What is titanium dioxide
Titanium dioxide (TiO2) can also be called titanium oxide or titania. Titanium (Ti) is the ninth most abundant element in the earth’s crust and Titanium never appears in a metallic state in nature. Titanium dioxide (TiO2), an odorless powder with a molecular weight of 79.9 g/mol, also known as Ti(IV) oxide, constitutes the naturally occurring oxide 1). Titanium dioxide minerals contain impurities such as iron, chromium, vanadium or zirconium that confer a spectrum of different colors. Manufactured titanium dioxide is, instead, a white powder commonly used as a pigment in ceramics, paints, coatings, plastics and paper due to its high refractive index. Pure titanium dioxide assembles in three crystal structures, i.e., anatase, rutile (with tetragonal coordination of Ti atoms) and brookite (with rhombohedral coordination of Ti atoms), but only anatase/rutile or mixtures of these two polymorphs are employed in food 2).
Food-grade titanium dioxide (TiO2) is manufactured from titanium minerals by either a sulfuric acid-based process, which can yield anatase, rutile or a mixture of both polymorphs depending on the reaction conditions, or a chlorine-based process yielding only the rutile form 3). Specifications for food use include a minimum purity of 99.0%, thus allowing some contamination with arsenic, cadmium and mercury (up to 1 mg/kg), antimony (up to 2 mg/kg) or lead (up to 10 mg/kg) 4). Also, food-grade titanium dioxide (TiO2) may be coated with a small proportion (no more than 2% in total) of alumina and silica to enhance technological properties, for example to improve dispersion in host matrices 5). All titanium dioxide particles are insoluble in water, organic solvents, hydrochloric acid and dilute sulfuric acid. They are highly stable to heat and remain unaffected by food processing. Also, titanium dioxide particles are not or only minimally degraded or dissolved under conditions, including low pH, which mimic the gastrointestinal milieu. Such indigestible particles, once released from the food matrix during their gastrointestinal transit, reach the intestinal mucosa raising the question of whether they might be prone to absorption and systemic distribution.
Titanium dioxide (TiO2) is a food color authorized as a food additive in the European Union (E 171). It was previously evaluated by the Scientific Committee on Food in 1975 and 1977, by the Joint FAO/WHO Expert Committee of Food Additives (JECFA) in 1969 6). The food additive titanium dioxide (E 171) is a white to slightly colored powder and it is insoluble in water and in organic solvents 7).
- Titanium dioxide (E 171) as a food additive is safe 8)
- Although titanium dioxide is generally regarded as a nontoxic mild lung irritant, some laboratory studies have reported lung adenomas in rats exposed to high levels of titanium dioxide. Limited data on health effects among humans exist. The International Agency for Research on Cancer 9) concluded that there is inadequate evidence from epidemiological studies to assess whether titanium dioxide dust causes cancer in humans, but that there is sufficient evidence for carcinogenicity in experimental animals, based on the induction of respiratory tract tumors in rats after prolonged titanium dioxide (TiO2) inhalation. Therefore, International Agency for Research on Cancer classified titanium dioxide as a Group 2B carcinogen 10).
The European Food Safety Authority Panel noted that, according to the data provided by interested parties and from the literature, titanium dioxide (E 171) as a food additive would not be considered as a nanomaterial according to the European Union Recommendation on the definition of a nanomaterial (i.e. ‘a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1–100 nano meter’).
Figure 1. Titanium dioxide
The European Food Safety Authority Panel was aware of the extensive database on titanium dioxide nanomaterials, however, most of these data were not considered relevant to the evaluation of titanium dioxide as the food additive (E 171). Therefore, the European Food Safety Authority Panel considered the titanium dioxide nanomaterials data could not be directly applied to the evaluation of titanium dioxide as food additive 11).
From the available data on absorption, distribution and excretion, the European Food Safety Authority Panel concluded that 12):
- the absorption of orally administered titanium dioxide is extremely low;
- the bioavailability of titanium dioxide (measured either as particles or as titanium) is low;
- the bioavailability measured as titanium appeared to be independent of particle size;
- the vast majority of an oral dose of titanium dioxide is eliminated unchanged in the feces;
- a small amount (maximum of 0.1%) of orally ingested titanium dioxide was absorbed by the gut‐associated lymphoid tissue (GALT) and subsequently distributed to various organs and elimination rates from these organs were variable.
