Myra L Karstadt and Morando Soffritti in Environmental Health
Perspectives agree on need for adaquate safety testing of acesulfame-K:
Murray 2006.08.04
http://groups.yahoo.com/group/aspartameNM/message/1362


----- Original Message -----
From: Kathryn Knowles
To: development@...
Sent: Friday, August 04, 2006 4:04 AM
Subject: Testing Artificial Sweeteners:
Letters to the Editor of Environmental Health Perspectives

For your information:

A letter to the Editor entitled
"Testing Needed for Acesulfame Potassium, an Artificial Sweetener"
by Dr. Myra L. Karstadt of the Drexel University School of Public Health
and response by Dr. Morando Soffritti
of the European Ramazzini Foundation
are currently in press in Environmental Health Perspectives.

The letters may be accessed via EHP Online at:
www.ehponline.org/docs/2006/9260/letter.html
and via the website of the European Ramazzini Foundation at:
www.ramazzini.it.
The full text is also included below.

Regards, Kathryn Knowles, Director of Resource Development
European Foundation of Oncology and Environmental Sciences
"B. Ramazzini" Castello di Bentivoglio via saliceto, 3
40010 Bentivoglio (BO) Italy
Tel. +39 051 6640460 (int.3) Fax. +39 051 6640223
skype: kathrynknowles
development@... www.ramazzini.it

Correspondence-in-Press

Testing Needed for Acesulfame Potassium, an Artificial Sweetener
Letter: Karstadt ML
Response: Soffritti M

Testing Needed for Acesulfame Potassium, an Artificial Sweetener

Referencing: First Experimental Demonstration of the Multipotential
Carcinogenic Effects of Aspartame Administered in the Feed
to Sprague-Dawley Rats

In their article "First Experimental Demonstration of the Multipotential
Carcinogenic Effects of Aspartame Administered in the Feed of
Sprague-Dawley Rats," Soffritti et al. (2006) present interesting data
on the carcinogenic effects of long-term exposure to aspartame,
an artificial sweetener, in experimental animals (rats).

Recently, aspartame was supplanted as the leading artificial sweetener
by sucralose, marketed in the United States under the trade name
Splenda (McNeil Nutritionals, LLC, Ft. Washington, PA).
As of 2005, Splenda was reported to have > 50% of the market for
artificial sweeteners,
while aspartame [Equal (Merisant Company, Chicago, IL);
NutraSweet (NutraSweet Property Holdings Inc., Chicago, IL)]
had < 20% (Associated Press 2005).
Splenda is typically used in sweetener blends, most frequently with
acesulfame potassium (CAS RN 55589-62-3)
(Sunett; marketed in the United States by Nutrinova, Somerset, NJ).

The Food and Drug Administration's (FDA) multiple approvals of food
additive petitions (FAPs) for acesulfame began in 1988 (FDA 1988),
and culminated in 1998 with approval of the use
of acesulfame in soft drinks (FDA 1998),
historically the largest single use of artificial sweeteners.
All of the FDA's approvals of FAPs for acesulfame were grounded on
the conclusion that safety studies, including long-term animal tests of
acesulfame carried out for Hoechst,
the manufacturer of the chemical, in the Netherlands in the 1970s,
were adequate and the test results indicated safety.

The 1970s tests of acesulfame-two tests carried out in rats and one
in mice -- are inadequate to establish lack of potential carcinogenicity.
Here are a few reasons why the tests are inadequate
[Center for Science in the Public Interest (CSPI) 1996]:

a.. Subchronic tests were not conducted for the rats and mice used in
the tests on which the FAPs rested
b.. It is likely the minimum toxic dose/maximum tolerated dose (MTD)
was not achieved in the rat and mouse studies
c.. Randomization of test groups was not carried out properly
d.. Mice were held on test for only 80 weeks,
rather than the 104 weeks characteristic of NTP bioassays
e.. Animal husbandry and monitoring of animals on test were
evidently poor, as indicated by high disease rates in the animals
and extensive autolysis of tissues.
Even with the flaws in design and execution of the Hoechst tests,
results indicated an association between treatment with acesulfame
and carcinogenesis (CSPI 1996).

Working-level staff members at the FDA identified deficiencies in the
acesulfame tests in the 1980s (McLaughlin 1986; Taylor 1986).
Thus, an FDA staff member (Taylor 1986) noted in 1986, when the
FDA had decided to accept the Hoechst studies, that

The question remains whether these studies are sufficiently definitive
or rigorous in light of the potential for widespread, [sic] high exposure
to acesulfame K in all group [sic] in the population.

