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genotoxins, Comet assay in mice: Ace-K, stevia fine; aspartame poor; sucralose, cyclamate, saccharin bad: Sasaki YF, Aug, Dec 2002: Rencuzogullari E et al, Aug 2004: Murray 2003.01.27, 2004.10.17 rmforall

Rich Murray rmforall at att.net
Tue Oct 19 08:45:18 EST 2004

genotoxins, Comet assay in mice: Ace-K, stevia fine; aspartame poor;
sucralose, cyclamate, saccharin bad: Sasaki YF, Aug, Dec 2002:
Rencuzogullari E et al, Aug 2004: Murray 2003.01.27, 2004.10.17 rmforall

Jan 27 2003

Rich Murray, MA    Room For All    rmforall at comcast.net
1943 Otowi Road, Santa Fe, New Mexico 87505 USA  505-501-2298
136 members,  1,122 posts in a public searchable archive   also Co-Moderator

Summary of Review by Rich Murray:

This study tests 39 common food additives for DNA damage,
comparing a control group of 4 mice against
test groups of 4 mice each, killed 3 hr and 24 hr
after oral ingestion of up to 2000 mg/kg.

However, there are only 21 unique control groups, with widely varying
By using the averages for all 21 control groups to make
comparison with the groups exposed to the food additives, it is easy
to see that many additives cause about 140% to about 180% to over 300%
of the averages of all control groups for the 8 organs measured.
By using more mice, statistical significance may be easily proved for most
of these easily noticable high values, which are not significant for
just 4 mice.

Mutat Res 2002 Aug 26; 519(1-2): 103-19
The comet assay with 8 mouse organs: results with 39 currently used food
additives.   Yu F. Sasaki
Sasaki YF, Kawaguchi S, Kamaya A, Ohshita M, Kabasawa K, Iwama K,
Taniguchi K, Tsuda S.
Laboratory of Genotoxicity, Faculty of Chemical and Biological
Engineering, Hachinohe National College of Technology,
Tamonoki Uwanotai 16-1, Aomori 039-1192, Japan.
yfsasaki-c at hachinohe-ct.ac.jp ; s.tsuda at iwate-u.ac.jp

We determined the genotoxicity of 39 chemicals currently in use as food
They fell into six categories-- dyes, color fixatives and
preservatives, preservatives, antioxidants, fungicides, and sweeteners.

We tested groups of four male ddY mice once orally with each additive at
up to 0.5xLD(50) or the limit dose (2000 mg/kg) and
performed the comet assay on the
glandular stomach, colon, liver, kidney, urinary bladder,
lung, brain, and bone marrow
3 and 24 h after treatment.

Of all the additives, dyes were the most genotoxic.
Amaranth, Allura Red, New Coccine, Tartrazine, Erythrosine, Phloxine, and
Rose Bengal
induced dose-related DNA damage in the
glandular stomach, colon, and/or urinary bladder.

All seven dyes induced DNA damage in the gastrointestinal organs at a
low dose (10 or 100mg/kg).

Among them, Amaranth, Allura Red, New Coccine, and Tartrazine induced
DNA damage in the colon at close to the acceptable daily intakes (ADIs).

Two antioxidants (butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT)),
three fungicides (biphenyl, sodium o-phenylphenol, and thiabendazole), and
four sweeteners (sodium cyclamate, saccharin, sodium saccharin, and
sucralose) also induced DNA damage
in gastrointestinal organs.

Based on these results, we believe that more extensive assessment of
food additives in current use is warranted.  PMID: 12160896

Also tested were acesulfame K, aspartame, stevia, and glycyrrhizin--
which all came out nonsignificant, while, as the abstract mentions,
sodium cyclamate had 4, saccharin 3, sucralose 3, and sodium saccharin 5
significant results.