The European Food Safety Authority Panel further concluded that there were significant and highly variable background levels of titanium in animals and humans, which presented challenges in the analysis at the low levels of titanium uptake reported and could complicate interpretation of the reported findings.
The European Food Safety Authority Panel concluded that, based on the available genotoxicity database and the European Food Safety Authority Panel’s evaluation of the data on absorption, distribution and excretion of micro‐ and nanosized titanium dioxide particles, orally ingested titanium dioxide particles (micro‐ and nanosized) are unlikely to represent a genotoxic hazard in vivo.
The European Food Safety Authority Panel noted that possible adverse effects in the reproductive system were identified in some studies conducted with material which was either non‐food‐grade or inadequately characterized nanomaterial (i.e. not E 171). There were no such indications in the available, albeit limited, database on reproductive endpoints for the food additive (E 171). The European Food Safety Authority Panel was unable to reach a definitive conclusion on this endpoint due to the lack of an extended 90‐day study as in the submission of food additives 13) or a multigeneration or extended‐one generation reproduction toxicity study with the food additive (E 171). Therefore, the European Food Safety Authority Panel did not establish an acceptable daily intake (ADI). Acceptable daily intake (ADI) is a measure of the amount of a specific substance (originally applied for a food additive, later also for a residue of a veterinary drug or pesticide) in food or drinking water that can be ingested orally on a daily basis over a lifetime without an appreciable health risk 14).
From a carcinogenicity study with titanium dioxide in mice and in rats, the European Food Safety Authority Panel chose the lowest no observable adverse effect level (NOAEL) reported which was 2,250 mg titanium dioxide/kg body weight per day for males from the rat study, the highest dose tested in this species and sex.
For the safety assessment of titanium dioxide used as a food additive, based on information reported in the examined literature and information supplied following calls for data taking into account the following considerations:
- the food additive E 171 mainly consists of microsized titanium dioxide particles, with a nanosized (< 100 nm) fraction less than 3.2% by mass;
- the absorption of orally administered titanium dioxide particles (micro‐ and nanosized) in the gastrointestinal tract is negligible, estimated at most as 0.02–0.1% of the administered dose;
- no difference is observed in the absorption, distribution and excretion of orally administered micro‐ and nanosized titanium dioxide particles;
- no adverse effect resulting from the eventual accumulation of the absorbed particles is expected based on the results of long‐term studies which did not highlight any toxicity up to the highest administered dose;
- the uncertainties in the toxicological database arising from limitations in the available reproductive toxicity studies;
The European Food Safety Authority Panel considered that an acceptable daily intake (ADI) should not be established, and that a margin of safety approach would be appropriate 15).
To assess the dietary exposure to titanium dioxide (E 171) from its use as a food additive, the exposure was calculated based on: maximum levels of data provided to European Food Safety Authority (defined as the maximum level exposure assessment scenario) and reported use levels (defined as the refined exposure assessment scenario) as provided by industry and the Member States.
Based on the available dataset, the European Food Safety Authority Panel calculated two refined exposure estimates based on different assumptions: a brand‐loyal consumer scenario, in which it is assumed that the population is exposed over a long period of time to the food additive present at the maximum reported use/analytical levels for one food category and to a mean reported use/analytical level for the remaining food categories; and a non‐brand‐loyal scenario, in which it is assumed that the population is exposed over a long period of time to the food additive present at the mean reported use/analytical levels in all relevant food categories.
For the maximum level exposure assessment scenario, at the mean, the exposure estimates ranged from 0.4 mg/kg body weight per day for infants and the elderly to 10.4 mg/kg body weight per day for children. At the 95th percentile, exposure estimates ranged from 1.2 mg/kg body weight per day for the elderly to 32.4 mg/kg body weight per day for children.
In the case of titanium dioxide, the European Food Safety Authority Panel did not identify brand loyalty to a specific food category and therefore the European Food Safety Authority Panel considered that the non‐brand‐loyal scenario covering the general population was the more appropriate and realistic scenario for risk characterization because it is assumed that the population would probably be exposed long term to food additives present at the mean reported use/analytical levels in processed food.