In 1996, the CSPI nominated acesulfame for testing in the
National Toxicology Program (NTP) bioassay program (CSPI 1996),
and provided the NTP with detailed information on the Hoechst tests
and their flaws. Although an individual familiar with test design and
implementation could have concluded with ease that the Hoechst tests
were not consistent with the criteria established for NTP bioassays
or the test guidelines set out in the FDA's Redbook, (FDA 1982)
and it was likely that, at some point, many people would be exposed to
acesulfame, the NTP rejected CSPI's nomination.

In 2003, the NTP announced the results of tests of both aspartame and
acesulfame in genetically modified mice (GMM) (NTP 2005).
Both chemicals gave negative results in the tests,
carried out in two strains of GMM.

The NTP's final report on those GMM studies (NTP 2005) noted that aspartame
and acesulfame had been selected as "negative controls" for validation tests
for the GMM models.
The chemicals did indeed test negative, but that negative result did not
advance our understanding of potential carcinogenicity of acesulfame.
Regarding the GMM tests of aspartame and acesulfame, Martha Sandy
of the California Environmental Protection Agency, stated that

Negative results [in the GMM tests] are not informative as to the test
substance's carcinogenicity, and point to the need to conduct standard
two-year carcinogenicity studies. At this time, transgenic models cannot
replace the two-year bioassay and it would be unwise to list a chemical
as safe for human exposure based upon negative results
in not yet validated model systems. (Sandy 2003)

The findings of Soffritti et al. (2006) of multipotential carcinogenesis
in rats fed aspartame over their lifetimes provide support for Sandy's
(2003) statements.

I have sent the NTP a new nomination of acesulfame
for 2-year bioassay testing (Karstadt 2006).

The author declares that she has no competing financial interests.

Myra L. Karstadt
Department of Environmental and Occupational Health
Drexel University School of Public Health Philadelphia, Pennsylvania
E-mail: myrakarstadt@...

References

Associated Press. 2005. Splenda War Turns More Sour Available:
http://www.msnbc.msn.com/id/6936203 [accessed 10 July 2006].

CSPI. 1996. Letter from M Karstadt and MF Jacobson,
Center for Science in the Public Interest, to Errol Zeiger,
National Toxicology Program. Acesulfame, 29 May 1986.

FDA. 1982. Toxicological Principles for the
Safety Assessment of Direct Food Additives and Color Additives.
Washington, DC: Food and Drug Administration.

FDA (Food and Drug Administration). 1988. Food additives
permitted for direct addition to food for human consumption:
acesulfame potassium. Final rule. Fed Reg 53: 28379.

FDA (Food and Drug Administration). 1998. Food additives
permitted for direct addition to food for human consumption;
acesulfame potassium. Final rule. Fed Reg 63(128): 36344-36361.

Karstadt M. 2006. Letter from M Karstadt,
Drexel University School of Public Health,
to S Masten, National Toxicology Program.
Nomination of acesulfame potassium for testing in NTP's
bioassay program, 1 May 2006.

McLaughlin PJ. 1986. Memorandum from PJ McLaughlin,
Food and Drug Administration (FDA),
Center for Food Safety and Applied Nutrition,
to four participants from Hoechst (registrant of acesulfame)
and five participants from FDA. Memorandum of conference;
industry/FDA, 19 June 1986.

NTP. 2005. Toxicity Studies of Acesulfame Potassium
(CAS No. 55589-62-3) in FVB/N-TgN(v-Ha-ras)
Led (Tg.AC) Hemizygous Mice and Carcinogenicity Studies
of Acesulfame Potassium in B6.129-Trp53tm1Brd(N5)
Haploinsufficient Mice (Feed Studies).
NTP GMM2. Research Triangle Park:
National Toxicology Program. Available:
http://ntp.niehs.nih.gov/files/GMM2_Web.pdf
[accessed 10 July 2006].

Sandy MS. 2003. Letter from MS Sandy,
California Office of Environmental Health Hazard Assessment,
California Environmental Protection Agency,
to K Olden, National Toxicology Program/National Institute
of Environmental Health Sciences.
GMM tests of aspartame and acesulfame, 16 May 2003.
[ see also:
http://groups.yahoo.com/group/aspartameNM/message/1189
Michael F Jacobson of CSPI now and in 1985 re aspartame
toxicity, letter to FDA Commissioner Lester Crawford;
California OEHHA aspartame critique 2004.03.12; Center for
Consumer Freedom denounces CSPI: Murray 2005.07.27 ]

Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L, Tibaldi E,
Rigano A. 2006. First Experimental Demonstration of the
Multipotential Carcinogenic Effects of Aspartame
Administered in the Feed to Sprague-Dawley Rats.
Environ Health Perspect 114:379-385.

