Genotoxicity of iron compounds inSalmonella typhimurium and L5178Y mouse lymphoma cells

Dunkel, Virginia C.; San, Richard H.C.; Seifried, Harold E.; Whittaker, Paul

doi:10.1002/(sici)1098-2280(1999)33:1<28::aid-em4>3.0.co;2-s

Cited by 27 publications

(14 citation statements)

References 31 publications

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“…EDTA compounds are not carcinogenic in experimental bioassays and are not directly genotoxic. In this latter context, NaFeED-TA, like other iron salts, was not mutagenic in the Ames Salmonella assay but did cause a mild increase in mutants when added at high concentrations to a mouse lymphoma assay [43]. Similar findings were noted with ferrous sulfate and other iron compounds.…”

Section: Toxicity Of Edta-metal Complexessupporting

confidence: 60%

The Potential Role of NaFeEDTA as an Iron Fortificant

Bothwell

Macphail

2004

International Journal for Vitamin and Nutrition Research

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Ethylene diamine tetraacetic acid (EDTA) is a hexadentate chelator, which can combine with virtually every metal in the periodic table. CaNa2EDTA and Na2EDTA (ADI 2.5 mg EDTA/kg body weight/day) are widely used as sequestering agents in canned products, while NaFeEDTA is a promising iron fortificant. Binding of EDTA with iron is favored in the acid milieu of the stomach, irrespective of whether the EDTA is administered as CaNa2EDTA, Na2EDTA, or NaFeEDTA, but in the more alkaline medium of the duodenum the iron is exchanged, in part, with other metals. The iron released from EDTA is absorbed by the normal physiological mechanisms. When NaFeEDTA is present in a meal, the iron moiety exchanges with the intrinsic food iron and the EDTA partially protects the iron in this common non-heme iron pool from the effects of inhibitors of iron absorption, such as phytates and polyphenols. When iron is added as NaFeEDTA to an inhibitory meal, it is two to three times better absorbed than is iron added as ferrous sulfate. It also has a similar effect on the intrinsic food iron in the meal. Fortification with NaFeEDTA is most efficacious when administered with cereal- and legume-based diets but offers no advantages over other fortificants when added to meals of high bioavailability. Its potential as a fortificant has been confirmed in five extended fortification trials carried out in developing countries. There is no evidence that NaFeEDTA in the dose range proposed for food fortificants (5 to 10 mg iron daily) will have any direct toxic effects. Na2EDTA and CaNa2EDTA have proved safe over a number of years, while the Joint FAO/WHO Expert Committee on Food Additives concluded in 1999 that NaFeEDTA "could be considered safe when used in supervised fortification programs". Animal and human studies, including the results of two fortification trials, suggest that NaFeEDTA has little or no effect on overall zinc metabolism. Indeed, if anything, it increases zinc and possibly copper absorption. Data on potentially toxic metals, such as lead mercury, aluminum, and manganese, are limited but the evidence that is available is uniformly negative thus far. Further studies in this field are desirable. The long-term potential of NaFeEDTA fortification to cause iron overload is conjectural but the available evidence suggests that homeostatic controls would prevent excess iron accumulation in the normal population. NaFeEDTA, which is pale yellow in color, causes fewer organoleptic changes in a number of stored vehicles, including cereals, than do other soluble iron salts. Other potential vehicles include condiments, several of which have been successfully used in fortification trials. What is currently lacking is a consolidated body of published evidence on the stability of NaFeEDTA during processing, storage, and household cooking in widely consumed food vehicles, coupled with standardized testing of consumer acceptance of each fortified vehicle. While NaFeEDTA seems to be an appropriate fortificant for developing countries, its cost is about...