The European Food Safety Authority Panel noted that the lowest margin of safety calculated from the no observable adverse effect level (NOAEL) of 2,250 mg titanium dioxide/kg body weight per day identified in the available toxicological data and exposure data obtained from the reported use/analytical levels of titanium dioxide (E 171) considered in this opinion is above 100. In the Guidance for submission of food additives 16), the European Food Safety Authority Panel considered that, for non‐genotoxic and non‐carcinogenic compounds ‘a margin of safety of 100 or more between a NOAEL or benchmark dose level (BMDL) and the anticipated exposure would be sufficient to account for uncertainty factors for extrapolating between individuals and species’. Consequently, the European Food Safety Authority Panel considered that on the database currently available and the considerations on the absorption of titanium dioxide the margins of safety calculated from the NOAEL of 2,250 mg titanium dioxide/kg body weight per day identified in the toxicological data available and exposure data obtained from the reported use/analytical levels of titanium dioxide (E 171) considered in this opinion would not be of concern.
The European Food Safety Authority Panel concluded that once definitive and reliable data on the reproductive toxicity of E 171 were available, the full dataset would enable the European Food Safety Authority Panel to establish a health‐based guidance value of an acceptable daily intake (ADI).
Is titanium dioxide safe to eat
The re‐evaluation of titanium dioxide as a food additive (E 171) was completed by European Food Safety Authority in June 2016 and a scientific opinion was published in September 2016 17). In that opinion, European Food Safety Authority concluded, on the basis of the available evidence, that titanium dioxide (E 171) when used as a food additive does not raise a concern with respect to genotoxicity and that it is not carcinogenic after oral administration. However, several data gaps were also identified by European Food Safety Authority in the opinion. These warranted a follow‐up by the European Commission and new scientific evidence is being generated by interested parties in order to address the uncertainties highlighted by European Food Safety Authority in its scientific opinion.
From the available data on absorption, distribution and excretion, the European Food Safety Authority Panel on Food Additives and Nutrient Sources added to Food concluded in June 2016 that the absorption of orally administered titanium dioxide (TiO2) is extremely low and the low bioavailability of titanium dioxide (TiO2) appears to be independent of particle size 18). The European Food Safety Authority Panel concluded that the use of titanium dioxide (TiO2) as a food additive does not raise a genotoxic concern 19). From a carcinogenicity study with titanium dioxide (TiO2) in mice and in rats, the European Food Safety Authority Panel chose the lowest no observed adverse effects levels (NOAEL) which was 2,250 mg TiO2/kg body weight per day for males from the rat study, the highest dose tested in this species and sex. The European Food Safety Authority Panel noted that possible adverse effects in the reproductive system were identified in some studies conducted with material which was either non‐food‐grade or inadequately characterised nanomaterial (i.e. not E 171). There were no such indications in the available, albeit limited, database on reproductive endpoints for the food additive (E 171). The European Food Safety Authority Panel was unable to reach a definitive conclusion on this endpoint due to the lack of an extended 90‐day study or a multigeneration or extended‐one generation reproduction toxicity study with the food additive of titanium dioxide (TiO2, E 171). Therefore, the European Food Safety Authority Panel did not establish an acceptable daily intake (ADI). The European Food Safety Authority Panel considered that, on the database currently available and the considerations on the absorption of TiO2, the margins of safety calculated from the no observed adverse effects levels (NOAEL) of 2,250 mg TiO2/kg body weight per day identified in the toxicological data available and exposure data obtained from the reported use/analytical levels of TiO2 (E 171) would not be of concern 20). The European Food Safety Authority Panel concluded that once definitive and reliable data on the reproductive toxicity of E 171 were available, the full dataset would enable the European Food Safety Authority Panel to establish a health‐based guidance value of an acceptable daily intake (ADI).
On 22 March 2018, the European Commission, requested European Food Safety Authority to provide a scientific opinion in relation to four new animal and test tube studies by Heringa et al., 2016 21); Bettini et al., 2017 22); Guo et al., 2017 23) and Proquin et al., 2017 24), published after the scientific opinion in 2016 (see above), on the potential toxicity of titanium dioxide used as a food additive (E 171). In particular, European Food Safety Authority is requested to carry out a scientific evaluation of those studies and to indicate whether they would merit re‐opening the existing opinion of European Food Safety Authority related to the safety of titanium dioxide (E 171) as a food additive.
The European Food Safety Authority Panel has assessed the four publications as requested in the last mandate from the European Commission and made specific comments on each individual studies which have been considered in the context of the conclusions of the European Food Safety Authority opinion of 2016 25).
- Overall, based on the data provided in the Bettini et al. 26) publication, and the negative results of the carcinogenicity studies in mice and rats performed by National Cancer Institute 27), the European Food Safety Authority Panel considered that the new findings were not sufficient to raise a concern on the potential initiation or promotion properties of titanium dioxide (E 171) on colon cancer.