Each test condition had just 4 mice, and, according to the text, each
additive had its own control group of 4 mice.
However, there are only 21 unique sets of control groups,
with 8 sets used once, 10 sets used twice, 2 sets used 3 times, and 1 set
used 4 times, a total of 38 food additives listed
[Sodium erythorbic acid was left out of Table 2, while
mentioned in the report 3 times, "...erythorbic acid and its sodium salt
did not increase DNA damage in any of the organs studied."].

Aspartame was assigned the control group that had the highest levels of
Migration of damaged nuclear DNA for Liver and  Bladder, and the second
highest for Brain.
The same control group was used for the xanthene
dye, erythrosinc, which had Migration as high as 42.4+-2.17 um
[micro-meter], measured on 50 nuclei from stomach cells, 3 hours
after ingestion.
So, the high control groups values had no effect on
the statistical analysis for erythrosinc.

The available range of the 21 control groups ranged for the Liver from
1.1 to 3.6 um.

For aspartame, the Liver Migration, the average length
of the "comet" tail of damaged, broken DNA pulled out of 50 Liver cell
nuclei by an electric field for 15 minutes, was, average of 4 mice:

control value used  3.59+-0.50 um [1.1 to 3.6 range in 21 controls]

2000 mg/kg  3 hr    3.26+-0.16 um

2000 mg/kg 24 hr    0.57+-0.22 um

The 3 hr aspartame test value was about the same as the control value.

This may be discordant with the Trocho (1998) findings that rats given
200 mg/kg oral doses of aspartame for 11 days,
about the same total dose,
had accumulation of formaldehyde adducts, bound to DNA, RNA, and
proteins, in liver, kidneys, brain, retinas, and other tissues, at about
the same total dose, spread over 11 days.

Appying the lowest available control group liver level 1.06+-0.12 um
would make the aspartame level of 3.26+-0.16 um significant [ratio 3.1].

How significant is a ratio of about 2?

I found two examples in the data, where P<.05 existed for BHT, Bladder,
1000 mg/kg, 3 hr:

10.9+-1.32 vs control 4.77+-0.40 [range 3.6 to 7.1 for 21 controls],
[ratio 2.3]

and sodium cyclamate, Stomach, 1000 mg/kg, 3 hr:

12.2+-1.38 vs control 6.37+-0.57 [range 4.3 to 8.6 for 21 controls]
[ratio 1.9].

However, not significant was:

sodium saccharin, Liver, 2000 mg/kg, 3 hr:

5.95+-2.42 vs control 1.94+-0.36  [range 1.1 to 3.6 for 21 controls]
[ratio 3.1], since the +- error was 33% of the test value.

So, if the data for 4 mice is scattered,
then the mean value of the test group has
to be over 3 times that of the control group to be significant.

For Liver, 5 of the 21 control groups, with values 1.67, 1.63, 1.29,
1.06, 1.65 would make some 3 hr aspartame values approach or reach

Ratios about 2 for different tissues with aspartame that would be close
to significant would exist for many of the 21 control groups:

Stomach 1  Colon 5   Liver 5   Bladder 11   Lung 5 .

The aspartame values at 3 hr are compared with
the mean values for the 21 control groups:

Somach      Colon       Liver       Kidney       Bladder      Lung

DNA Migration at 3 hr from 2000 mg/kg dose

8.49+-0.48  9.18+-0.56  3.26+-0.16  1.91+-0.26   10.7+-2.77   4.13+-1.26

mean of 21 control groups

6.31        5.81        2.15        2.25          5.40        2.61

range of values for 21 control groups

4.3--8.6    4.0--8.1    1.1--3.6    1.2--2.9      3.6--7.1    1.6--4.7

ratio = DNA Migration/control mean

1.4         1.6         1.5         0.9           2.0         1.6

Brain       Bone [marrow]

0.37+-0.70  1.01+-0.59  DNA Migration at 3 hr from 2000 mg/kg dose

1.48        1.12        mean of 21 control groups

0.8--2.6    0.6--1.9    range of values for 21 control groups

0.3         0.9         ratio = DNA Migration/control mean

Wouldn't the average of all the 21 control groups be the best control
values to use?
What would then be the appropriate statistical test?
How many mice would it take to reach significance for the 5 tissues with
ratios over 1.4: Stomach, Colon, Liver, Bladder, Lung?