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Section: Toxicity Of Edta-metal Complexessupporting

confidence: 60%

The Potential Role of NaFeEDTA as an Iron Fortificant

Bothwell

Macphail

2004

International Journal for Vitamin and Nutrition Research

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“…Moreover, iron can damage biomolecules mainly through Fenton and Haber-Weiss chemistry, leading to the production of hydroxyl radicals and other reactive oxygen species (ROS) (Halliwell and Guterridge 2000). Iron compounds have been reported to be mutagenic in mammalian culture cells, as detected by Syrian hamster embryo cell transformation/viral enhancement assay (Heidelberger et al 1983), base tautomerization in rat hepatocyte cultures (Abalea et al 1999) and genetic alterations in the mouse lymphoma assay (Dunkel et al 1999). However, negative results have also been reported, including from recombinational assay in DNA repair-deficient Bacillus subtilis (Leifer et al 1981), sister chromatic exchange in hamster cell culture (Tucker et al 1993), sex-linked recessive lethal gene mutation in Drosophila melanogaster (Lee et al 1983), gene mutation in Glycine max (Vig 1982) and tryptophan reverse gene mutation in Escherichia coli (Brusick et al 1980).…”

mentioning

confidence: 99%

Genotoxicity and mutagenicity of iron and copper in mice

et al. 2007

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The toxicity of trace metals is still incompletely understood. We have previously shown that a single oral dose of iron or copper induces genotoxic effects in mice in vivo, as detected by single cell gel electrophoresis (comet assay). Here, we report the effect of these metals on subchronic exposure. Mice were gavaged for six consecutive days with either water, 33.2 mg/kg iron, or 8.5 mg/kg copper. On the 7th day, the neutral and alkaline comet assays in whole blood and the bone marrow micronucleus (MN) test were used as genotoxicity and mutagenicity endpoints, respectively. Particle induced X-ray emission was used to determine liver levels of the metals. Females showed a slightly lower DNA damage background, but there was no significant difference between genders for any endpoint. Iron and copper were genotoxic and mutagenic. While copper was more genotoxic in the neutral version, iron was more genotoxic in the alkaline version of the comet assay. Copper induced the highest mutagenicity as evaluated by the MN test. Iron was not mutagenic to male mice. Iron is thought to induce more oxidative lesions than copper, which are primarily detected in the alkaline comet assay. Treatment with iron, but not with copper, induced a significant increase in the hepatic level of the respective metal, reflecting different excretion strategies.

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“…The cytotoxicity of moderate to high concentrations is becoming well recognized (Connor and Ghio 2009). Although mildly mutagenic (Dunkel et al 1999), iron is toxic primarily by virtue of its strong induction of oxidative stress. Iron-catalyzed formation of hydroxyl (free) radicals can destroy proximate cells by initiating lipid peroxidation, denaturation of enzymes, depolymerization of polysaccarides and rupture of DNA strands (McCord 1996).…”

Section: Cytotoxicity Of Ironmentioning

confidence: 99%

Can iron be teratogenic?

Weinberg

2009

Biometals

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Several kinds of evidence indicate that elevated iron during the 3-8 week embryonic (organogenesis) period of human gestation may be teratogenic. (1) In the embryonic period, the natural maternal absorption of food iron is 30% below the estimated daily iron loss. (2) As compared with maternal serum, embryonic fetal coelomic fluid contains only one-fourth as much iron but nearly six times the quantity of the iron withholding protein, ferritin. (3) In the embryonic period, intraplacental oxygen pressure is 2-3 times lower than in the subsequent fetal growth period. (4) Iron is a strong inducer of emesis which peaks in the embryonic period. (5) In a murine gestation model, iron was neurotoxic at a sharp peak of 8-9 days. Thus it would be prudent, in human pregnancy, to delay any needed iron supplementation until the embryonic period has been completed.

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Genotoxicity of iron compounds inSalmonella typhimurium and L5178Y mouse lymphoma cells

Cited by 27 publications

References 31 publications

The Potential Role of NaFeEDTA as an Iron Fortificant

The Potential Role of NaFeEDTA as an Iron Fortificant

Genotoxicity and mutagenicity of iron and copper in mice

Can iron be teratogenic?

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