arsenic carcinogenicity in rats, Ramazzini Foundation, M Soffritti, F
Belpoggi, Annals NY Academy Sciences 2006 Sept, parts of 14 pages:
Murray 2006.12.01
http://groups.yahoo.com/group/aspartameNM/message/1384

[ For related information and links:

Fiorella Belpoggi & Morando Soffritti of Ramazzini Foundation prove
lifetime carcinogenicity of Coca-Cola, aspartame, and arsenic, Annals
of the NY Academy of Sciences: Murray 2006.11.28
http://groups.yahoo.com/group/aspartameNM/message/1382

http://groups.yahoo.com/group/aspartameNM/message/1383 aspartame

http://groups.yahoo.com/group/aspartameNM/message/1385 Coca-Cola

http://www.ramazzini.it/fondazione/eng/eventidettagli.asp?id=33

NEWS AND EVENTS 01 November 2006
Results of 3 long term ERF carcinogenesis bioassays published in the
Annals of the New York Academy of Sciences

Aspartame, Sodium Arsenite, Coca-Cola

The proceedings of the Collegium Ramazzini's 2005 conference "Framing
the Future in Light of the Past: Living in a Chemical World" have been
published in the Annals of the New York Academy of Sciences. The volume
includes the results of three long term carcinogenesis bioassays
conducted by the European Ramazzini Foundation:

http://www.ramazzini.it/fondazione/docs/NYAS_Aspartame_Ramazzini.pdf
Ann. N.Y. Acad. Sci. 1076: 559-577 (2006)
Results of Long-Term Carcinogenicity Bioassay on Sprague-Dawley Rats
Exposed to Aspartame Administered in Feed
FIORELLA BELPOGGI, MORANDO SOFFRITTI, MICHELA PADOVANI, DAVIDE DEGLI
ESPOSTI, MICHELINA LAURIOLA, AND FRANCO MINARDI.

http://www.ramazzini.it/fondazione/docs/NYAS_Sodium_Arsenite_Ramazzini.pdf
Ann. N.Y. Acad. Sci. 1076: 578-591 (2006)
Results of a Long-Term Carcinogenicity Bioassay on Sprague-Dawley Rats
Exposed to Sodium Arsenite Administered in Drinking Water
MORANDO SOFFRITTI, FIORELLA BELPOGGI, DAVIDE DEGLI ESPOSTI, AND LUCA
LAMBERTINI.

http://www.ramazzini.it/fondazione/docs/NYAS_Coca-Cola_Ramazzini.pdf
Ann. N.Y. Acad. Sci. 1076: 736-752 (2006)
Results of Long-Term Carcinogenicity Bioassays on Coca-Cola
Administered to Sprague-Dawley Rats
FIORELLA BELPOGGI, MORANDO SOFFRITTI, EVA TIBALDI, LAURA FALCIONI,
LUCIANO BUA, AND FRANCESCA TRABUCCO.


http://www.ramazzini.it/fondazione/docs/NYAS_Sodium_Arsenite_Ramazzini.pdf
Ann. N.Y. Acad. Sci. 1076: 578-591 (2006)

Results of a Long-Term Carcinogenicity Bioassay on Sprague-Dawley Rats
Exposed to Sodium Arsenite Administered in Drinking Water
MORANDO SOFFRITTI,
FIORELLA BELPOGGI,
DAVIDE DEGLI ESPOSTI, AND
LUCA LAMBERTINI
Cesare Maltoni Cancer Research Center, European Foundation of Oncology
and Environmental Sciences 'B. Ramazzini', Bologna, Italy

ABSTRACT:

Arsenic (As) is a metal found in nature whose acute and
chronic toxic effects have been known for decades.

Hundreds of millions of people are at risk of exposure to As and its
various chemical forms which can occur in the occupational and general
environment in air, water, soil, food, and medicines.

Several epidemiological studies have shown that prolonged exposure to
As can induce various types of malignant tumors in humans,
namely, skin, lung, liver, kidney, and bladder cancers.

These effects have been observed particularly in geographic areas where
people are exposed to well water with high concentrations of As.

While the risks of As at high concentrations are well documented,
there is still a great deal of uncertainty regarding the risk of
exposure to As at very low levels.

This uncertainty is due to the absence of adequate epidemiological
data and the insufficiency of experimental data currently available.

