Biosafety Evaluation of Nanoparticles in View of Genotoxicity and Carcinogenicity Studies: A Systematic Review

Hasan Turkez1, a, Kubra Celik2,b and Bulent Cakmak1,3,c

1Molecular Biology and Genetics Department, Faculty of Science, Erzurum Technical University, Erzurum, Turkey

2 Biology Department, Faculty of Science, Atatürk University,

Erzurum, Turkey

3Department of Electrical and Electronics, Engineering Faculty, Ataturk University, Erzurum, Turkey

Keywords: Nanoparticle, Biosafety, Tungsten trioxide, In vivo, Risk Assessment, Genotoxicity

Abstract. Nanoparticles (NPs) are used in various forms in consumer products including,

cosmetics, food packaging, textiles and also in air and water cleaning, production of electro chromic

windows, or smart windows and gas sensors. Many NPs have also been evaluated for potential use

in biomedical applications as efficient delivery carriers for cancer diagnosis and therapy.

Nowadays, NPs are being developed to create fascinating nanotechnology products. To develop

NPs for broad applications, potential risks to human health and the environment should be

evaluated and taken into consideration. Again, to translate these nanomaterials to the clinic and

industrial domains, their biosafety needs to be verified, particularly in terms of genotoxic and

carcinogenic effects. To evaluate evidenced-based practices for NPs safety, we performed a

systematic review of the published English-language literature. We performed a systematic

keyword search of PubMed for original research articles pertaining to reports on assessment of risks

due to carcinogenic and mutagenic effects by different NPs. We identified 362 original articles

available for analysis. The included studies were published between 1993 and 2012. The in vivo or

in vitro genotoxicity studies were performed on only 18 out of 148 kinds of NPs in industry today.

Likewise, the carcinogenicity investigations were performed on only 14 out of 148 NPs. The 10

types of the NPs including some titanium, aluminium, carbon black and silver molecules were

found to have both mutagenic and carcinogenic potential. The important finding was also that there

is a lack of systematic assessment of the DNA damaging and carcinogenic potential of NPs in spite

of their extensive use in nanotechnological applications.

Introduction

Nanoparticles are generally defined as particles whose diameter is 1-100 nm [1]. The new scientific

innovation of engineering nanoparticles (NPs) has led to numerous novel and useful wide

applications of several aluminum, antimony, barium, bismuth, boron, calcium, carbon, cerium,

chromium, cobalt, copper, diamond, dysprosium, erbium, europium, gadolinium, gold, graphite,

hafnium, indium, iron, lanthanum, lead, lithium, magnesia, manganese, molybdenum, neodymium,

nickel, niobium, palladium, platinum, praseodymium, ruthenium, silicon, silver, strontium,

tantalum, terbium, tin, titanium, tungsten, vanadium, yttrium, zinc and zirconium NPs in many

domains including electronics, chemicals, environmental protection and biological medicine [2].

Today, these NPs are being introduced into the market without adequate assessment of their

potential toxicities. Thence, it is reported that urgently important to conduct risk assessment of

commercial NPs and establish a framework enabling risk management which is not subordinate to

their commercial production [3]. Recently, it was suggested that data on nanoparticles

characteristics especially associated with genotoxicity, carcinogenicity and mechanisms involved

could probably be used in risk assessment [4]. In this review, we performed a systematic keyword

search of PubMed for original research articles were published between 1993 and 2012, and

pertaining to reports on assessment of risks due to carcinogenic and mutagenic effects by NPs. We

think that an overview of currently available carcinogenicity and/or mutagenicity risk evaluation

results of NPs will provide a reliable response for the serious doubts on their safety.