- Overall, the European Food Safety Authority Panel considered that the results reported in the Proquin et al. 28) study may be useful for an evaluation of the hazard of nano-titanium dioxide (nano-TiO2) under the specific conditions of the study protocol, including the cell model used and the conditions of culture. However, the Panel also considered that the relevance of the results for risk assessment of the food additive E 171 has not been established. The European Food Safety Authority Panel considered that these ongoing in vivo transcriptomics studies could be evaluated when completed, and if deemed necessary, the overall database reassessed considering the entire literature available at that time.
- Regarding the Guo et al. 29) study, the European Food Safety Authority Panel noted that the study was performed with engineered nano-titanium dioxide (nano-TiO2) and not with titanium dioxide as a food additive and it was difficult to extrapolate these results to the in vivo situation.
- Regarding the Heringa et al. 30) study, the European Food Safety Authority Panel considered that the aforementioned evaluations and considerations indicated that there was significant uncertainty in the assessment by Heringa et al. 31) and noted that there was not a weight of evidence analysis of the whole database on E 171. The European Food Safety Authority Panel considered that the assessment was consistent with a hazard from nano-titanium dioxide (nano-TiO2) when dosed as in the selected studies but the relevance to nanoparticles in a food matrix could not be assessed. The European Food Safety Authority Panel concluded that the additional studies called for in its 2016 opinion should provide a more robust basis for addressing the reported effects in reproductive organs in the studies used by Heringa et al. 32).
Based on the evaluation of the four studies concerning the potential adverse health effects of titanium dioxide the European Food Safety Authority Panel considered that:
- the results of the Bettini et al. 33) study did not provide enough justification for a new carcinogenicity study, but, should additional useful mechanistic information become available, this could be reconsidered in future;
- the new in vitro findings in the study by Proquin et al. 34) did not modify the conclusion on the genotoxicity of titanium dioxide as stated in the 2016 European Food Safety Authority opinion 35) on the safety of titanium dioxide (E 171) when used as a food additive;
- the effects of engineered nano-titanium dioxide (nano-TiO2) particles reported by the Guo et al. 36) study were of uncertain biological significance and therefore of limited relevance for the risk assessment of the food additive titanium dioxide (E 171);
- there was significant uncertainty in the risk assessment performed by Heringa et al. 37), which did not include a weight of evidence analysis of the whole database;
- the four studies evaluated, highlighted some concerns but with uncertainties, therefore their relevance for the risk assessment was considered limited and further research would be needed to decrease the level of uncertainties.
More research exploring the possible effects observed in three of the four studies could address their applicability to the risk assessment of the food additive titanium dioxide (E 171) under realistic conditions of use.
Altogether, the European Food Safety Authority Panel concluded that the outcome of the four studies did not merit re‐opening the existing 2016 opinion of European Food Safety Authority related to the safety of titanium dioxide (E 171) as a food additive.
The European Food Safety Authority Panel recommended that:
- in order to substantiate the observations in the Bettini et al. (2017), biomarkers for putative preneoplastic lesions in the colon as additional parameters should be examined in the extended one‐generation reproductive toxicity study recommended by European Food Safety Authority 38);
- further studies on nano-TiO2 should include administration in a food matrix.
What is nano titanium dioxide?
The “nano” form of this substance (nano-TiO2) refers to particles that are less than 100 nanometers in size. One nanometer is one billionth of a meter. Due to their small size and unique properties, the physical, chemical, and biological behaviors of nanoparticles may differ from naturally occurring or non-nano materials. Nano-titanium dioxide is used in various consumer products as a ultra-violet (UV) blocking agent, whitening agent, and antibacterial agent. Some common consumer products that use nano-titanium dioxide include: sunscreen, creams, cosmetics, toothpaste, bacteria-free socks, swimsuits, paints and coatings, car wax, paper, and inks. Nano-titanium dioxide is also used as a food coloring (e.g. to whiten skim milk) and a drug-delivery system in certain medicines. Nano-titanium dioxide can also be used in air purification and water treatment facilities, plastic and packaging films, electronics, and to preserve wood and textile fibers.
