Beskæftigelsesudvalget 2019-20
BEU Alm.del Bilag 101
Offentligt
Version 4 TiO2 28022019-final
Short report from the Danish Working Environment Authority´s (AT) Occupational exposure
limit quality committee. Evaluation of the report: Titanium dioxide nanomaterials: Scientific
basis for setting a health-based occupational exposure limit.
Members of the Quality committee: Anne Mette Zenner Boisen (Miljøstyrelsen); Anoop Kumar Sharma
(DTU Fødevareinstituttet); Ane Marie Thulstrup (Arbejdsmedicin AUH); Jesper Bo Nielsen (Institut for
Sundhedstjenesteforskning, SDU); Vivi Schlünssen (NFA)
This report is based on a meeting 14
th
November 2018 at AT, where the results from the report were
discussed after the authors presented the content of the report. The members of the quality committee had the
chance to ask questions to the authors.
The Report: Anne Thoustrup Saber, Sarah Søs Poulsen, Niels Hadrup, Karin Sørig Hougaard, Nicklas Raun
Jacobsen and Ulla Vogel. Titanium dioxide nanomaterials: Scientific basis for setting a health-based
occupational exposure limit The National Research Centre for the Working Environment (NFA) September
2018. 978-87-7904-351-0
Erratum: Page 27, table 3 in the report. In column 3, third section: 4/100 Adenocarcinoma should be 4/100
adenoma
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Version 4 TiO2 28022019-final
Overall evaluation of the report
The report reviews data relevant to assessing the hazards of TiO2 nanomaterials (TiO2 NMs) in humans and
animals. Furthermore, toxicokinetics and mechanisms of toxicity are reviewed, and core previous risk
assessments of TiO2 NMs are summarized. The scientific basis for setting an occupational exposure limit
(OEL) are presented and based on this, the authors suggest a health based OEL for TiO2 NM.
In general, the report is well written with a clear structure and easy to follow. More tables displaying the
articles dealt with in each section would have increased the overview even more.
The committee judge the included literature in general to be sufficient and covering. The literature search
was performed by a research librarian, and we recommend to including details of searched databases and the
search strings including dates for covering of the search as an appendix in the report. Recently ECHA´s
committee for Risk Assessment (RAC) published an Opinion proposing harmonized classification and
labelling at EU level of Titanium dioxide (:
https://echa.europa.eu/registry-of-clh-intentions-until-outcome/-
/dislist/details/0b0236e18075daff).
It is relevant also to include the RAC evaluation in the section where
previous risk assessments of TiO2 NMs are summarized.
The authors chose to focus on studies dealing with occupational exposure by inhalation, and the committee
support that decision, as inhalation is the major route of exposure for TiO2 NMs.
The authors based the suggested health-based OEL on data from experimental animal studies due to a lack of
epidemiological studies, and the committee supports this decision.
The authors regards inflammation and carcinogenicity as the critical adverse effects, and the committee agree
on this decision. It is noted however, that the authors in the risk assessment uses a measure where they
include both benign and malign tumors in the evaluation of cancer risk, which tends to overestimate the
carcinogenic effects of TiO2 NM.
The authors states correctly secondary genotoxicity due to particle-induced inflammation to be an important
and well documented mechanism of action for the development of lung cancer. Apart from this oxidative
stress is a key mechanism for secondary genotoxicity (ECHA 2017). The committee supports to consider
carcinogenicity as a non-threshold effect as the available data did not allow ruling out that TiO2 NM could
also induce cancer through a direct genotoxic mechanism, although the evidence for a direct mechanism is
sparse (Shi et al 2013).
The committee agree on the REACH approach used in the report, despite the overestimation of cancer due to
inclusion of both benign and malign tumors in REACH. The authors have used the data from Heinrich et al.
1995, a chronic inhalation study of mice and rats and the only study where ultrafine particles were used. The
limitation in the study is that only one dose (about 10 mg/m
3
) was applied. In rats, a significant increase in
total number of tumor bearing animals with all types of lung tumors was observed compared to the control
dose group. No statistically significantly increase was observed in lung tumors in mice.
The committee aimed at performing additional analysis based on the benchmark approach. By a benchmark
approach the available data are used more efficiently compared to the NOAEL approach used by REACH. A
NOAEL value is very dependent of study design, number of exposure groups and the exposure contrast
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between exposure groups compared to the benchmark approach. Due to few data including only one
exposure level in Heinrich et al 1995, it was not possible actually to successfully complete the modelling.
NIOSH performed an analysis from three different studies (Lee at al. 1985, Muhle et al. 1991 and Heinrich et
al. 1995). In these studies different particle sizes were used (ultrafine and fine). NIOSH concluded that they
fit on the same dose response curve in a benchmark dose modelling approach when the dose was expressed
as total particle surface area in the lungs (NIOSH 2011). NIOSH calculated the excess risk of lung cancer
tumors based on benchmark dose modelling including data from the above mentioned three studies. Based on
the analysis by NIOSH, it is indicated that a dose response relationship exists for TiO
2
particles including
ultrafine particles and lung tumors. The committee agrees on this assumption.
For non-threshold effects, two approaches are used in the report, namely measured lung burden in rats
exposed by inhalation, and air concentrations directly. The authors suggest using the first approach.
A section discussing challenges with possible overload of exposure in the animal models due to the high
exposure doses used in the models would be helpful to interpret the experimental results. TiO2 RAC has
made an estimation of the level of lung overload in the studies conducted via inhalation or intra-tracheal
administration of TiO2 in rats and/or mice and concluded that lung tumours were reported in rats in an
overload context defined by an impairment of normal pulmonary clearance due to high accumulation of
particles. The level of lung overload in the Heinrich et al 1995 study was described as ‘not yet excessive
conditions of particle loading of lung macrophages’.
