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; (2) Implementation of meaningful hazard studies for gauging EHS safety issues – pulmonary bioassay data and development of the Nano Risk Framework for developmental nano TiO2 compounds; (3) Epidemiological study findings on titanium dioxide workers – the most heavily-exposed populations; (4) Methodologies for setting occupational exposure limits including benchmarking or bridging comparisons; and (5) The importance of particle overload data in the lungs of rats as it relates to gauging the relevance of health effects for humans. A comprehensive evaluation of the existing animal and human health data is a necessary prerequisite for facilitating accurate assessments of human health risks to TiO2 exposures.

Warheit DB 《-》

Risk assessment strategies for nanoscale and fine-sized titanium dioxide particles: Recognizing hazard and exposure issues.

The basic tenets for assessing health risks posed by nanoparticles (NP) requires documentation of hazards and the corresponding exposures that may occur. Accordingly, this review describes the range and types of potential human exposures that may result from interactions with titanium dioxide (TiO2) particles or NP - either in the occupational/workplace environment, or in consumer products, including food materials and cosmetics. Each of those applications has a predominant route of exposure. Very little is known about the human impact potential from environmental exposures to NP - thus this particular issue will not be discussed further. In the workplace or occupational setting inhalation exposure predominates. Experimental toxicity studies demonstrate low hazards in particle-exposed rats. Only at chronic overload exposures do rats develop forms of lung pathology. These findings are not supported by multiple epidemiology studies in heavily-exposed TiO2 workers which demonstrate a lack of correlation between chronic particle exposures and adverse health outcomes including lung cancer and noncancerous chronic respiratory effects. Cosmetics and sunscreens represent the major application of dermal exposures to TiO2 particles. Experimental dermal studies indicate a lack of penetration of particles beyond the epidermis with no consequent health risks. Oral exposures to ingested TiO2 particles in food occur via passage through the gastrointestinal tract (GIT), with studies indicating negligible uptake of particles into the bloodstream of humans or rats with subsequent excretion through the feces. In addition, standardized guideline-mandated subchronic oral toxicity studies in rats demonstrate very low toxicity effects with NOAELs of >1000 mg/kg bw/day. Additional issues which are summarized in detail in this review are: 1) Methodologies for implementing the Nano Risk Framework - a process for ensuring the responsible development of products containing nanoscale materials; and 2) Safe-handling of nanomaterials in the laboratory.

Warheit DB ，Donner EM 《-》

Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles.

Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of adverse toxicological effects. Apart from reporting the findings of these three studies, this publication also focuses on additional critical issues associated with particle and nanotoxicology studies. First, describing the detailed methodology requirements and rigor upon which the standardized OECD 408 guideline subchronic oral toxicity studies are conducted. Moreover, an attempt is made to reconcile the complex issue of particle size distribution as it relates to measurements of nanoscale and pigment-grade TiO2 particles. Clearly this has been a confusing issue and often misrepresented in the media and the scientific literature. It is clear that the particle-size distribution for pigment-grade TiO2, contains a small ("tail") component of nanoscale particles (i.e., 21% by particle number and <1% by weight in the test material used in the 90-day study). However, this robust particle characterization finding should not be confused with mislabeling the test materials as exclusively in the nanoscale range. Moreover, based upon the findings presented herein, there appears to be no significant oral toxicity impact contributed by the nanoscale component of the TiO2 Test Material sample in the 90-day study. Finally, it seems reasonable to conclude that the study findings should be considered for read-across purposes to food-grade TiO2 particles (e.g., E171), as the physicochemical characteristics are quite similar.

Warheit DB ，Brown SC ，Donner EM 《-》

Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area.

Warheit DB ，Webb TR ，Sayes CM ，Colvin VL ，Reed KL ... -  《-》

What is the impact of surface modifications and particle size on commercial titanium dioxide particle samples? - A review of in vivo pulmonary and oral toxicity studies - Revised 11-6-2018.

There is an ongoing discussion on the influence of surface-modifications on the toxicity of commercial particulate materials and how alterations in physical-chemical properties of surfaces impact toxicity. Titanium dioxide (TiO2) is a poorly soluble particulate material of significant socioeconomic importance that largely exists as surface-modified particle-types in commerce. The observed toxicological effects of TiO2 are primarily due to particle effects rather than substance chemistry, as such TiO2 is commonly considered to be a poorly soluble low toxicity (PSLT) particle. This review provides an overview of the effect of surface modifications on the pulmonary and oral toxicity of commercial TiO2 particles with emphasis on in vivo studies with appropriate controls, and where both surface modified and untreated materials are present in the same study. Published literature findings involving pulmonary and oral exposures to surface modified TiO2 particles were reviewed and evaluated for quality and commercial relevance. Suitable publications involving animal studies were identified and summarized. Several studies were identified that have evaluated commercially-relevant surface-modified forms of titanium dioxide with appropriate data quality and with direct comparison to untreated counterparts. Hydrophilic inorganic surface modifications including silica, alumina/alumina hydroxide depositions have been tested along with common hydrophilic and hydrophobic-organic surface treatments. The results for both pigmentary and nanoscale materials demonstrate similar behaviour and indicate limited impact of particle size, surface chemistry, surface charge and surface wettability on observed pulmonary or oral toxicity effects. The low intrinsic toxicity of the TiO2 base particle and evaluated surface modifications may account for the observed outcomes. A few published studies have drawn different conclusions; however, these were either not conducted using commercial TiO2 samples (with surface coatings), had several confounding variables to investigate, or were carried out using mouse strains. The differences in experimental designs are described. The identified pulmonary and oral toxicity studies largely indicate that surface modifications and particle size alone have little or no impact on the lung toxicity of TiO2 particles, following pulmonary exposures when all constituent materials are comprised of chemicals of low specific toxicity particles. In addition, based upon the results of 2 oral toxicity studies, one with surface treated TiO2 particles (OECD 408) and one without surface treated (OECD 407) TiO2 particles, there appears to have been no adverse impact on toxicity with the surface-coated material, as both studies produced no adverse effects at the very high doses tested.

Warheit DB ，Brown SC 《-》