the toxicological and environmental hazards, exposures and risks of tetrahydrofuran (THF; CASRN 109-99-9). THF is a polar solvent and monomer that is easily absorbed by all routes of exposure. The acute toxicity of THF is low to moderate by all routes. Irreversible corrosive damage to the eye can result from direct contact. However, THF is neither a skin irritant, nor sensitizer. Studies in vitro and in vivo have shown that THF is not mutagenic. Chronic studies have found benign tumors in the kidneys of male rats and in the livers of female mice. These findings have been examined, and although a mode of action is not known, the weight of evidence suggests that these tumors are likely not relevant to human health, but instead secondary to rodent-specific modes of action. THF produces transient sedative effects in rats at high concentrations but no significant neurobehavioral changes or neuropathology in sub-chronic studies. There were no specific effects reported on reproduction or developmental toxicity in rats or mice, with non-specific developmental toxicity observed only in the presence of significant maternal toxicity. The log K_ow value for THF is less than 3, indicating a low potential for bioaccumulation. THF is inherently biodegradable, thus is not expected to be environmentally persistent. THF does not present an ecotoxicity hazard based on test results in fish, aquatic invertebrates and plants. Exposures to THF in the workplace, to consumers and via environmental releases were modeled and all found to fall below the derived toxicity thresholds.     

In vitro influences of alcohols on mouse synaptosomes,and structure-activity relationships

 Little information is available on the structure-central nervous system membrane toxicity relationship of alcohols. The purpose of the present study was to study in vitro influence of alcohols (n=20) on the activity of the toxic indicator Na⁺/K⁺-adenosine triphosphatase (Na⁺/K⁺-ATPase) and acetylcholinesterase (AchE), and membrane fluidity in mouse brain synaptosomes, in terms of the structure-activity relationship. The potency of inhibition for the enzymes (IC₅₀) and the potency of increasing membrane fluidity (IC_12.5) were determined experimentally, and n-octanol/water partition coefficient (P) and the steric constant Taft Es are cited from the literature. Regression analysis revealed that log 1/IC₅₀ for Na⁺/K⁺-ATPase is a function of log P and Taft Es. The situation was true for AchE activity. The results indicate that the hydrophobicity expressed as log P and the steric effect of the alcohols play an important role in inhibiting both enzyme activities. A linear relationship between log 1/IC_12.5 for membrane fluidity and log P is shown, indicating a significant effect of the alcohols on membrane fluidity. Based on these results, it is suggested that the alcohols inhibit the Na⁺/K⁺-ATPase and AchE activity through a direct action on the enzymes and/or through changing the membrane fluidity. Received: 20 December 1994/Accepted: 2 March 1995     

Predicting toxic potencies of metal oxide nanoparticles by means of nano-QSARs

Background: The enormous physicochemical and structural diversity of metal oxide nanoparticles (MeONPs) poses significant challenges to the testing of their biological uptake, biodistribution, and effects that can be used to develop understanding of key nano-bio modes of action. This has generated considerable uncertainties in the assessment of their human health and environmental risks and has raised concerns about the adequacy of their regulation. In order to surpass the extremely resource intensive case-by-case testing, intelligent strategies combining testing methods and non-testing predictive modeling should be developed.

Methods: The quantitative structure-activity relationship (QSARs) in silico tools can be instrumental in understanding properties that affect the potencies of MeONPs and in predicting toxic responses and thresholds of effects.

Results: The present study proposes a predictive nano-QSAR model for predicting the cytotoxicity of MeONPs. The model was applied to test the relationships between 26 physicochemical properties of 51 MeONPs and their cytotoxic effects in Escherichia coli. The two parameters, enthalpy of formation of a gaseous cation (?H_me+) and polarization force (Z/r), were elucidated to make a significant contribution for the toxic effect of these MeONPs. The study also proposed the mechanisms of toxic potency in E. coli through the model, which indicated that the MeONPs as well as their released metal ions could collectively induce DNA damage and cell apoptosis.

Significance: These findings may provide an alternative method for prioritizing current and future MeONPs for potential in vivo testing, virtual prescreening and for designing environmentally benign nanomaterials.     