Key Engineering Materials Vol. 543 (2013) pp 200-203Online available since 2013/Mar/11 at www.scientific.net© (2013) Trans Tech Publications, Switzerlanddoi:10.4028/www.scientific.net/KEM.543.200

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Genotoxicity Studies

The genotoxicity studies have been conducted using limited quantities of nanomaterials and mainly

in in vitro experiments. Table 1 shows the mutagenic NPs in detail. From our literature screening, it

was understood that genotoxicity studies were performed on only 18 out of 148 kinds of

nanoparticles in industry up to date. And a major part of these studies were focused on titanium and

silver NPs. Although the genotoxicity of titanium and silver NPs have been investigated with a

variety of genetic endpoints in animals and cultured mammalian cells, they remained controversial

like others. On the other hand, recent findings indicated that mutagenicity of NPs depended on their

particle size [5]. The genotoxicity of many engineered nanomaterials has commonly been related to

oxidative stress (by elevated reactive oxygen species (ROS) levels, reduced antioxidant levels, and

increased lipid peroxidation) and subsequent inflammation (by leading to apoptosis) [6,7].

Table 1. The mutagenicity studies on NPs

Carcinogenicity Studies

The present database is generally accepted as not adequate for an assessment of the carcinogenic

potential of NPs Multitudinous investigations provided evidence of a nano-specific potential to

induce tumors, although other studies did not. This ambiguity was explained by insufficient

characterization of the test materials, difference in the experimental design, the use of different

animal models and species and/or differences in dosimetry [27]. The International Agency for

Research on Cancer (IARC) found sufficient evidence for the carcinogenicity of carbon black and

of titanium dioxide NPs in experimental animals. [28]. In accordance to this evidence by IARC,

Kind of NP Genotoxicity End-point Reference

Aluminum oxide Sister chromatid exchange (SCE),

micronucleus (MN) assays in Chinese hamster

ovary (CHO) cells

[8]

Carbon black

nanoparticles

Comet assay in mouse lung cells [9]

Cobalt NPs MN and Comet assays in human lymphocytes [10]

Copper oxide Ames test [11]

Dysprosium oxide,

Indium oxide,

Tungsten oxide

Ames test [5]

Gold NPs Expression levels of genes related to DNA

repair in human lung fibroblasts

[12]

Iron oxide MN and Comet assays in human human lung

cell

[13]

Silver NPs Wing spot assay in Drosophila melanogaster,

Chromosomal aberrations (CAs) in fish, Ames

test, MN assay in human lymphocytes

[14,15,16]

Silicon carbide Comet assay in human lung cells [17]

Titanium dioxide Ames test,

Comet, SCE, CA and MN assays, 8-oxo-

Guanine analysis in human lung and

lymphocyte cells

[18,19,20,

21,22,23]

Vanadium oxide SCE, MN and CAs assays in peripheral

lymphocytes

[24]

Zinc oxide Ames test, Comet assay in human

keratinocytes

[25,26]

Key Engineering Materials Vol. 543 201

titanium dioxide and carbon black NPs were reported as carcinogenic to the lung of female rats, and

the tumors preferentially included squamous cell morphology. Besides, carbon nanotubes induced

mesotheliomas when applied intraperitonally in both rats and mice [3]. Again, silver, copper and

aluminum NPs were also reported to be carcinogenic in experimental and aquatic animals

[29,30,31]. On the contrary, repeated administration of the fullerenes (C60) for up to 24 weeks post-

initiation did not result in either benign or malignant skin tumor formation in mice although serious

concerns had also arisen about the potential carcinogenic effects of this molecule [32] .

Conclusions

� The in vivo or in vitro genotoxicity studies were performed on only % 12 of all NPs which

were being extensively used in commercial products.

� The carcinogenic potentials were performed on only % 9 of all present NPs.

� There is a lack of systematic assessment of the DNA damaging and carcinogenic potential of

NPs in spite of their extensive use in nanotechnological applications.

� Further genotoxicity and carcinogenicity evaluations should be carried out on in vivo and in

vitro mammalian cells for determining their causes, mechanisms and new application

domains.

� The carcinogenic potential of NPs should be taken into consideration seriously when

exploring or developing new nanotechnological products

� New testing strategies should be developed since well known risk assesment techniques

were not so suitable for evaluating NPs threats on human and environmental health.

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