Given the limited evidence demonstrating the carcinogenic potential of
As in animals, a long-term carcinogenicity bioassay on sodium arsenite
(NaAsO2)was performed at the Cesare Maltoni Cancer Research Center
(CMCRC) of the European Ramazzini Foundation (ERF).

NaAsO2 was administrated with drinking water at concentrations of 200,
100, 50, or 0 mg/L, for 104 weeks to Sprague-Dawley rats
(50/sex/group), 8 weeks old at the start of the study.

The animals were monitored until spontaneous death
at which time each animal underwent complete necropsy.

Histopathological evaluation of all pathological lesions and of all
organs and tissues collected was routinely performed on each animal.

The results demonstrate that in our experimental conditions NaAsO2
induces sparse benign and malignant tumors among treated rats.

The types of tumors observed are infrequent in the strain of
Sprague-Dawley rats of the colony used in our laboratory, namely,
lung adenomas and carcinomas, kidney adenomas/papillomas and
carcinomas, and bladder carcinomas.

Notably, an elevated incidence of these types of oncological lesions is
also observed among people living in geographical areas where As is
present at higher concentrations in drinking water.

KEYWORDS: sodium arsenite; carcinogenicity; long-term bioassays; rat

Address for correspondence: Morando Soffritti, M.D., Cesare Maltoni
Cancer Research Center, European Ramazzini Foundation, Castello di
Bentivoglio, Via Saliceto, 3, 40010 Bentivoglio, Bologna,Italy.
Voice: +39-051-6640460; fax: +39-051-6640223.
e-mail: crcfr@... www.ramazzini.it

Ann. N.Y. Acad. Sci. 1076: 578-591 (2006).
c 2006 New York Academy of Sciences.
doi: 10.1196/annals.1371.075


INTRODUCTION

Arsenic (As) is a metalloid widely distributed in the earth's crust,
found particularly in igneous and sedimentary rocks.

It can exist in four valency states: - 3, 0, +3, and +5.

Under reducing conditions, the +3 valency state as arsenite may be
the dominant form;
the +5 valency state as arsenate is generally the more stable formin
oxygenized environments.1

Arsenic compounds usually occur in trace quantities in rock, soil,
water, and air.

However, concentrations may be higher in certain areas as a result of
weathering and anthropogenic activities including metal mining and
smelting, fossil fuel combustion, and pesticide use.2

In soils, a global average concentration level of 5 mg/kg was estimated
by Koljonen,3 but concentrations may vary considerably among geographic
regions.

In some areas of South-West England, near old smelters or mining
areas, concentrations of As range from 24 to 161,000 mg/kg. 4

In natural waters, As is mostly found in inorganic forms as oxyanions
of trivalent arsenite or pentavalent arsenate.

Background concentrations of As in groundwater range from less than 0.5
to 5000 microg/L. 5

Most high levels of As occur naturally,
but cases of As pollution by mining are numerous, albeit localized.

In surface waters, levels of dissolved As range from 0.1 to 1.7
microg/L in uncontaminated stream waters,6
however, in some areas characterized by volcanic activity,
As levels may reach 3000 microg/L. 7

Concentrations in air in remote locations range
from less than 1 to 4 ng/m3;
however, in cities, concentrations may reach up to 200 ng/m3
and may be greater than 1000 ng/m3 in the vicinity of industrial
sources, particularly near nonferrous smelters.2

It has been estimated that the atmospheric flux of As is
about 75,540 tons/year of which 60% is of natural origin and the
remaining 40% is derived from anthropogenic sources.8

The estimated world production of As (expressed as As trioxide
equivalent) was 35,000 tons in 2002, representing a slight decrease
compared to the world production at the end of 1990s (about 40,000 tons
in 1998 and 1999).9

As is mostly used for the production of wood preservatives,
but also for the production of some agricultural chemicals, pesticides
(mainly herbicides), glass, nonferrous alloys, and semiconductors.9

In the United States, As consumption is predicted to decline
drastically because of regulations aimed toward ceasing use of
chromated copper arsenate as a wood preservative.9

In both humans and rodents, ingested As compounds are quickly absorbed
and enter the bloodstream.