Taylor L. 1986. Memorandum from L Taylor,
Food and Drug Administration,
to R Lorentzen, Center for Food Safety and Applied Nutrition.
Request for CAC Evaluation of the carcinogenic potential
of acesulfame potassium; update, 19 June 1986.
------------------------------------------------------------------


Acesulfame Potassium: Soffritti Responds

Karstadt makes an important point regarding the need for more
adequate long-term carcinogenicity testing of the artificial sweetener
acesulfame K. The issues raised in her letter stimulated me to offer
some additional considerations.

As reported in a previous paper (Soffritti et al. 1999),
one of the most important issues in environmental and industrial
carcinogenesis is how to deal with diffused carcinogenic risks,
to which most of the planet's population may be exposed.
These carcinogenic risks are represented by
a) agents that are slightly carcinogenic at any dose;
b) low or extremely low doses of a carcinogenic agent of any kind;
or c) mixtures of small doses of carcinogenic agents.

Epidemiologic and experimental studies are fundamental in the
identification and quantification of diffused carcinogenic risks,
but they must be designed and conducted to be as powerful
as possible with adequate methodology.
In the case of experimental studies, it is not sufficient to follow
the standard protocol used in ordinary experiments.
Instead, it is necessary to conduct studies that may be defined as
"mega-experiments," using a vast number of animals
(at least 200-1,000 per experimental group)
in order to express a marked difference in the variation of effects,
and exposing the animals in all phases of development
to allow the agent to express its full carcinogenic potential.

It is based on this rationale that the European Ramazzini Foundation
performed a mega-experiment on 1,800 rats and demonstrated
that, in our experimental conditions, aspartame is a multipotential
carcinogenic agent (Soffritti et al. 2005; Soffritti et al. 2006).

The results of our study (Soffritti et al. 2005; Soffritti et al. 2006)
attracted the attention of the scientific community, consumer and
industry associations, and the national and international agencies
responsible for food safety. Among various comments,
the opinion expressed on 5 May 2006 by the
European Food Safety Authority (EFSA 2006)
and the general interpretation of an epidemiologic study
conducted by the National Cancer Institute (NCI 2006)
necessitate comment on our part.

In examining the raw data of our study, the EFSA (2006)
observed a high incidence of chronic pulmonary inflammation
in males and females in both treated groups and in the control group.
Based on this observation, it was concluded that
"the increased incidence of lymphomas/leukemias reported
in treated rats was unrelated to aspartame,
given the high background incidence of chronic inflammatory
changes in the lungs . . . ."
In my opinion, this conclusion is bizarre for the following reasons:

First, the EFSA (2006) overlooked the fact that the study was
conducted until the natural death of the rodents.
It is well known that infectious pathologies are part of the
natural dying process in both rodents and humans.

Second, if the statistically significant increased incidence of
lymphomas/leukemias observed was indeed caused by an
infected colony, one would expect to observe an increased
incidence of lymphomas/leukemias not only in females
but also in males.
The EFSA (2006) did not comment on this discrepancy in their logic.

Finally, in support of the hypothesis regarding the safety of aspartame,
the EFSA (2006) cited the negative results of recent carcinogenicity
studies carried out in transgenic mice by the NTP;
the ESFA did not mention that, because the NTP studies on
genetically altered mice were performed using a new experimental
model, the NTP subcommittee unanimously agreed "
there is uncertainty whether the study possessed sufficient sensitivity
to detect a carcinogenic effect" (NTP 2005).

Interestingly, the same scrutiny applied to our study has not been
applied to a recent abstract published by Lim et al. (2006)
from the NCI diet questionnaire survey (NCI 2006)
in which self-reported aspartame consumption
showed no increases in either leukemia/lymphomas or in brain cancer.
These results have been used by industry, the EFSA,
and others to argue that aspartame is not a risk for humans,
in spite of our animal study results.
Without specific information on each individual's consumption rate
and duration it is difficult to assess the power of the survey,
in spite of the large number of participants.
The second related issue is whether aspartame
is an early- or late-stage carcinogen.
If it is an early-stage initiator of cancer,
then reporting the lack of effects
in older individuals who have not consumed aspartame
since early childhood would be expected to show
little or no increased cancer (Hoel 1985).