Exposure of newborns to aflatoxin M1 and B1 from mothers’ breast milk in Ankara,Turkey

Aflatoxins (AFs) are important risks for human health due to their widespread presence in foods and environment. However, contamination risk of breast milk with different pollutants including AFs is high in today’s life conditions. Since breast milk is a major nutrient for infants, feeding of infants with safe milk is essential. Therefore, the objective of this study was to determine the levels of AF M₁ and B₁ in breast milk samples collected from 75 mothers in Ankara, Turkey. AF M₁ and B₁ levels were investigated by high performance liquid chromatography (HPLC) with a fluorescence detector following an extraction procedure. The limit of detection was found to be 5 ng/l. Both AFs were detected in diverse degrees in all breast milk samples: The level of AF M₁ were in the ranges of 60.90–299.99 ng/l, and AF B₁ were in the ranges of 94.50–4123.80 ng/l. These results pointed out the exposure of mothers and neonates to AF M₁ and B₁, and the necessity of further research on mycotoxin contamination both in foods and biological fluids as well as protection strategies.     

Quantitative structure-permeation relationships for solute transport across silicone membranes

Purpose. The purpose of this work was to assess the molecular properties that influence solute permeation across silicone membranes and to compare the results with transport across human skin. Methods. The permeability coefficients (log K _p) of a series of model solutes across silicone membranes were determined from the analysis of simple transport experiments using a pseudosteady-state mathematical model of the diffusion process. Subsequently, structure-permeation relationships were constructed and examined, focusing in particular on the difference between solute octanol/water and 1,2-dichloroethane/water partition coefficients (log P _oct-dce), which reported upon H-bond donor activity, and the computationally derived molecular hydrogen-bonding potential. Results. The hydrogen-bond donor acidity and the lipophilicity of the compounds examined greatly influenced their permeation across silicone membranes. Furthermore, for a limited dataset, a significant correlation was identified between solute permeation across silicone membranes and that through human epidermis. Conclusion. The key molecular properties that control solute permeation across silicone membranes have been identified. For the set of substituted phenols and other unrelated compounds examined here, a similar structure-permeation relationship has been derived for their transport through human epidermis, suggesting application of the results to the prediction of flux across biological barriers.     

Glutathione depletion in rat hepatocytes: a mixture toxicity study with α,β-unsaturated esters

1. Glutathione (GSH) depletion is often reported as an early cytotoxic effect, caused by many reactive organic chemicals. In the present study, GSH depletion in primary rat hepatocytes was used as an in vitro effect-equivalent to measure the toxic potency of α,β-unsaturated esters (acrylates and methacrylates). 2. When these compounds were administered as a mixture, GSH depletion was dose additive. The result of the mixture study shows that GSH depletion may be a useful effect-equivalent for the risk assessment of mixtures of α,β-unsaturated esters. 3. To get more insight in the underlying mechanisms of GSH depletion, the metabolism of two esters was investigated in greater detail. One of them, allyl methacrylate, was metabolized to acrolein. This metabolic pathway can explain the high potency of allyl methacrylate to deplete GSH despite its low intrinsic chemical reactivity.     

Toxicity of ZnO/TiO2‐conjugated carbon‐based nanohybrids on the coastal marine alga Thalassiosira pseudonana

Increasing consumption of metal‐oxide nanoparticles (NPs) and carbon‐based nanomaterials has caused significant concern about their potential hazards in aquatic environments. The release of NPs into aquatic environments could result in adsorption of NPs on microorganisms. While metal‐oxide NP‐conjugated carbon‐based nanohybrids (NHs) may exhibit enhanced toxicity toward microorganisms due to their large surface area and the generation of reactive oxygen species (ROS), there is a lack of information regarding the ecotoxicological effects of NHs on marine diatom algae, which are an indicator of marine pollution. Moreover, there is scant information on toxicity mechanisms of NHs on aquatic organisms. In this study, four NHs (ie, ZnO‐conjugated graphene oxide [GO], ZnO‐conjugated carbon nanotubes [CNTs], TiO₂‐conjugated GO, and TiO₂‐conjugated CNT) that were synthesized by a hydrothermal method were investigated for their toxicity effects on a Thalassiosira pseudonana marine diatom. The in vitro cellular viability and ROS formation employed at the concentration ranges of 50 and 100 mg/L of NHs over 72 hours revealed that ZnO‐GO had the most negative effect on T. pseudonana. The primary mechanism identified was the generation of ROS and GO‐induced dispersion that caused electrostatic repulsion, preventing aggregation, and an increase in surface areas of NHs. In contrast to GO‐induced dispersion, large aggregates were observed in ZnO/TiO₂‐conjugated CNT‐based NHs. The scanning electron microscopy images suggest that NHs covered algae cells and interacted with them (shading effects); this reduced light availability for photosynthesis. Detailed in vitro toxicity effects and mechanisms that cause high adverse acute toxicity on T. pseudonana were unveiled; this implied concerns about potential hazards of these mechanisms in aquatic ecosystems.     