Inhaled As is not absorbed as readily as ingested As,
even though a study on smelter workers showed an 80% absorption rate
of inhaled As.10

Once absorbed, arsenate is reduced to arsenite in the blood
through reactions with glutathione and then transported to the liver.

Arsenite is detoxified by methylation in the liver both enzymatically
by methyltransferases
[to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)]
and nonenzymatically (to methanearsonic acid).11

An unusual feature of the metabolism of As is that there are deep
interspecies differences in methylation:
humans are more sensitive to As toxicity than are several other species
because As methylation in humans is believed to be less efficient.11,12

In humans, ingestion of high levels of As (>1 g) induces acute effects
characterized by severe gastrointestinal damage which may result in
shock, multi-organ failure, and death.2

Subacute exposure affects primarily the respiratory,
gastrointestinal, cardiovascular, nervous, and hematopoietic systems.1

Chronic As toxicity is mainly manifested in the skin in forms, such as
hyperpigmentation and hyperkeratosis, with pigmentation affecting
trunks and limbs and keratosis affecting hands and feet.

Chronic lung disease, peripheral neuropathy, and peripheral vascular
disease have been frequently associated with chronic exposure to As.1

Few studies have been conducted to evaluate the immunotoxicity of As.

>From studies on humans, it appears that inorganic As is immunotoxic
13,14
and As-induced apoptosis could be a major mechanism of
immunosuppression.15

Reproductive and developmental effects have been studied in humans and
in experimental animals.

Human data, albeit limited, suggest that exposure to
high concentrations of As in drinking water during pregnancy may
increase the risk of fetal and neonatal mortality.16,17

The results in rodents show that MMA and DMA have developmental
toxicity effects.1

In humans, As is a chromosomal mutagen (an agent that induces mutations
involving more than one gene).

Micronuclei, chromosomal aberration, and aneuploidy have been detected
in both peripheral lymphocytes, and urothelial cells of people exposed
to elevated levels of As.1

In prokaryotic in vitro systems, As has been reported to be
nonmutagenic.18-20

In mammalian and human cell in vitro systems, As has been shown
to be genotoxic.

Moore et al. 21 reported sodium arsenite and, to a lesser extent
sodium arsenate, to induce chromosomal aberrations, micronuclei
polyploidy, and endoreduplication in the L5178Y/TK±mouse lymphoma
assay.

Chromosome alteration in Chinese hamster ovary cells are also reported
to be induced by arsenite.22

In human lymphocytes and fibroblasts, inorganic As was reported
to induce dose-dependent chromosomal aberrations and DNA-protein
cross-links; the effects were observed to be more potent with sodium
arsenite than with sodium arsenate.23,24

Epidemiological studies on cancer risks in relation to As exposure in
drinking water include mostly ecological studies that can provide
important information on causal inference due to large exposure
contrasts and limited population migration.

Several epidemiological studies have shown that prolonged exposure
to As in drinking water can induce various types of malignant tumors in
humans, namely, tumors of the skin, lung, liver, kidney, and urinary
bladder.

Many reports several decades ago described skin cancers following
ingestion of arsenical medicine, exposure to arsenical pesticides, and
As-contaminated water.25-27

Typical As-associated skin tumors include squamous-cell carcinoma
and multiple basal-cell carcinoma.27-29

Arsenic in drinking water was reported to increase the risk for lung
cancer in epidemiological studies which included large population
groups and different levels of exposure.30-32

Exposure to As was also reported to induce liver angiosarcoma and to
increase the risk for liver cancer, mainly hepatocarcinoma.30,31,33

Moreover, a positive correlation between exposure to As in drinking
water and cancers of the kidney and urinary bladder was found in many
epidemiological studies.30-32,34

Various As compounds have been tested for carcinogenicity by oral
administration in rats and mice,
by intratracheal administration in hamsters, and by
transplacental exposure in mice.1

In a Fischer rat study, groups of 36 males, 10 weeks of age at the
start of the experiment, were administered DMA at concentrations
of 0, 12.5, 50, and 200 ppm in drinking water for 104 weeks.

A statistically significant increase of the incidence of transitional
cell carcinomas of the urinary bladder was observed in the two highest
dose groups.35

Studies were also conducted on mice to evaluate the potential
carcinogenicity of different As compounds. DMA was administered in
drinking water at various concentrations to different mice strains,
namely: (a) groups of 10-14 male A/J mice were given 0, 50, 200, or 400
ppm beginning at 6 weeks of age and lasting for 25 or 50 weeks,
respectively.