The safety-in particular, the noncarcinogenicity-of today's most
widely diffused artificial sweeteners and their blends is largely based
on studies conducted decades ago.
I second Karstadt's nomination of acesulfame K for further study;
however, I add that it should be evaluated
using a long-term mega-experiment.

The author declares he has no competing financial interests.

Morando Soffritti Cesare Maltoni Cancer Research Center
European Foundation of Oncology and Environmental Sciences
"B. Ramazzini" Bologna, Italy E-mail: crcfr@...

References

EFSA (European Food Safety Authority). 2006.
Opinion of the Scientific Panel AFC Related to a New Long-Term
Carcinogenicity Study on Aspartame. Available:
http://www.efsa.eu.int/science/afc/afc_opinions/1471_en.html
[accessed 1 June 2006].

Hoel DG. 1985.
Epidemiology and the inference of cancer mechanisms.
Natl Cancer Inst Monogr 67: 199-203.

NCI (National Cancer Institute). 2006.
NIH-AARP Diet and Health Study. Available:
http://dietandhealth.cancer.gov/ [accessed 1 June 2006].

NTP. 2005.
Toxicology Studies of Aspartame (CAS No. 22839-47-0)
in Genetically Modified (FVB Tg.AC Hemizygous)
and B6.129-Cdkn2atm1Rdp (N2) Deficient Mice
and Carcinogenicity Studies on Aspartame
in Genetically Modified B6.129-Trp53tm1Brd (N5)
Haploinsufficient Mice (Feed Studies).
Technical report GMM1. Research Triangle Park, NC:
National Toxicology Program. Available:
http://ntp.niehs.nih.gov/files/GMM1_Web.pdf
[accessed 11 July 2006].

Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L. 2005.
Aspartame induces lymphomas and leukaemias in rats.
Eur J Oncol 10: 107-116.

Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L,
Tibaldi E, Rigano A. 2006.
First experimental demonstration of the multipotential carcinogenic
effects of aspartame administered in the feed to Sprague-Dawley rats.
Environ Health Perspect 114: 379-385.

Soffritti M, Belpoggi F, Minardi F, Bua L, Maltoni C. 1999.
Mega-experiments to identify and assess diffuse carcinogenic risks.
Ann NY Acad Sci 895:34-55.

Lim U, Subar AF, Mouw T, Hartge P, Morton LM,
Stolzenberg-Solomon R, et al. 2006.
Prospective study of aspartame-containing beverages
and risk of hematopoietic and brain cancers [Abstract].
In: Proceedings of the 97th AACR Annual Meeting, 1-5 April 2006, Washington,
DC. Available:
http://www.aacr.org/default.aspx?p=6036 [accessed 11 July 2006].
*******************************************************


unexamined diet research cofactors:
formaldehyde from tobacco and wood smoke,
it also forms from methanol in dark wines and liquors
and 11% methanol part of aspartame: Murray 2006.08.04


http://groups.yahoo.com/group/aspartameNM/message/1340
aspartame groups and books: updated research review of 2004.07.16:
Murray 2006.05.11


http://groups.yahoo.com/group/aspartameNM/message/1341
Connecticut bans artificial sweeteners in schools, Nancy Barnes,
New Milford Times: Murray 2006.05.25

http://groups.yahoo.com/group/aspartameNM/message/1353
carcinogenic effect of inhaled formaldehyde, Federal Institute of Risk
Assessment, Germany -- same safe level as for Canada:
Murray 2006.06.02

http://groups.yahoo.com/group/aspartameNM/message/1352
Home sickness -- indoor air often worse, as our homes seal in pollutants
[one is formaldehyde, also from the 11% methanol part of aspartame],
Megan Gillis, WinnipegSun.com: Murray 2006.06.01


"Of course, everyone chooses, as a natural priority,
to actively find, quickly share, and positively act upon the facts
about healthy and safe food, drink, and environment."

Rich Murray, MA Room For All rmforall@...
505-501-2298 1943 Otowi Road Santa Fe, New Mexico 87505

http://groups.yahoo.com/group/aspartameNM/messages
group with 73 members, 1,362 posts in a public, searchable archive
http://RMForAll.blogspot.com


http://groups.yahoo.com/group/aspartameNM/message/1143
methanol (formaldehyde, formic acid) disposition: Bouchard M
et al, full plain text, 2001: substantial sources are
degradation of fruit pectins, liquors, aspartame, smoke:
Murray 2005.04.02

http://groups.yahoo.com/group/aspartameNM/message/1349
NIH NLM ToxNet HSDB Hazardous Substances Data Bank
inadequate re aspartame (methanol, formaldehyde, formic acid):
Murray 2006.08.04

http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~HwoSfJ:1
HSDB Hazardous Substances Data Bank: Aspartame

ASPARTAME CASRN: 22839-47-0
METHANOL CASRN: 67-56-1
FORMALDEHYDE CASRN: 50-00-0
FORMIC ACID CASRN: 64-18-6

http://groups.yahoo.com/group/aspartameNM/message/1307
formaldehyde from 11% methanol part of aspartame or from red wine
causes same toxicity (hangover) harm: Murray 2006.05.24

Dark wines and liquors, as well as aspartame, provide
similar levels of methanol, above 120 mg daily, for
long-term heavy users, 2 L daily, about 6 cans.