Synthesis and Neuropeptide Y Y1 Receptor Antagonistic Activity of N,N-Disubstituted ω-Guanidino- and ω-Aminoalkanoic Acid Amides

Potent arpromidine-type histamine H₂ receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y₁ receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr³⁶ in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y₁ antagonists in human erythroleukemia (HEL) cells (Ca²⁺ assay) achieving pKB values in the range of 6.3–6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H₂ receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y₁ antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.     

Potencies of antagonists chemically related to iodoproxyfan at histamine H3 receptors in mouse brain cortex and guinea-pig ileum: evidence for H3 receptor heterogeneity?

We determined the affinities of 16 newly synthesized H₃ receptor antagonists in an H₃ receptor binding assay and the potencies of 12 of these compounds at functional H₃ receptors in the mouse brain cortex and guinea-pig ileum. The compounds differ from histamine in that the C-C-N side chain is replaced by a chain of the structure C-C-C-O. The two major aims of the study were (1) to investigate whether the two functional H₃ receptors are pharmacologically different and (2) to derive structure-activity relationships.The specific binding of ³H-N ^a -methylhistamine to rat mine for its inhibitory effect on the electrically induced contraction in guinea-pig ileum strips; the apparent pA₂ values ranged from 5.97 to 9.00. Iodoproxyfan decreased the electrically induced contraction by itself and this effect was counteracted by the H₃ receptor antagonist thioperamide. The apparent pA₂ values in the two functional H₃ receptor models showed a highly significant correlation (r=0.882; P<0.001). Highly significant correlations were also obtained when the pK_i values of the compounds in the binding assay were compared to their apparent pA₂ values in the mouse brain (r=0.799; P<0.004) and in the guinea-pig ileum (r=0.851; P<0.001). In each of the three experimental models, iodoproxyfan was the most potent compound; its deiodo analogue was less potent by more than 1.1 log units.The present results show that the compounds under study possess moderate to high affinity and/or (partial) H₃ receptor antagonist potency. The two functional H₃ receptors in the mouse brain cortex and the guinea-pig ileum may be slightly different; further studies are necessary to clarify whether this difference is due to H₃ receptor heterogeneity, species variants or differences in the efficiency of receptor coupling. The marked difference in the affinity/potency between iodoproxyfan and its deiodo analogue may suggest that a highly lipophilic residue in that part of the molecule favours a high affinity/antagonistic potency at H₃ receptors.     

The use of genetically modified mice in cancer risk assessment: Challenges and limitations

Abstract

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53^+/?, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.     

Bilastine: an environmental risk assessment

Context: Bilastine is a new oral selective, non-sedating histamine H₁ antagonist for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. The European Medicines Agency requires an Environmental Risk Assessment (ERA) for all novel medicines for human use. Objective: To calculate the bilastine predicted environmental concentration in surface water (PEC_sw; phase I ERA), and to determine the effects of bilastine on aquatic systems (phase II [tier A]). Materials and methods: Bilastine PEC_sw was calculated using the maximum daily dosage (20?mg), assuming that all administered bilastine was released into the aquatic environment. A persistence, bioaccumulation and toxicity assessment was conducted using the log K_ow from the molecular structure. In phase II (tier A), a ready biodegradability test was performed, and bilastine’s potential toxicity to various aquatic and sediment-dwelling micro-organisms was evaluated. Results: Bilastine PEC_SW was calculated as 0.1?μg?L^?1, and the compound was not readily biodegradable. Bilastine had no significant effects on Chironomus riparius midges, or on the respiration rate of activated sludge. For green algae, the bilastine no observed effect concentration (NOEC) was 22?mg?L^?1; bilastine had no effect on zebra fish development, or on the reproduction rate of daphnids. Discussion: Bilastine NOEC values against zebra fish, algae, daphnids, and aerobic organisms in activated sludge were at least 130?000-fold greater than the calculated PEC_SW value. Conclusion: No environmental concerns exist from bilastine use in patients with allergic rhinoconjunctivitis or urticaria.     