After 50 weeks, an increase (although nonsignificant) in the incidence
of lung tumors was observed in treated mice 36;

(b) groups of 20-30 K6/ODC transgenic mice were administered 0, 10, or
100 ppm of DMA beginning at 7 weeks of age and lasting for 5 months.
One additional group was administered sodium arsenite at 10 ppm.

The incidence of squamous skin tumors increased in all treated groups
compared to the control 37;

(c) groups of 29-30 male p53+/- heterozygous or p53+/+ mice were
exposed to 0, 50, 200 ppm DMA in drinking water for 80 weeks.
In the p53+/- mice, a nonsignificant increase in the incidence of total
tumors was observed, while in p53+/+ mice a significant increase in the
incidence of total tumors was observed, but with no dose-dependence.38

In an other study, groups of 25 male and female C3H mice were exposed
exclusively during fetal life to 0, 42.5, and 85 ppm of inorganic As.
Males and females were then observed for 72 and for 90 weeks,
respectively.

A dose related increase in the incidence of hepatocarcinomas and
adrenal cortical adenomas was observed in males;
in females, a dose-related increase in the incidence of total ovarian
tumors (benign and malignant) and lung carcinomas was observed.39

The carcinogenicity of As trioxide, calcium arsenate, and As
trisulphide was evaluated in groups of 30 male Syrian golden hamsters,
treated by intratracheal instillation beginning at 8 weeks of age, once
a week for 15 weeks and followed until death (113-121 weeks after the
initial instillation). A group of 20 males served as a control.
Each compound, containing 0.25 mg As, was suspended in 0.1 mL of saline
buffer; the controls received buffer solution alone.

A statistically significant increase of the incidence of lung tumors
(benign and malignant combined)was observed in animals treated with
calcium arsenate.40

IARC reviewed the aforementioned studies and concluded that there is
sufficient evidence in experimental animals to determine the
carcinogenicity of DMA, but there is limited evidence to confirm the
carcinogenicity of sodium arsenite, calcium arsenate, and As trioxide.1

Given the limited evidence demonstrating the carcinogenic potential of
As and the importance of obtaining additional experimental data to
better assess the carcinogenic risks among people exposed to As in
drinking water, a longterm carcinogenicity bioassay on sodium arsenite
(NaAsO2) was performed at the Cesare Maltoni Cancer Research Center
(CMCRC) of the European Ramazzini Foundation (ERF).

The results of the study are presented in this article.

MATERIALS AND METHODS

The sodium arsenite (NaAsO2) used was produced by Sigma of St. Louis,
MO and supplied by Prodotti Gianni of Milan, Italy.

Its purity was 98% by titration.

NaAsO2 was administered in drinking water at concentrations of
200, 100, 50, or 0 mg/L ad libitum for 104 weeks to male (M) and female
(F) Sprague-Dawley rats (50/sex/group),
8 weeks old at the start of the experiment.