Titanium dioxide is produced from iron titanate or titanium slag by digesting with sulfuric acid or from ores with a high titanium content by heating with coke and chlorine to form titanium tetrachloride, then oxidizing to titanium chloride 39). Workers that make or use nano-titanium dioxide may breathe in mists or have direct skin contact. The general population may also breathe in mists or have direct skin contact while using consumer products that contain nano-titanium dioxide, such as sunscreens or cosmetics. Exposure may also occur through the ingestion of drinking water, food, or drugs containing nano-titanium dioxide. Patients receiving injections containing nano-titanium dioxide can also be exposed. If titanium oxide nanoparticles are released to the environment they will not be broken down in air. Nanoparticles can remain in the air and travel long distances due to their small size and light weight. They may not move into air from moist soil and water surfaces. The particles may move slowly to quickly through soil, depending on the soil type. It is not known if titanium nanoparticles will be broken down by microorganisms. In water, they may be broken down by sunlight. water. Titanium oxide nanoparticles may build up in aquatic organisms.
Data on the potential for nano-titanium dioxide to produce toxic effects in humans were not available. Mild respiratory irritation has been observed in workers exposed to titanium dioxide, but no major health effects or cancers have been clearly associated with occupational exposure to titanium dioxide 40). Several national agencies are conducting research to determine if nanoparticles (including nano-titanium dioxide) pose a threat to exposed workers or consumers 41). Nano-titanium dioxide is not a skin or eye irritant in laboratory animals. Allergic skin reactions did not occur following direct skin contact. Damage to the lung and spleen and changes in brain chemical levels have been reported in laboratory animals that repeatedly breathed nano-titanium dioxide. Altered behavior and changes in brain chemical levels occurred in laboratory animals following repeated oral exposure. Mild kidney and liver damage were observed in laboratory animals exposed to oral or dermal levels of nano-titanium dioxide. Damage to the liver, kidneys, heart and brain, altered blood sugar and cholesterol levels, tremors, and sluggishness were seen in laboratory animals injected with nano-titanium dioxide. In all animal studies, levels of nano-titanium dioxide were much higher than expected human exposure. The potential for nano-titanium dioxide to cause infertility, abortion, or birth defects has not been assessed in laboratory animals. Altered brain development and impaired learning and memory have been observed in offspring of laboratory animals exposed to nano-titanium dioxide during pregnancy. The potential for nano-titanium dioxide to cause cancer in humans has not been assessed by the U.S. EPA IRIS program, the International Agency for Research on Cancer, or the U.S. National Toxicology Program 13th Report on Carcinogens 42). The International Agency for Research on Cancer has classified titanium dioxide as possibly carcinogenic to humans 43). The National Institute for Occupational Safety and Health has determined ultrafine titanium dioxide is a potential occupational carcinogen based insufficient evidence in humans and sufficient evidence in animals, but determined that data are insufficient to classify the carcinogenicity of fine titanium dioxide. Lung tumors were increased in rats following lifetime exposure to ultrafine or fine titanium dioxide in the air. It is not known if these findings apply to nano-titanium dioxide.
The International Agency for Research on Cancer 44) concluded that there is inadequate evidence from epidemiological studies to assess whether titanium dioxide dust causes cancer in humans, but that there is sufficient evidence for carcinogenicity in experimental animals, based on the induction of respiratory tract tumors in rats after prolonged inhalation. Therefore, International Agency for Research on Cancer classified titanium dioxide as a Group 2B carcinogen 45).
What is titanium dioxide used for?
Titanium dioxide (TiO2) have been used in the food sector for more than 50 years as a pigment to enhance the white color and opacity of foods like coffee creamer, sauces, spreads, pastries, candies and edible ices 46).
Also, titanium dioxide confers brightness to toothpaste and is added to enhance the flavor of non-white foods (processed fish, fruits, meat, vegetables, breakfast cereals, fermented soybean, soups and mustard) and to clear beverages (beer, cider and wine) 47), 48).
Currently, the annual consumption volume of titanium dioxide particles reaches four million tons, which makes it the most widely used pigment globally 49). In the United States, the Food and Drug Administration allows up to 1% by weight of titanium dioxide particles as a food colorant 50). In the European Union (EU), titanium dioxide is an authorized food additive (listed as E 171) at quantum satis, meaning that no maximum level is imposed as long as the additive is used in accordance with good manufacturing practice, i.e., at a level not higher than necessary to achieve the intended scope 51). A comparison of use levels reported by the food industry show that the highest titanium dioxide concentrations are expected in chewing gum (up to 16,000 mg/kg), food supplements delivered in a solid form (up to 12,000 mg/kg), processed nuts (up to 7000 mg/kg) and ready-to-use salads and sandwich spreads (up to 3000 mg/kg) 52). Titanium dioxide particles can, therefore, be viewed as a paradigmatic case for the safety assessment of inorganic particles employed as food additive and comprising a nano-scale fraction.