Aspartame at 24 hours had levels too low to reach significance with any
of the 21 control groups.

However, people who are heavy users of aspartame for years are bound
to accumulate toxic metabolites of the three components of aspartame:
methanol 11%, phenylalanine 50%, aspartic acid 29%, all genotoxic
[Trocho (1998), Karakis (1998)].

Comparing the mean control values to the values for the other 7
Best is acesulfame K, with no significant or high values.

Good is glycyrrhizin (derived from licorice), two 1.4 ratios for Stomach
and Brain.

Next is stevia, with one high value [above ratio 1.4],
9.48+-1.99 for Bladder, 2000 mg 3 hr,  ratio 1.8 .

Aspartame has high values for 2000 mg 3 hr for Stomach, Colon, Liver,
Bladder, Lung.

Sucralose has 3 significant values and 13 high values, for Stomach,
Colon, Kidney, Bladder, Lung, Brain.

Sodium cyclamate has 4 significant values and 10 high values for
Stomach, Colon, Liver, Kidney, Bladder, Lung, Brain, Bone.

Saccharin has 3 highly significant values for Colon, and 13 high values
for Stomach, Colon, Kidney, Lung, Brain, Bone.

Sodium saccharin has 5 highly significant values for Stomach and Colon,
and 14 high values for Stomach, Liver, Kidney, Bladder, Lung, Brain,

We should keep in mind that toxicity in humans involves
many vulnerable groups,
years of daily use,
often evolution of allergies and hypersensitivity,
and complex interactions with a multitude of  diseases,
additives, other toxins, and foods.

Some of the dye data was earlier published in Tsuda (2001):
Toxicol Sci 2001 May; 61(1): 92-9.
DNA damage induced by red food dyes orally administered to pregnant
and male mice.
Tsuda S, Murakami M, Matsusaka N, Kano K, Taniguchi K, Sasaki YF.
Laboratory of Veterinary Public Health, Department of Veterinary
Medicine, Faculty of Agriculture, Iwate University, Ueda 3-18-8,
Morioka, Iwate 020-8550, Japan.  s.tsuda at iwate-u.ac.jp

We determined the genotoxicity of synthetic red tar dyes currently used
as food color additives in many countries, including JAPAN:
For the preliminary assessment, we treated groups of 4 pregnant mice
(gestational day 11) once orally at the limit dose (2000 mg/kg) of
amaranth (food red No. 2),
allura red (food red No. 40),
or acid red (food red No. 106),
and we sampled brain, lung, liver, kidney, glandular
stomach, colon, urinary bladder, and embryo
3, 6, and 24 h after treatment.

We used the comet (alkaline single cell gel electrophoresis) assay to
measure DNA damage.
The assay was positive in the colon 3 h after the
administration of amaranth and allura red and weakly positive in the
lung 6 h after the administration of amaranth.

Acid red did not induce DNA damage in any sample at any sampling time.

None of the dyes damaged DNA in other organs or the embryo.

We then tested male mice with amaranth, allura red, and a related
color additive, new coccine (food red No. 18).
The 3 dyes induced DNA damage in the colon starting at 10 mg/kg.

Twenty ml/kg of soaking liquid from commercial red ginger pickles, which
contained 6.5 mg/10 ml of new coccine,
induced DNA damage in colon, glandular stomach, and bladder.

The potencies were compared to those of other rodent carcinogens.
The rodent hepatocarcinogen p-dimethylaminoazobenzene induced colon DNA
damage at 1 mg/kg, whereas it damaged liver DNA only at 500 mg/kg.