Rats were bred from the colony used at the CMCRC/ERF laboratories for
nearly 30 years.
Extensive historical data are available on the tumor incidence among
untreated rats.
Each morning, leftover solution from the previous day was removed and
glass drinking bottles were washed and refilled with fresh solution.
Control animals received tap water.
Animals were fed with the standard Corticella diet (Corticella S.p.A,
Bologna, Italy), used for more than 30 years in our laboratories.
The experiment was performed according to Good Laboratory Practices
using the Standard Operating Procedure (SOP) of the CMCRC/ERF.
After weaning at 4-5 weeks of age, the experimental animals were
randomized in order to have no more than one male and one female from
each litter in the same group.
Animals were then housed in groups of five in makrolon cages
(41 cm X 25 cm X 15 cm) with stainless-steel wire tops and a shallow
layer of white wood-shavings as bedding.
Cages were kept in rooms used exclusively for this experiment at a
temperature of 21 +- 2 deg C and relative humidity of 50-60%.
A light/dark cycle of 12 hours was maintained using both natural and
artificial light sources.
Mean daily drinking water and feed consumption were measured once
weekly per cage for the first 13 weeks,
and then every 2 weeks until 111 weeks of age.
Body weight was measured individually once weekly for the
first 13 weeks and then every 2 weeks until 111 weeks of age.
Measurement of body weight continued every 8 weeks until the end of the
experiment.
The animals were clinically examined for gross changes every 2 weeks
for the duration of the study.
The biophase ended at 159 weeks, with the death of the last animal at
167 weeks of age.
Upon death, all animals underwent complete necropsy.
Histopathology was routinely performed on the following organs and
tissues of each animal from each group:
skin and subcutaneous tissue, the brain (three sagittal sections),
pituitary gland, Zymbal glands, salivary glands, Harderian glands,
cranium (five sections, with oral and nasal cavities and external and
internal ear ducts), tongue, thyroid, parathyroid, pharynx, larynx,
thymus and mediastinal lymph nodes, trachea, lung and mainstem bronchi,
heart, diaphragm, liver, spleen, pancreas, kidneys, adrenal glands,
esophagus, stomach (fore and glandular), intestine (four levels),
urinary bladder, prostate, gonads, interscapular brown fat pad,
subcutaneous and mesenteric lymph nodes, and other organs or tissues
with pathological lesions.
All organs and tissues were preserved in 70% ethyl alcohol,
except for bones, which were fixed in 10% formalin and then decalcified
with 10% formaldehyde and 20% formic acid in water solution.
The normal specimens were trimmed, following SOP.
Trimmed specimens were processed as paraffin blocks and 3-5 micrometer
sections of every specimen were obtained.
Sections were routinely stained with Hematoxylin-Eosin.
All slide swere examined microscopically by the same group of
pathologists, following the same criteria of histopathologic evaluation
and classification.
A senior pathologist reviewed all tumors and all other lesions of
oncologic interest.
Multiple tumors of different types and sites, of different types in the
same site, of the same types in bilateral organs, of the same types in
the skin, subcutaneous tissue or mammary glands, or at distant sites of
diffuse tissue (i.e., bones and skeletal muscle) were plotted as
single/independent tumors.
Multiple tumors of the same type in the same tissue and organ, apart
from those mentioned above, were plotted only once.
Three statistical tests were used to analyze neoplastic and
non-neoplastic lesion incidence data.
The X2 test and the Fisher's exact test 41 were used to evaluate
differences in tumor incidence between treated and control groups.
The Cochran-Armitage trend test 42,43 was used to test for linear
trends in tumor incidence.

RESULTS

A dose-related lower intake of water containing various levels of
NaAsO2 was observed in both male and female rats (FIG. 1).

In females, water consumption became similar between the group treated
at 50 mg/L and the control after 88 weeks of age.

A dose-related lower intake of feed was also observed in both
male and female rats (FIG. 2).

This difference was less marked between the group treated at 50 mg/L
and the control in both males and females.

A dose related difference in mean body weight was observed in males.

The difference was more evident in the males treated at 200 mg/L (circa
15% when compared with controls).

Differences in mean body weight were also observed in females
of the groups treated at 200 and 100 mg/L.

Mean body weight was about 20% less in females treated at 200 mg/L
compared with control and about 10% less in females treated at 100
mg/L.

No treatment-related differences in body weight were observed in
females treated at 50 mg/L.

Differences in survival rates were observed in both males and females;
a slight decrease in the survival rate was observed in males treated at
200 and 100 mg/L,
particularly from 40 weeks of age until 88 weeks of age,
whereas in females, a decrease in survival rate was observed
from 104 weeks of age until the end of the experiment.

Long-term exposure of sodium arsenite administered in drinking water to
Sprague-Dawley rats has been shown to induce toxic effects on the
kidneys at concentrations as high as 200 mg/L and, to a lesser extent
100 mg/L and 50 mg/L.

Nephropathies were characterized by diffuse acute/chronic inflammation,
tubular enlargement with deposits of ialin casts and marked fibrosis
around glomeruli with distension of Bowman's space.

The main oncologic results of the experiment are reported in TABLE 1
for males and TABLE 2 for females.

Among males treated at 100 mg/L, a slightly increased incidence of
animals bearing malignant tumors and a statistically significant
increased number of total malignant tumors (P < 0.05) were observed
when compared to controls.