Titanium dioxide sunscreen
Sunscreens are used to provide protection against adverse effects of ultraviolet (UV)B (290–320 nm) and UVA (320–400 nm) radiation 53). According to the United States Food and Drug Administration, the protection factor against UVA should be at least one-third of the overall sun protection factor. Titanium dioxide (TiO2) and zinc oxide (ZnO) minerals are frequently employed in sunscreens as inorganic physical sun blockers 54). Advantages offered by sunscreens based on inorganic compounds comprise absence of skin irritation and sensitization, inertness of the ingredients, limited skin penetration, and a broad spectrum protection 55). As Titanium dioxide (TiO2) is more effective in UVB and zinc oxide in the UVA range, the combination of these particles assures a broad-band UV protection.
The natural opaqueness of these microsized sunscreen components is eliminated without reducing their UV blocking efficacy by utilizing nanosized zinc oxide (ZnO) and titanium dioxide particles 56). Since the surface area to volume ratio of particles increases as the particle diameter decreases, nanoparticles, may be more (bio)reactive than normal bulk materials. That is why the safety of cosmetic products containing nanoparticles, in particular the sunscreens, has been frequently discussed 57). Sunscreens are ultimately aimed as UV protection, and the introduction of nanoparticles in this product should not cause more trouble than sun exposure itself. Recent reports and reviews on safety aspects of nanoparticle sunscreens mainly focus on various kinds of toxicological and skin penetration studies 58). However, safety also concerns the physicochemical properties of sunscreen ingredients to be taken up by skin in both the absence and presence of light. A more physicochemical approach could lead to new nanoparticle formulations displaying an accurate balance between safety and effectiveness. However, investigations that address the subject of nanoparticle sunscreen safety from a physicochemical point of view are scarce.
In noncommercial research of sunscreens that contain nanoparticles, the subject of safety mainly concerns skin penetration studies. Microsized titanium dioxide and zinc oxide have been used as particulate sunscreen ingredients (average size approximately 0.1–10.0 μm) for more than 15 years 59). Various microsized anatase and rutile titanium dioxide and wurtzite zinc oxide particles, coated and uncoated, have been utilized. The UV attenuation results from both reflection and scattering of UV radiation and visible light (clarifying the opaqueness of these sunscreen formulations) and from UV absorption. UV attenuation properties of these two particles are complementary; titanium dioxide being primarily a UVB absorbing compound, while zinc oxide is more efficient in UVA absorption. Apart from size-related optical particle properties, the ability of particles to attenuate UV radiation is determined by the surrounding medium.The replacement of microsized titanium dioxide and zinc oxide particles by nanoparticles ensures the cosmetically desired sunscreen transparency, but at the expense of broad UVA protection. Skin exposure to the nanoparticle sunscreens leads to incorporation of titanium dioxide and zinc oxide nanoparticles into the deepest stratum corneum layers and in the hair follicles that may serve as long-term reservoirs. Within skin, nanoparticle aggregation, particle–skin and skin–particle-light physicochemical interactions influence the overall UV attenuation efficacy, a complex process that is still poorly understood.
Titanium dioxide side effects
Although titanium dioxide is generally regarded as a nontoxic mild pulmonary irritant, some laboratory studies have reported lung adenomas in rats exposed to high levels of titanium dioxide. Limited data on health effects among humans exist. A retrospective cohort mortality study was conducted among 4241 titanium dioxide workers who were employed for at least 6 months, on or after January 1, 1960, at four titanium dioxide plants in the United States. Exposure categories, defined by plant, job title, and calendar years in the job, were created to examine mortality patterns in those jobs where the potential for titanium dioxide exposure is greatest. Standardized mortality ratios and their 95% confidence intervals were calculated to compare the mortality pattern of the workers with the general background population. Standardized Mortality Ratio is a ratio between the observed number of deaths in an study population and the number of deaths would be expected, based on the age- and sex-specific rates in a standard population and the age and sex distribution of the study population. If the ratio of observed:expected deaths is greater than 1.0, there is said to be “excess deaths” in the study population 60). Relative risks were estimated and trend tests were conducted to examine risk of disease among different exposure level groups in internal analyses. Workers experienced a significantly low overall mortality. No significantly increased standardized mortality ratios were found for any specific cause of death. Deaths from lung cancer were as expected, and standardized mortality ratios for this cancer did not increase with increasing titanium dioxide levels. Workers in jobs with greatest titanium dioxide exposure had significantly fewer than expected total deaths. Internal analyses revealed no significant trends or exposure-risk associations for total cancers, lung cancer, or other causes of death 61). Results from that study indicate that the exposures at these United States plants are not associated with increases in the risk of death from cancer or other diseases. Moreover, workers with likely higher levels of titanium dioxide exposure had similar mortality patterns to those with less exposure, as internal analyses among workers revealed no increase in mortality by level of titanium dioxide exposure.