Although 1 mg/kg of N-nitrosodimethylamine induced DNA damage in liver
and bladder, it did not induce colon DNA damage.
N-nitrosodiethylamine at 14 mg/kg did not induce DNA damage in any organs
Because the 3 azo additives we examined induced colon DNA damage at a very
low dose, more extensive assessment of azo additives is warranted.
PMID: 11294979

comet assay finds DNA damage from sucralose, cyclamate, saccharin in
mice: Sasaki YF & Tsuda S  Aug 2002: Murray 1.1.3 rmforall

The Single Cell Gel Assay is able to detect single-strand and
double-strand DNA breaks in individual eukaryotic cells;
requires small numbers of cells (<20,000 per sample);
can detect DNA damage from low levels of toxic or physical insults;
and is rapid, simple and efficient.
In this assay, cells are treated with the agent of interest,
embedded in agarose on a histological slide,
the cell membranes are lysed, and the
slides are placed in an electric field.
If the DNA has single or double-strand breaks,
it will flow out of the cells and move toward the anode,
causing the cell and its DNA to resemble a comet.
The more DNA released from the cell, the greater the DNA damage.
A computerized imaging system is used to score and measure the comets.
The Comet assay is not FDA approved as a human medical test, so it is not
covered by insurance.
It is used in many human research studies.

http://cometassay.com/  Comet Assay Interest Group



http://www.ems-us.org/   Environmental Mutagen Society

DNA repair Interest Group  about a thousand members

Integrated Laboratory Systems    Comet assays for $155-300

http://www.mdbiotechinc.com/  MD Biotech, Inc.
Comet assays on four 10 ml blood samples for $800

Here I summarize the mean +- variation values for the 21 control groups,
for each tissue, giving the smallest variation and the largest.

Stomach     Colon       Liver       Kidney      Bladder     Lung

4.90+-0.26  4.49+-0.19  1.91+-0.19  1.81+-0.13  5.89+-0.24  2.44+-0.17

    5%              4%             10%              7%                4%

5.55+-1.26  7.91+-1.95  1.29+-0.69  1.73+-0.96  5.68+-1.30  2.56+-1.04

   23%             25%            53%             56%             23%

Brain       Bone [marrow]

2.58+-0.40  1.16+-0.15

     16%         13%

1.09+-1.09  0.75+-0.75

    100%        100%

We have +- mean variation, for the 21 control groups of 4 mice,
from 4 to 100%.

What causes this variation, for a specific strain of mice,
with the same diet, environment, and age?

Are there a number of genotoxins in the laboratory diet, with the mice
exhibiting many genetic susceptibilities?

Rich Murray, MA    Room For All    rmforall at comcast.net
1943 Otowi Road, Santa Fe, New Mexico 87505 USA  505-501-2298
136 members,  1,122 posts in a public searchable archive   also Co-Moderator

http://groups.yahoo.com/group/aspartame/messages  bryanth at brooksdata.net
Aspartame Victims Support Group    Edward Bryant Holman, Chief Moderator
849 members, 17,522 posts in a public, searchable archive

http://www.HolisticMed.com/aspartame    mgold at holisticmed.com
Aspartame Toxicity Information Center    Mark D. Gold     also Co-Moderator
12 East Side Drive #2-18 Concord, NH 03301     603-225-2110
"Scientific Abuse in Aspartame Research"

safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
Murray 2003.01.12 rmforall  EU Scientific Committee on Food, a whitewash

Mark Gold exhaustively critiques European Commission Scientific
Committee on Food re aspartame ( 2002.12.04 ): 59 pages, 230 references

UN FAO & WHO approve Steviol glycosides as sweetener June 2004, imports to
UK no longer blocked: Martini: Murray 2004.10.17 rmforall

http://www.dorway.com/tldaddic.html  5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter  2000 Jan;  HJRobertsMD at aol.com
http://www.sunsentpress.com/    sunsentpress at aol.com
Sunshine Sentinel Press  P.O.Box 17799  West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax

1038-page medical text   "Aspartame Disease: An Ignored Epidemic"
published May 30  2001    $ 60.00 postpaid    data from 1200 cases
available at  http://www.amazon.com
over 600 references from standard medical research

Moseley: review Roberts "Aspartame Disease: An Ignored Epidemic":
Murray 2002.02.07 rmforall

Roberts, Hyman J., 1924- ,
Useful insights for diagnosis, treatment and public heath: an updated
anthology of original research, 2002, 798 pages,
aspartame disease, pages 627-685, 778-780

Roberts: the life work of a brilliant clinician: aspartame toxicity:
Murray 2002.08.02 rmforall

J Toxicol Sci. 2002 Dec; 27 Suppl 1: 1-8.
[Genotoxicity studies of stevia extract and steviol by the comet assay]
[Article in Japanese]
Sekihashi K, Saitoh H, Sasaki Y.   yfsasaki-c at hachinohe-ct.ac.jp
Safety Research Institute for Chemical Compounds Co., Ltd., 363-24 Shin-ei,
Kiyota-ku, Sapporo 004-0839, Japan.

The genotoxicity of steviol, a metabolite of stevia extract, was evaluated
for its genotoxic potential using the comet assay.
In an in vitro study, steviol at 62.5, 125, 250, and 500 micrograms/ml did
not damage the nuclear DNA of TK6 and WTK1 cells in the presence
and absence of S9 mix.
In vivo studies of steviol were conducted by two independent organizations.
Mice were sacrificed 3 and 24 hr after one oral administration of steviol at
250, 500, 1000, and 2000 mg/kg.
DNA damage in multiple mouse organs was measured by the comet assay as
modified by us.
After oral treatment, stomach, colon, liver, kidney and testis DNA were not
The in vivo genotoxicity of stevia extract was also evaluated for its
genotoxic potential using the comet assay.
Mice were sacrificed 3 and 24 hr after oral administration of stevia extract
at 250, 500, 1000, and 2000 mg/kg.
Stomach, colon and liver DNA were not damaged.
As all studies showed negative responses, stevia extract and steviol are
concluded to not have DNA-damaging activity in cultured cells and mouse
organs.  PMID: 12533916

"Schwartz (1999) also reported that methanol is converted to formaldehyde
which then accumulates in the cells.
Formaldehyde has been considered an inducer of cancer and acts to alter DNA
(Ewertz, 1993;
Ewertz and Gill, 1990).

Olney et al. (1996) reviewed and explained that ASP had mutagenic

In this study, we found that, ASP did appear to have genotoxic potential
consistent with potential carcinogenicity.

According to these results, phenyalanine and methanol, which are metabolic
products of ASP, have a genotoxic risk for humans.

In contrast, ASP was not found as a mutagen in in vivo studies.

However, in the present study, ASP induced CA and micronuclei in human
lyphocytes dose-dependently.

ASP did not change the osmolality of the medium at the maximum
concentrations (346 milliosmol) when compared with untreated medium (342

It was reported that a deviation from physiological osmolality
(approximately 300 milliosmol) can lead to genotoxic effects
(Nowak, 1984, 1997;
Seeberg et al., 1989).

According to these results, we can conclude that ASP induced CA and
percentage of micronuclei by itself because it did not alter the pH and
osmolality of the medium.

As shown, there are several contradictory studies about genotoxicity and
carcinogenicity of ASP.

However, it must be taken into account that ASP induced the CA and
micronuclei formation in a dose-dependent manner.

It is not possible to conclude that ASP is safe according to these results.

Therefore, it is necessary to be careful when using it in food and beverages
as a sweetener."