Within hours, methanol is inevitably largely turned into formaldehyde,
and thence largely into formic acid -- the major causes of the dreaded
symptoms of "next morning" hangover.

Fully 11% of aspartame is methanol -- 1,120 mg aspartame
in 2 L diet soda, almost six 12-oz cans, gives 123 mg
methanol (wood alcohol). If 30% of the methanol is turned
into formaldehyde, the amount of formaldehyde, 37 mg,
is 18.5 times the USA EPA limit for daily formaldehyde in
drinking water, 2.0 mg in 2 L average daily drinking water.

Any unsuspected source of methanol, which the body always quickly
and largely turns into formaldehyde and then formic acid, must be
monitored, especially for high responsibility occupations, often with
night shifts, such as pilots and nuclear reactor operators.

http://www.HolisticMed.com/aspartame mgold@...
Aspartame Toxicity Information Center Mark D. Gold
12 East Side Drive #2-18 Concord, NH 03301 603-225-2100

http://www.holisticmed.com/aspartame/abuse/methanol.html
"Scientific Abuse in Aspartame Research"
*******************************************************


http://groups.yahoo.com/group/aspartameNM/message/1291
European Food Safety Authority to decide aspartame safety by May:
caffeine diet drinks cause female hypertension, WC Winkelmayer et al,
JAMA 2005.11.09: PubMed lists 50 items for "diet soft drinks" since
2004 Oct.: Murray 2006.01.24

http://groups.yahoo.com/group/aspartameNM/message/1279
all three aspartame metabolites harm human erythrocyte [red blood cell]
membrane enzyme activity, KH Schulpis et al, two studies in 2005,
Athens, Greece, 2005.12.14: 2004 research review, RL Blaylock:
Murray 2006.01.14

http://groups.yahoo.com/group/aspartameNM/message/939
aspartame (aspartic acid, phenylalanine) binding to DNA:
Karikas July 1998: Murray 2003.01.05 rmforall
Karikas GA, Schulpis KH, Reclos GJ, Kokotos G
Measurement of molecular interaction of aspartame and
its metabolites with DNA. Clin Biochem 1998 Jul; 31(5): 405-7.
Dept. of Chemistry, University of Athens, Greece
http://www.chem.uoa.gr gkokotos@...;
K.H. Schulpis inchildh@...; G.J. Reclos reklos@...;

http://groups.yahoo.com/group/aspartameNM/message/1271
combining aspartame and quinoline yellow, or MSG and brilliant blue,
harms nerve cells, eminent C. Vyvyan Howard et al, 2005
education.guardian.co.uk, Felicity Lawrence: Murray 2005.12.21

http://groups.yahoo.com/group/aspartameNM/message/1329
aspartame or MSG affects circadian rhythms in rats, two studies,
P. Subramanian, T. Manivasagam et al 2004:
Murray 2006.04.27

http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text Trocho & Alemany 1998.06.26
Universitat Autònoma de Barcelona : Murray 2002.12.22


http://groups.yahoo.com/group/aspartameNM/message/1316
PubMed abstract: aspartame (methanol becoming formaldehyde) causes
many cancers in rats, Ramazzini Foundation, M Soffritti et al:
Murray 2006.03.06

http://www.ehponline.org/members/2005/8711/8711.html free full text

Environ Health Perspect. 2006 Mar; 114(3): 379-85.
First experimental demonstration of the multipotential carcinogenic
effects of aspartame administered in the feed to sprague-dawley rats.
Soffritti M, Belpoggi F, Esposti DD,
Lambertini L, Tibaldi E, Rigano A.
Cesare Maltoni Cancer Research Center, European Ramazzini
Foundation of Oncology and Environmental Sciences, Bologna, Italy.

The Cesare Maltoni Cancer Research Center of the European
Ramazzini Foundation has conducted a long-term bioassay on
aspartame (APM), a widely used artificial sweetener.