To assess the risk of lung cancer mortality related to occupational exposure to titanium dioxide, a mortality follow-up study of 15,017 workers (14,331 men) employed in 11 factories producing titanium dioxide in Europe was performed 62). Exposure to titanium dioxide dust was reconstructed for each occupational title; exposure estimates were linked with the occupational history. Observed mortality was compared with national rates, and internal comparisons were based on multivariate Cox regression analysis. The cohort contributed 371,067 person-years of observation (3.3% were lost to follow-up and 0.7% emigrated). 2652 cohort members died during the follow-up, yielding standardized mortality ratios of 0.87 among men and 0.58 among women. Standardized Mortality Ratio is a ratio between the observed number of deaths in an study population and the number of deaths would be expected, based on the age- and sex-specific rates in a standard population and the age and sex distribution of the study population. If the ratio of observed:expected deaths is greater than 1.0, there is said to be “excess deaths” in the study population 63). Among men, the Standardized Mortality Ratio of lung cancer was significantly increased; however, mortality from lung cancer did not increase with duration of employment or estimated cumulative exposure to titanium dioxide dust 64). Data on smoking were available for over one third of cohort members. In three countries, the prevalence of smokers was higher among cohort members compared to the national populations. The results of the study do not suggest a carcinogenic effect of titanium dioxide dust on the human lung 65).
A total of 1,576 employees exposed to titanium dioxide were observed from 1956 through 1985 for cancer and chronic respiratory disease incidence, and from 1935 through 1983 for mortality 66). A cross sectional sample of 398 employees was evaluated for chest roentgenogram abnormalities. Cohort analyses suggest that the risks of developing lung cancer and other fatal respiratory diseases were no higher for titanium dioxide exposed employees than for the referent groups. Nested case control analysis found no statistically significant associations between titanium dioxide exposure and risk of lung cancer, chronic respiratory disease, and chest roentgenogram abnormalities. No cases of pulmonary fibrosis were observed among titanium dioxide exposed employees.
To investigate titanium dioxide exposure level in the finished product workshop, and its short-term cardiopulmonary effects, based on exposure assessment, seven workers were recruited into the panel. Personal titanium dioxide exposure information, cardiopulmonary function, and the particle size distribution data were collected during working days 67). Linear mixed effect model was used to examine the association between titanium dioxide exposure and cardiopulmonary function changes. The weight percentage of titanium dioxide particles more than 10 um, 1 to 10 um, and less than 1 um in the total dust was 14.5%, 69.5%, and 16%, respectively. Linear mixed effect model analysis showed that 1 mg/m³ increase in daily personal titanium dioxide exposure was associated with the decline in maximum voluntary ventilation, peak expiratory flow, maximum mid-expiratory flow, and 75% of maximum expiratory flow. The study provided new evidence for health effects of occupational inhalable titanium dioxide exposure, which suggests setting up new occupational exposure standards for fine titanium dioxide.
A study of 67 subjects in a small titanium oxide paint factory in Nigeria showed 50-54% frequency for airway symptoms, 20-40% for neurological symptoms, and 10-27% for other symptoms 68). The symptoms were well correlated with exposure and pulmonary function tests. The directly exposed subjects had likelihood odds ratios of 5 to 17 of presenting symptoms compared to controls. The pulmonary function test deficit, relative to the expected value, was significantly higher for those with airway symptoms than for those of other symptom categories. There were 28 (42%) cases of restrictive lung impairment. Exposure to cotton dust had confounding influence on the pulmonary function test of subjects previously exposed. Smoking rate was very low. These findings indicate the need for worker protection in a manufacturing plant in Nigeria 69).
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