Sparse very infrequent benign and malignant tumors were observed in the
treated groups, namely,
one adenocarcinoma of the lung in a male treated at 200 mg/L;
one carcinoma of the kidney and one papilloma
of the pelvis in a male treated at 100 mg/L
and two papillomas of the renal pelvis in another rat treated at the
same dose.

Renal pelvis papillomas were also observed
in two males treated at 50 mg/L.

Among females treated at 100 mg/L, a slightly increased incidence of
animals bearing malignant tumors and an increased number of total
malignant tumors were observed when compare to controls.

Among the females treated at 200 mg/L, one adenocarcinoma of the lung
was observed.

The same group also included two animals bearing kidney adenomas,
two bearing kidney carcinomas,
and one bearing a renal pelvis carcinoma.

In the group treated at 100 mg/L, three animals were observed bearing
kidney adenomas,
one bearing a kidney carcinoma
and one bearing a renal pelvis papilloma.

One animal bearing a bladder carcinoma was also observed among the
females treated at 100 mg/L.

It must be noted that among the untreated Sprague-Dawley rats used in
our laboratories over the last 20 years (2265 males and 2274 females),
the overall incidence of lung adenomas was 0.2% in males (range:
0-2.0%) and 0.1% in females (range: 0-1.0%),
while the overall incidence of lung carcinomas
was 0.1% in both males (range: 0-1.0%) and females (range: 0-1.3%).

The overall incidence of the kidney adenomas was 0.1% in males (range:
0-1.3%)
and 0.2% in females (range: 0-2.0%),
while the overall incidence of kidney carcinomas was 0.2% in males
(range: 0-0.3%) and 0.3% in females (range: 0-1.8%).

With regard to historical data on the transitional cell epithelium of
the renal pelvis and ureter, no papillomas were observed in either
males or females,
while only one carcinoma was observed in a female (overall incidence:
0.04% and range: 0-1.0%).

No carcinomas in the transitional cell epithelium of the bladder were
observed in either males or females.

CONCLUSIONS

In our experimental conditions, it has been shown that sodium arsenite
administered for 104 weeks in drinking water to male and female
Sprague-Dawley rats, 8 weeks old at the start of the experiment and
kept under observation until spontaneous death, induces an increased
incidence (albeit not statistically significant) of benign and
malignant tumors of the lung, kidney, and bladder.

Because these benign and malignant tumors are extremely rare in our
extensive historical controls, the observation of adenomas and
carcinomas of the lung, of adenomas and carcinomas of the kidney, of
papillomas and one carcinoma of the renal pelvis transitional cell
epithelium, and of one carcinoma of the bladder transitional cell
epithelium among treated rats should not be considered casual.

The biological significance of these results are reinforced if we
consider that these tumors are among the same types observed in humans
living in geographical areas with an elevated concentration of As in
drinking water.

The aforementioned results have shown that Sprague-Dawley rats
represent a good animal model to express the carcinogenic potential of
As in drinking water.

In light of the utility of this model and the results observed, in our
opinion, a life-span mega-experiment exposing large groups of male and
female Sprague-Dawley rats to As in drinking water at doses much lower
than 50 mg/L, starting from embryonic life and lasting until
spontaneous death, is urgently required to provide a more adequate
scientific basis to the current exposure standards:

50 microg/L in developing countries and 10 microg/L in industrialized
countries.44,45

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dermal tumours following arsenic.
Acta Derm. Venereol. 40: 400-409.

29. YEH, S., S.W. HOW & C.S. LIN. 1968.
Arsenical cancer of skin. Histologic study
with special reference to Bowen's disease.
Cancer 21: 312-339.

30. CHEN, C.J. & C.J. WANG. 1990.
Ecological correlation between arsenic level in
well water and age-adjusted mortality from malignant neoplasms.
Cancer Res. 50: 5470-5474.

31. TSAI, S.M., T.N. WANG & Y.C. KO. 1999.
Mortality for certain diseases in areas
with high levels of arsenic in drinking water.
Arch. Environ. Health 54: 186-193.

32. HOPENHAYN-RICH, C., M.L. BIGGS & A.H. SMITH. 1998.
Lung and kidney cancer mortality associated with arsenic in drinking
water in Cordoba, Argentina.
Int. J. Epidemiol. 27: 561-569.