APM was administered with feed to 8-week-old Sprague-Dawley rats
(100-150/sex/group), at concentrations of
100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm.

The treatment lasted until natural death, at which time
all deceased animals underwent complete necropsy.

Histopathologic evaluation of all pathologic lesions and of all organs
and tissues collected was routinely performed
on each animal of all experimental groups.

The results of the study show for the first time that APM,
in our experimental conditions, causes
a) an increased incidence of malignant-tumor-bearing animals
with a positive significant trend in males (p 0.05)
and in females (p 0.01),
in particular those females treated at 50,000 ppm (p 0.01);

b) an increase in lymphomas and leukemias
with a positive significant trend in both males (p 0.05)
and females (p 0.01),
in particular in females treated at doses of
100,000 (p 0.01), 50,000 (p 0.01), 10,000 (p 0.05),
2,000 (p 0.05), or 400 ppm (p 0.01);

c) a statistically significant increased incidence,
with a positive significant trend (p 0.01),
of transitional cell carcinomas of the renal pelvis and ureter and
their
precursors (dysplasias) in females treated at
100,000 (p 0.01), 50,000 (p 0.01), 10,000 (p 0.01),
2,000 (p 0.05), or 400 ppm (p 0.05);

and d) an increased incidence of malignant schwannomas
of peripheral nerves with a positive trend (p 0.05) in males.

The results of this mega-experiment indicate that APM
is a multipotential carcinogenic agent,
even at a daily dose of 20 mg/kg body weight,
much less than the current acceptable daily intake. [ 50 mg/kg bw ]

On the basis of these results,
a reevaluation of the present guidelines
on the use and consumption of APM is urgent
and cannot be delayed.

Key words: artificial sweetener, aspartame, carcinogenicity,
lymphomas, malignant schwannomas, rats, renal pelvis carcinomas.
PMID: 16507461 Feb 24 2006 04:49:50

Address correspondence to M. Soffritti, Cesare Maltoni Cancer
Research Center, European Ramazzini Foundation of Oncology and
Environmental Sciences, Castello di Bentivoglio, Via Saliceto, 3,
40010 Bentivoglio, Bologna, Italy. 39-051-6640460
Fax: 39-051-6640223 crcfr@...
We thank the U.S. National Toxicology Program for convening a group
of pathologists at the
National Institute of Environmental Health Sciences
to provide a second opinion for a set of malignant lesions and their
precursors related to aspartame treatment, and for their help in
statistical analysis.
We also thank all of the staff involved in the project.
This research was supported by the European Ramazzini Foundation of
Oncology and Environmental Sciences.
The authors declare they have no competing financial interests.
Received 3 October 2005; accepted 16 November 2005.


http://www.ehponline.org/members/2005/8711/tab1.jpg
[ transcribed to plain text ]
Table 1. Beverages and diet products studied at the CMCRC/ERF:
status of studies.

Study---------------------------No. of bioassays
---Products-------------------------Species---------No. Study status

1 Water in
polyvinyl chloride bottles---------2 rat a--------------2,200 P b

2 Coca-Cola---------------------4 rat a--------------1,999 RP

3 Pepsi Cola----------------------1 rat-----------------400 E

4 Ethyl alcohol--------------------4 rat, mouse a------1,458 P c

5 Sucrose-------------------------1 rat-----------------400 E

6 Aspartame (APM)--------------6 rat, mouse a------4,460 BO, PP d

7 Sucralose (Splenda)-------------1 mouse *-----------760 BO

8 Caffeine-------------------------1 rat-----------------800 E

9 Vitamin A-----------------------5 rat----------------5,100 E

10 Vitamin C----------------------5 rat----------------3,680 E

11 Vitamin E----------------------5 rat----------------3,680 E

12 Feed sterilized by--------------1 rat a---------------2,000 E
gamma radiation

Total-----------------------------36-------------------26,937

Abbreviations:
BO, biophase ongoing
E, in elaboration
P, published
PP, partially published
RP, ready for publication
a, treatment started from embryonic life
b, data from Maltoni et al. (1997)
c, data from Soffritti et al. (2002a)
d, data from Soffritti et al. (2005).
*, data from Soffritti et al. (1992)


Investigations into the metabolism of APM have shown that,
in rodents, nonhuman primates, and humans,
it is metabolized in the gastrointestinal tract
into three constituents --
aspartic acid, phenylalanine, and methanol --
which are absorbed into the systemic circulation (Ranney et al. 1976).

For each molecule of APM,
one molecule of each constituent is produced.