RAC further noted that although the evidence presented indicates a lower sensitivity of non-human primates
and humans to PSLT induced lung inflammation (including alveolar inflammation) the observed lung
adenocarcinomas are considered relevant to humans and TiO2 warrants a Category 2 classification for
carcinogenicity.
The committee agree on the decision to include data from two rat inhalation studies as the basis for the risk
assessment (for Inflammation Bermudez et al 2004; for cancer Heinrich et al 1995). The committee also
considers Ferin et al 1992, but due to only one exposure level in Ferin et al, the data from Bermudez et al was
considered more useful. Muhle et al 1991 and Lee et al 1985 was not considered due to the dust fraction
(fine, not ultrafine) and due to the extraordinary high dust levels in Lee et al 1985 (10, 50, 250 mg/m3).
Both studies used for the risk assessment P25 TiO2 NM (15-40 nm diameter, 80% anatase/20% rutile).
Which is the most commonly studied TiO2 NMs. Whether this reflect the actual use of TiO2 NMs is not
clear from the report, but apparently, this knowledge is not available.
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Setting an occupational exposure limit for TiO2
Inflammation
In setting an occupational exposure limit with inflammation as the critical endpoint the authors used the
(NOAECBermudez) of 0.5 mg/m3 for pulmonary influx of neutrophils immediately after end of exposure
(table 2 in the report). They corrected this value to an 8 hours working day and also took into account the
breathing rate for workers at light work: NOAECCorrected = NOAECBermudez *6 hour/8 hour * 6.7 m3/10
m3 = 0.25 mg/m3. They decided on the following default assessment factors:
Interspecies extrapolation 2.5; Intraspecies interpolation 5; Extrapolation from sub-chronic to chronic: 2
This results in a DNEL for chronic inhalation for pulmonary inflammation of: 10 µg/m3.
The quality committee judge this DNEL to be too low based on the evidence and based on default assessment
factors used in previous risk assessments of TiO2.
We support to adjust for number of hours exposed as well as the breathing rate for workers at light work, but
recommend to use the NOAECBermudez) of 2 mg/m3 for pulmonary influx of neutrophils seen after 4-52
weeks of exposure, as we judge this to be the most relevant exposure window for inflammation related to
health. Furthermore we suggest to use the following default assessment factors: Interspecies extrapolation
2.5; Intraspecies interpolation 2.5; Extrapolation from sub-chronic to chronic: 2. Both interspecies and
intraspecies assessment factors include variation in metabolism of the substance of interest. As TiO2 is not
metabolised we find it most correct to use an intraspecies assessment factor of 2.5.
We therefore suggest a DNEL for pulmonary inflammation of: 2.00 mg/m3*6
hour/8 hour * 6.7 m3/10
m3
/ 12.5 = 0.08 mg/m3 = 80 µg/m3*
* The committee wants to express one reservation. The inflammatory outcomes can be reversible which is not
clear from the report. As a consequence information on the nature of the exposure (continuous or short term
intermittent with large non-exposed intervals) is of importance to emphasise in the final risk assessment.
Cancer
About cancer, the quality committee recommend to use the DNEL based on air concentrations directly. This
decision is primarily based on the uncertainty with overloading of exposure, which is an issue with the
alternative method using lung burden. Otherwise, we agree with the calculations performed. Of note, the
calculations are based on both benign and malign tumors and included benign tumors cystic keratinizing
squamous cell tumors, a benign tumor of unknown human relevance. The suggested OEL is therefore based
on an overestimation of the risk
The expected excess lung cancer risk in relation to occupational exposure to TiO2 NMs is 1:1 000 at 47
µg/m3, 1:10 000 at 4.7 µg/m3 and 1:100 000 at 0.47 µg/m3 TiO2 NM.
 BEU, Alm.del - 2019-20 - Bilag 101: Orientering om NFA’s forslag til grænseværdier for fem kemiske stoffer, fra beskæftigelsesministeren
Version 4 TiO2 28022019-final
References
Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI. Pulmonary responses
of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci
2004;77:347-357.
Committee for Risk Assessment (RAC). Opinion proposing harmonised classification and labelling at EU
level of Titanium dioxide. ECHA 2017
Ferin J, Oberdörster G, Penney DP. Pulmonary Retention of Ultrafine and Fine Particles in Rats. Am J
Respir Cell Mol Biol 1992;6:535-542.
Heinrich U, Fuhst R, Rittinghausen S, Creutzenberg O, Bellmann B, Koch W, Levsen K. Chronic inhalation
exposure of wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium
dioxide. Inhal Toxicol 1995;7:533-556.
Lee KP, Trochimowicz HJ, Reinhardt CF. Pulmonary response of rats exposed to titanium dioxide (TiO2) by
inhalation for two years. Toxicol Appl Pharmacol 1985;79:179-192.
Muhle H, Bellmann B, Creutzenberg O, Dasenbrock C, Ernst H, Kilpper R, MacKenzie JC, Morrow P, Mohr
U, Takenaka S. Pulmonary response to toner upon chronic inhalation exposure in rats. Fundam Appl Toxicol
1991;17:280-299.
NIOSH. Occcupational exposure to Titanium dioxide. Current Intelligence Bulletin 63. Cincinnati, OH:
Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute
for Occupational Safety and Health, 2011.
Shi H, Magaye R, Castranova V, Zhao J. Titanium dioxide nanoparticles: a review of current toxicological
data. Part Fibre Toxicol 2013;10:15.