33. International Agency for Research on Cancer. 1980.
Monographs on the evaluation of carcinogenic risks to humans.
Vol. 23. IARC. Lyon, France.

34. SMITH, A.H. et al. 1998.
Marked increase in bladder and lung cancer mortality in
a region of northern Chile due to arsenic in drinking water.
Am. J. Epidemiol. 147: 660-669.

35. WEI, M. et al. 2002.
Carcinogenicity of dimethylarsinic acid in male F344 rats
and genetic alterations in induced urinary bladder tumors.
Carcinogenesis. 23: 1387-1397.

36. HAYASHI, H. et al. 1998.
Dimethylarsinic acid, a main metabolite of inorganic arsenics, has
tumorigenicity and progression effects in the pulmonary tumors of A/J
mice.
Cancer Lett. 125: 83-88.

37. CHEN, Y. et al. 2000.
K6/ODC transgenic mice as a sensitive model for carcinogen
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Toxicol. Lett. 116: 27-35.

38. SALIM, E.I. et al. 2003.
Carcinogenicity of dimethylarsinic acid in p53±heterozygous
knockout and wild type C57BL/6J mice.
Carcinogenesis 24: 335-342.

39. WALKEES, M.P. 2003.
Transplacental carcinogenicity of inorganic arsenic in the
drinking water: Induction of hepatic, ovarian, pulmonary and adrenal
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Toxicol. Appl. Pharmacol. 186: 7-17.

40. YAMAMOTO, A., A. HISANAGA & L.N. ISHINISHI 1987.
Tumorigenicity of inorganic arsenic compounds following intratracheal
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Int. J. Cancer 40: 220-223.

41. HASEMAN, J.K. 1978.
Exact sample sizes with the Fisher-Irwin test for 2X2 tables.
Biometrics 34: 106-109.

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Statistical issues in interpretation of
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J. Natl. Cancer Inst. 62: 957-974.

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short aspartame (methanol, formaldehyde) toxicity research summary:
Murray 2006.12.01
http://groups.yahoo.com/group/aspartameNM/message/1379

"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 79 members, 1,385 posts in a public, searchable archive
http://RMForAll.blogspot.com

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/1378
11 members of New Mexico legislature sign letter to ban aspartame as a
source of toxic methanol and formaldehyde, Stephen Fox, NM Senator
Gerald Ortiz y Pino: Murray 2006.10.22

http://groups.yahoo.com/group/aspartameNM/message/1374
47 UK Members of Parliament now support aspartame ban initiative of
Roger Williams, MP: Murray 2006.10.16

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/1277
50% UK baby food is now organic -- aspartame or MSG
with food dyes harm nerve cells, CV Howard 3 year study
funded by Lizzy Vann, CEO, Organix Brands,
Children's Food Advisory Service: Murray 2006.01.13

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/1366
toxicity in rat brains from aspartame, Vences-Mejia A, Espinosa-Aguirre
JJ et al 2006 Aug: Murray 2006.09.06

http://groups.yahoo.com/group/aspartameNM/message/1373
aspartame rat brain toxicity re cytochrome P450 enzymes, expecially
CYP2E1, Vences-Mejia A, Espinosa-Aguirre JJ et al, 2006 Aug,
Hum Exp Toxicol: relevant abstracts re formaldehyde from methanol
in alcohol drinks: Murray 2006.09.29

http://groups.yahoo.com/group/aspartameNM/message/1369
Bristol, Connecticut, schools join state program to limit artificial
sweeteners, sugar, fats for 8800 students, Johnny J Burnham, The
Bristol Press: Murray 2006.09.22

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


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 2006.08.19

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://groups.yahoo.com/group/aspartameNM/message/1052
DMDC: Dimethyl dicarbonate 200mg/L in drinks adds methanol 98 mg/L
( becomes formaldehyde in body ): EU Scientific Committee on Foods
2001.07.12: Murray 2004.01.22

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/1371
Russell L. Blaylock, MD discusses MSG, aspartame, excitotoxins
with Mike Adams: Murray 2006.09.27

http://groups.yahoo.com/group/aspartameNM/message/1372
Mike Adams interviews Randall Fitzgerald on "The Hundred Year Lie:
How Food and Medicine are Destroying Your Health" 2006.06.21:
Murray 2006.09.28
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