After absorption, they are then used, metabolized, and/or excreted by
the body following the same metabolic pathways
as when consumed through the ordinary diet:

aspartate is transformed into alanine plus oxaloacetate (Stegink 1984);

phenylalanine is transformed mainly into tyrosine and, to a smaller
extent, phenylethylamine and phenylpyruvate (Harper 1984);

and methanol is transformed into formaldehyde and then to formic acid
(Opperman 1984).
*******************************************************

Morando Soffritti 1, Fiorella Belpoggi 1, Davide Degli Esposti 1, Luca
Lambertini 1, Eva Tibaldi 1,
and Anna Rigano 1
1 Cesare Maltoni Cancer Research Center,
European Ramazzini Foundation of Oncology and
Environmental Sciences, Bologna, Italy
Address of the institution:
Cesare Maltoni Cancer Research Center,
European Ramazzini Foundation of Oncology and Environmental Sciences.
Castello di Bentivoglio, Via Saliceto, 3, 40010 Bentivoglio,
Bologna, Italy
+39/051/6640460 Fax +39/051/6640223 crcfr@...

Address correspondence to
Dr. M. Soffritti, M.D., Scientific Director of the Cesare Maltoni
Cancer Research Center,
European Ramazzini Foundation
of Oncology and Environmental Sciences.
Castello di Bentivoglio, Via Saliceto, 3, 40010 Bentivoglio,
Bologna, Italy
+39/051/6640460 Fax +39/051/6640223 crcfr@...

Acknowledgements: A special thanks to the
US National Toxicology Program (NTP)
for convening a group of pathologists at NIEHS
in order to provide a second opinion
for a set of lesions of malignancies and their precursors
related to the APM treatment, and for the help in statistical analysis.

http://groups.yahoo.com/group/aspartameNM/message/1250
aspartame causes cancer in rats at levels approved for humans,
Morando Soffritti et al, Ramazzini Foundation, Italy &
National Toxicology Program
of National Institute of Environmental Health Sciences
2005.11.17 Env. Health Pers. 35 pages: Murray

http://groups.yahoo.com/group/aspartameNM/message/1226
USA National Institutes of Health National Toxicology
Program aids eminent Ramazzini Foundation, Bologna, Italy,
in more results on cancers in rats from lifetime low levels
of aspartame (methanol, formaldehyde), Felicity Lawrence,
www.guardian.co.uk: Murray 2005.09.30

http://groups.yahoo.com/group/aspartameNM/message/1186
aspartame induces lymphomas and leukaemias in rats, full plain text,
M Soffritti, F Belpoggi, DD Esposti, L Lambertini: Ramazzini
Foundation study 2005.07.14: main results agree with their previous
methanol and formaldehyde studies: Murray 2005.09.03

http://groups.yahoo.com/group/aspartameNM/message/1189
Michael F Jacobson of CSPI now and in 1985 re aspartame
toxicity, letter to FDA Commissioner Lester Crawford;
California OEHHA aspartame critique 2004.03.12; Center for
Consumer Freedom denounces CSPI: Murray 2005.07.27

http://groups.yahoo.com/group/aspartameNM/message/1016
President Bush & formaldehyde (aspartame) toxicity:
Ramazzini Foundation carcinogenicity results Dec 2002:
Soffritti: Murray 2003.08.03 rmforall

p. 88 "The sweetening agent aspartame hydrolyzes in the
gastrointestinal tract to become free methyl alcohol,
which is metabolized in the liver
to formaldehyde, formic acid, and CO2. (11)"
Medinsky MA & Dorman DC. 1994; Assessing risks of low-level
methanol exposure. CIIT Act. 14: 1-7.

Ann N Y Acad Sci. 2002 Dec; 982: 87-105.
Results of long-term experimental studies on the carcinogenicity of
formaldehyde and acetaldehyde in rats.
Soffritti M, Belpoggi F, Lambertin L,
Lauriola M, Padovani M, Maltoni C.
Cancer Research Center, European Ramazzini Foundation for Oncology
and Environmental Sciences, Bologna, Italy. crcfr@...
Formaldehyde was administered for 104 weeks in drinking water
supplied ad libitum at concentrations of
1500, 1000, 500, 100, 50, 10, or 0 mg/L
to groups of 50 male and 50 female Sprague-Dawley rats beginning at
seven weeks of age.
Control animals (100 males and 100 females) received tap water only.
Acetaldehyde was administered to 50 male and 50 female
Sprague-Dawley rats beginning at six weeks of age at concentrations of
2,500, 1,500, 500, 250, 50, or 0 mg/L.
Animals were kept under observation until spontaneous death.
Formaldehyde and acetaldehyde were found to produce an increase
in total malignant tumors in the treated groups
and showed specific carcinogenic effects on various organs and tissues.
PMID: 12562630

Ann N Y Acad Sci. 2002 Dec; 982: 46-69.

