In vitro genotoxicity data of nanomaterials compared to carcinogenic potency of inorganic substances after inhalational exposure

Our plain-English summary of In vitro genotoxicity data of nanomaterials compared to carcinogenic potency of inorganic substances after inhalational exposure, by M. Roller (Mutation Research, 2011).

The study

• Author: M. Roller
• Journal: Mutation Research
• Published: 2011;727(3):72-85
• Type of article: Review
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Literature data of epidemiological studies, carcinogenicity studies and in vitro studies on inorganic substances were surveyed with the aim to determine sensitivity and specificity of in vitro tests of nanomaterials. Asbestos, quartz and chromium and cadmium compounds were assigned to classes of highest carcinogenic potency. After 20 years of occupational exposure to long-term average concentrations of 0.5mg/m(3) of these dusts - or to even lower concentrations - an epidemiologically detectable increased lung cancer risk has to be expected. In contrast, diesel engine emissions, some nickel species and "ultrafine" versions (nanomaterials) of titanium dioxide and carbon black were also carcinogenic in inhalation studies, but show varied epidemiological results. The high frequency of lung cancer in the male general population due to cigarette smoking hampers unequivocal detection of occupationally caused lung cancer risks. Based on the experience from the inhalation studies, workers had to be exposed to long-term concentrations of 1mg/m(3) or more to identify epidemiologically a clear cause-and-effect relationship for a specific substance of intermediate potency. Respirable granular biodurable particles without known significant specific toxicity with primary particle sizes of more than 1μm have also shown carcinogenicity in rats. Their potency was even lower; and partially results after instillation rather than inhalation are available. Nearly all types of nanomaterials and control dusts used in the in vitro assays showed genotoxic effects in cell cultures (e.g., CoCr particles, diesel soot, SiO(2) crystalline and amorphous, TiO(2), carbon black), but not consistently in all studies; overall, the proportion of positive results was about 50%. No clear correlation of the probability of a positive in vitro test with particle properties was seen. I recommend trying and calibrating a sensitive in vitro model (e.g., micronucleus assay) against the described rank order of carcinogenic potency by testing a series of inorganic substances.

Copyright © 2011 Elsevier B.V. All rights reserved.