Genotoxicity of aspartame 2004.07.29 plain text, Rencuzogullari E et al,
Cukurova University, Adana, Turkey 2004 Aug

Drug Chem Toxicol. 2004 Aug; 27(3): 257-68.
Genotoxicity of aspartame.
Rencuzogullari E, Tuylu BA, Topaktas M, Ila HB, Kayraldiz A, Arslan M, Diler
Biology Department, Faculty of Arts and Sciences, Natural and Applied
Sciences Institute, Cukurova University, Adana, Turkey.
reyyup at mail.cu.edu.tr

[ http://www.cu.edu.tr/Content/Asp/English/index.asp

http://rektorluk.cukurova.edu.tr/en/rehber.asp ]

In the present study, the genotoxic effects of the low-calorie sweetener
aspartame (ASP), which is a dipeptide derivative, was investigated using
chromosome aberration (CA) test,
sister chromatid exchange (SCE) test,
micronucleus test in human lymphocytes       and also
Ames/Salmonella/ microsome test.
ASP induced CAs at all concentrations (500, 1000 and 2000 microg/ml) and
treatment periods (24 and 48 h) dose-dependently,
while it did not induce SCEs.
On the other hand, ASP decreased the replication index (RI) only at
the highest concentration for 48 h treatment period.
However, ASP decreased the mitotic index (MI) at all concentrations and
treatment periods dose-dependently.
In addition, ASP induced micronuclei at the highest concentrations only.
This induction was also dose-dependent for 48 hours treatment period.
ASP was not mutagenic for Salmonella typhimurium TA98 and TA100 strains in
the absence and presence of S9 mix.   PMID: 15478947


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Genotoxicity of Aspartame
Published in Drug and Chemical Toxicology , Volume 27 , Issue 3
Print ISSN: 0148-0545     Online ISSN: 1525-6014

Online Article World Price: $24.00

Eyyüp Rencüzoullar *Corresponding   reyyup at mail.cu.edu.tr

[  http://lokman.cu.edu.tr/ent/
Çukurova University Medical School
Adana, Turkey
This page was last updated on 07/06/00.

Webmaster: Assoc.Prof.Mete Kiroglu M.D.  metekbb at mail.cu.edu.tr

Çukurova University  Department of Biophysics
Address:  Balcali,   01330 Turkey
Email:  biyofiz at pamuk.cc.cu.edu.tr
Website:  http://lokman.cu.edu.tr/biophysics/     Chair: Dr. Ismail Guenay ]

Berrin Ayaz Tüylü 3

Mehmet Topakta 1

Hasan Basri la 1

Ahmet Kayraldz 2

Mehmet Arslan 2

Songül Budak Diler 2

1 Biology Department, Faculty of Arts and Sciences, Çukurova University
01330, Adana, Turkey

2 Biology Department, Natural and Applied Sciences Institute, Çukurova
University 01330, Adana, Turkey

3 Biology Department, Faculty of Sciences, Anadolu University
26470, Eskiehir, Turkey

Journal Article | Print Published: 08/01/2004 | Online Published: 07/29/2004
Pages: 257 - 268 | PDF File Size: 104 KB
DOI: 10.1081/DCT-120037506


Sweeteners, Aspartame, Chromosome aberrations, Sister chromatid exchange,
Micronuclei, Ames test

This study was funded by Çukurova University Research Fund FEF 2002 BAP 21.
We also thank Mr. L.K. Nakamura for his kind collaboration.

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UN links for public health in Turkey

The Scientific and Technical Research Council of Turkey
(+90 312) 4677798   (+90 312) 4673002   (+90 312) 4685300 / 4400-4401
fax: (+90 312) 4272672    E-mali:  aysegul at tubitak.gov.tr
Adress: Adres: TÜBITAK Atatürk Bulvari No:221, Kavaklidere,
06100 Ankara Tel: (+90 312) 468 5300 Faks: (+90 312) 427 7489

Turkish Journal of Medical Science    medsci at tubitak.gov.tr  free full texts

Turkish Journal of Biology       biol at tubitak.gov.tr  free full texts

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