Results of long-term experimental studies on the carcinogenicity of
methyl alcohol and ethyl alcohol in rats.
Soffritti M, Belpoggi F, Cevolani D,
Guarino M, Padovani M, Maltoni C.
Cancer Research Center, European Ramazzini Foundation for Oncology
and Environmental Sciences, Bologna, Italy. crcfr@...
Methyl alcohol was administered in drinking water
supplied ad libitum at doses of
20,000, 5,000, 500, or 0 ppm to groups of male and female
Sprague-Dawley rats 8 weeks old at the start of the experiment.
Animals were kept under observation until spontaneous death.
Ethyl alcohol was administered by ingestion in drinking water at a
concentration of 10% or 0% supplied ad libitum to groups of male and
female Sprague-Dawley rats; breeders and offspring were included in
the experiment.
Treatment started at 39 weeks of age (breeders), 7 days before mating,
or from embryo life (offspring)
and lasted until their spontaneous death.
Under tested experimental conditions, methyl alcohol and ethyl alcohol
were demonstrated to be carcinogenic for various organs and tissues.
They must also be considered multipotential carcinogenic agents.
In addition to causing other tumors, ethyl alcohol induced malignant
tumors of the oral cavity, tongue, and lips.
These sites have been shown to be target organs in man by
epidemiologic studies.
Publication Types: Review Review, Tutorial PMID: 12562628
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The Comet assay can quickly show whether aspartame or its body
products (methanol, formaldehyde, formic acid -- the same as in
hangovers from dark wines and liquors) are genotoxic:
Murray 2006.05.09

http://groups.yahoo.com/group/aspartameNM/message/1337
Comet assay finds DNA damage from sucralose, cyclamate, saccharin,
aspartame in mice: Sasaki YF & Tsuda S Aug 2002:
Murray 2006.05.08

[ Borderline evidence, in this pilot study of 39 food additives,
using test groups of 4 mice, for DNA damage from for stomach, colon,
liver, bladder, and lung 3 hr after oral dose of 2000 mg/kg
aspartame -- a very high dose.
Methanol is the only component of aspartame that
can lead to DNA damage. ]

http://groups.yahoo.com/group/aspartameNM/message/934
24 recent formaldehyde toxicity [Comet assay] reports:
Murray 2002.12.31

http://groups.yahoo.com/group/aspartameNM/message/961
genotoxins, Comet assay in mice: Ace-K, stevia fine; aspartame poor;
sucralose, cyclamate, saccharin bad: Y.F. Sasaki Aug 2002:
Murray 2003.01.27 [A detailed look at the data] ]
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http://groups.yahoo.com/group/aspartameNM/message/1345
EFSA, European Food Safety Authority says Ramazzini aspartame
cancer study is flawed, while Soffritti is half way through second huge
study, Felicity Lawrence, www.guardian.co.uk: Murray 2006.05.15

http://groups.yahoo.com/group/aspartameNM/message/1339
Obfuscation of the iatrogenic autism epidemic re mercury in kid
vaccines, Kenneth P. Stoller, Pediatrics 2006.05.06;
aspartame toxicity 2005.11.10: Comet assay can test genotoxicity,
EFSA admits ignorance re methanol residues, Murray 2006.05.10


http://groups.yahoo.com/group/aspartameNM/message/1335
Morando Soffritti of Ramazzini Foundation rebuts EFSA AFC critique,
www.laleva.org: Murray 2006.05.05

http://groups.yahoo.com/group/aspartameNM/message/1334
European Food Safety Authority discounts Ramazzini study re many
cancers in 1800 rats fed lifetime doses of aspartame:
Calorie Control Council press release: Murray 2006.05.05

http://www.efsa.eu.int/press_room/press_release/1472_en.html

http://www.efsa.eu.int/science/afc/afc_opinions/1471_en.html

http://www.efsa.eu.int/press_room/media_events/catindex_en.html

http://www.flyonthewall.com/FlyBroadcast/efsa.eu.int/AspartamePressConference/

http://www.efsa.eu.int/science/afc/afc_opinions/1471/afc_op_ej356_aspartame_en1.\
pdf

http://groups.yahoo.com/group/aspartameNM/message/1338
Aspartame: The healthy option? Richard A. Lovett, The New Scientist
2006.05.04: Murray 2006.05.08
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