Lipophilicity of Teicoplanin Antibiotics as Assessed by Reversed Phase High-performance Liquid Chromatography: Quantitative Structure-property and Structure-activity Relationships

Abstract— Structure-lipophilicity relationships of a large series of 63-COX teicoplanin antibiotic derivatives were examined, by correlating their capacity factors (log k_w), measured through reversed-phase high-performance liquid chromatography on Deltabond C₈ stationary phase, with some computed molecular properties such as fragmental log P constants (***_x), molecular volumes (V_x) and factors imparting hydrophilicity (e.g. amino groups in the X chain, nN). A number of equations were derived which demonstrate that variations of log k_w are mainly related to changes in bulk (modelled by V_x) and polarity (primarily modelled by nN) of X chains of teicoplanin derivatives. QSAR analysis revealed that in-vitro activity against E. coli increases as lipophilicity decreases and isoelectric point increases.     

Cultured fish cells for the ecotoxicity testing of aquatic pollutants

The volume of chemicals in everyday use that require ecotoxicity testing, the high-costs of using whole animals for initial screenings of chemicals for their cyto- and genotoxicities, and the need for a ?biological early warning signal”? to detect toxicants in aquatic environments have prompted the development of many microbial-based in vitro short-term bioassays. An area that has received relatively little study is the application of vertebrate cells, especially fish cells, for ecotoxicity testing of chemicals. From the few studies that are available it has been demonstrated that cultured, established fish cell lines can be used for (1) the in vitro cyto- and genotoxicity screening of known aquatic pollutants, (2) the in situ monitoring of natural waters and sediments for chemical cyto- and genotoxicants, and (c) elucidating structure-activity relationships among chemicals, which can thereby serve as a biological adjunct to computer-based mathematical predictions (QSARs) of chemical cyto- and genotoxicity.     

对氨基二苯醚类似物抑制细胞色素P-450的定量构效关系

测定了一组对氨基二苯醚类似物延长小鼠戊巴比妥睡眠时间和体外抑制未经处理的小鼠肝微粒体催化氧化对硝基茴香醚脱甲基的活性。用逐步多元回归分析法导出了这些类似物体内和体外抑制细胞色素P-450(P-450)的活性与量化指数的定量构效关系(QSAR)。结果表明:对氨基二苯醚类似物体内和体外抑制P-450的活性均与最低未占据分子轨道能级(E_LUMO)、氨基氮原子的亲核超离域度(S_N(N))和醚氧原子的亲核超离域度(S_N(O))相关。这些类似物的代谢中间体(MI)与P-450形成P-450代谢中间体络合物(P-450-MI)可能是它们能够抑制P-450的主要原因。     

Epidermal Iontophoresis: II. Application of the Ionic Mobility-Pore Model to the Transport of Local Anesthetics

Purpose. An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. Methods. The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. Results. The logarithm of the iontophoretic permeability coefficient (log PC _{j , iont} ) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PC _{j , iont} was best defined by ionic mobility (and its determinants: conductivity, pK_a and MW) and MW. Conclusions. Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pK_a) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.     

How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles

Due to its multifunctional applications, titanium dioxide particles have widespread use in commerce. The particle-types function as sources of pigment color, in food products, anti-bacterial components, ultraviolet radiation scavengers, catalysts, as well as in cosmetics. Because of its inherent properties in a diverse number of products, exposures may occur via any of the major point-of-entry routes, i.e., inhalation, oral or dermal. Although the majority of TiO₂ applications are known to exist in the pigment-grade form, nanoscale forms of TiO₂ are also common components in several products. This brief review is designed to identify relevant toxicology and risk-related issues which inform health effects assessments on the various forms of titanium dioxide particles. While there has been an abundance of hazard data generated on titanium dioxide particulates, many of the published reports have limited informational value for assessing health effects due, in large part, to shortcomings in experimental design issues, such as: (1) inadequate material characterization of test samples; (2) questionable relevance of experimental systems employed to simulate human exposures; (3) applications of generally high doses, exclusive focus on acute toxicity endpoints, and a lack of reference benchmark control materials, to afford interpretation of measured results; and/or (4) failure to recognize fundamental differences between hazard and risk concepts. Accordingly, a number of important toxicology issues are identified and integrated herein to provide a more comprehensive assessment of the health risks of different forms of pigment-grade and nanoscale titanium dioxide particles. It is important to note that particle-types of different TiO₂ compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings. In order to develop a more robust health risk evaluation of TiO₂ particle exposures, this review focuses on the following issues:

(1)

Introduction to TiO₂ particle chemistry/functionality and importance of robust material characterization of test samples;