In plain English

A literature survey (review) supported by the German Federal Institute of Occupational Safety and Health compared in vitro genotoxicity data for nanomaterials with in vivo carcinogenicity information for inorganic particles and fibres. The author collected 179 data sets from in vitro tests in mammalian cell cultures (carbon black, carbon nanotubes, silica, titanium dioxide, metal oxides, and control dusts including chrysotile asbestos) and analysed them by logistic regression. Of these, 100 data sets (56%) were positive. The micronucleus assay was positive in 76% (22/29) of tests, and in 89% (16/18) where no commercial dust producer or user was documented. A variable for presumably public research or funding explained the largest share of variance (odds ratio 3.21, p = 0.00083); a six-variable model explained 13.6%. In the author's potency ranking, asbestos was in the highest class with Cr(VI) compounds. For these, 0.1 mg/m3 (cumulative 2 mg/m3-yrs) was the estimated minimal 20-year average exposure at which an increased lung cancer risk, roughly a doubling, would be detectable epidemiologically. The author stated that no detected risk does not mean no risk. The author recommended calibrating a sensitive in vitro model against this rank order.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: review / literature survey of epidemiological, long-term animal and in vitro studies, with logistic regression analysis of the collected in vitro data
• Who was studied: 179 data sets (one dust, one test model, one study each) from published in vitro genotoxicity experiments in mammalian cell cultures, drawn from the studies listed in Table 2
• Exposure: nanomaterials (ultrafine), fine inorganic dusts and control dusts tested in cell cultures: carbon black, carbon nanotubes, diesel and other soots, crystalline and amorphous SiO2, TiO2 (anatase, rutile), Fe/Co/Mn/Cu/Zn oxides, CoCr particles, glass fibres, urban dust and chrysotile asbestos. For the potency table: inhaled asbestos, Cr(VI), Cd compounds, crystalline silica, Ni compounds, diesel soot and granular biodurable particles
• Main results:
  • 56% of the collected in vitro data sets (100 of 179) gave a positive genotoxicity result
  • The micronucleus test was positive in 76% (22/29) of tests overall and in 89% (16/18) of studies without documented participation of commercial dust producers or users. Where such participation was identifiable and another assay was used, 29% (10/35) were positive
  • In logistic regression, the variable PPR (presumably public research/funding) was most strongly associated with a positive genotoxicity outcome (odds ratio 3.21, p = 0.00083 in univariate analysis)
  • The six-variable multivariate model explained 13.6% of the variance of the genotoxicity outcome (p = 0.00024)
  • The author reported that particle size (ultrafine) and assumed specific toxicity showed almost no demonstrable influence on test outcome
  • In the author's potency ranking, asbestos and Cr(VI) compounds were placed in the highest class. Estimated minimal 20-year average exposures for epidemiological detection of increased lung cancer risk were 0.1 mg/m3 (cumulative 2 mg/m3-yrs) for this class; 0.3-0.5 mg/m3 for Cd compounds and crystalline silica; 1 mg/m3 for Ni compounds; 2.5 mg/m3 for diesel soot and nano-GBP; and 20 mg/m3 for large-fine GBP
  • The table values denote the exposure estimated to lead to about a doubling of lung cancer risk (RR about 2) or an absolute excess risk of about 5-7%
  • The author stated that absence of epidemiological detection of a risk at a given exposure level does not mean the particle type is not carcinogenic at that level
  • Chrysotile asbestos was included among the control dusts. In the study of Garza et al. it was examined for production of reactive oxygen species in the human cell line A549
  • For asbestos the author used a published linear model (relative risk = 1 + k times cumulative exposure, k = 0.01). The author noted that a 20-year average exposure to 1 f/mL would give a true relative risk of about 1.2, which would probably not be detected epidemiologically
• The authors' conclusion: The author recommended accepting a working hypothesis of a rank order of carcinogenic potency based on epidemiology and long-term rat studies. A series of inorganic substances should then be tested against that order with a sensitive assay such as the micronucleus test. The expected descending order began with amphibole asbestos (crocidolite or amosite)
• Limitations the authors state:
  • The author stated that no generally accepted numerical reference values for carcinogenic potency exist, so figures for sensitivity and specificity of the in vitro tests could not be calculated
  • Cytotoxicity information was not consistently reported in the original papers, limiting that variable
  • A large part of the variation in genotoxicity outcomes remained unexplained
  • The author stated that the potency values in Table 5 are not exact exposure-risk relationships and carry uncertainties about substance variants and low-dose extrapolation
  • The author noted that the identity of the tested substance was often unclear, including whether pigmentary or ultrafine TiO2 had been used

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Genotoxicity, Carcinogenic, Occupational Exposure, Lung Cancer, Crystalline.

Related studies

• The role of genotoxicity in asbestos-induced mesothelioma: an explanation for the differences in carcinogenic potential among fiber types — C.A. Barlow, L. Lievense, et al. (2013)
• Biomonitoring of genotoxic effects for human exposure to nanomaterials: The challenge ahead — L. Gonzalez, M. Kirsch-Volders (2016)
• The carcinogenic potential of nanomaterials, their release from products and options for regulating them — H. Becker, F. Herzberg, et al. (2011)
• A study of the effect of chrysotile fiber surface composition on genotoxicity in vitro — M.J. Keane, J.W. Stephens, et al. (1999)
• The utility of the in vitro micronucleus test for evaluating the genotoxicity of natural and manmade nano-scale fibres — P. Fowler, A. Homan, et al. (2016)
• Effect of exposure route on potency of carcinogens — W.E. Pepelko (1991)

Browse more research in Mutation Research, or return to medical research.