abstracts re toxicity of polycyclic aromatic carbohydrates: Hubner: Murray 2004.05.15

Rich Murray rmforall at att.net
Sat May 15 21:58:03 EST 2004


abstracts re toxicity of polycyclic aromatic carbohydrates: Hubner: Murray
2004.05.15

From: "R. Hubner" <roland.hubner at health.fgov.be>
Subject: degradation of polycyclic aromatic carbohydrates...
Date: Friday, May 14, 2004 7:22 PM

Dear bionetters,

I would be very grateful if a kind soul could point out to me any
comprehensive review paper, book chap, web publication or report that
has detailed information about how inhaled PACs are metabolized by a
human body and how many different (good?) methods are available to
monitor such products...

Presumably, such information might have been compiled to evaluate the
impact on public health of, e.g., NY's burning Twin Towers and similar
exposures to smoke...

Thank you so much for your goodwill.

With kindest regards,    R. Hübner
**************************************************************

Cancer Res. 2000 Jul 15; 60(14): 3749-52.
Cigarette smoking, CYP1A1 MspI and GSTM1 genotypes, and colorectal adenomas.
[  21 references ]
Inoue H, Kiyohara C, Marugame T, Shinomiya S, Tsuji E, Handa K, Hayabuchi H,
Onuma K, Hamada H, Koga H, Kono S.
Department of Preventive Medicine, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan.

http://cancerres.aacrjournals.org/cgi/content/full/60/14/3749  free, full
text

Cigarette smoking has been related to increased risk of colorectal adenomas,
but the underlying mechanisms are unknown.
Genetic polymorphisms are known for enzymes involved in the activation of
polycyclic aromatic hydrocarbons and other tobacco-related carcinogens.
Polycyclic aromatic hydrocarbons are activated by cytochrome P4501A1
(CYP1A1) and detoxified by glutathione S-transferases.
We investigated the relation of CYP1A1 MspI and GSTM1 genotypes to the risk
of colorectal adenomas with special reference to interaction with cigarette
smoking among 205 cases of colorectal adenomas and 220 controls with normal
total colonoscopy in a male Japanese population.
Cigarette smoking was strongly associated with increased risk of colorectal
adenomas.
Overall, neither the CYP1A1 MspI genotype nor the GSTM1 genotype was related
to colorectal adenomas.
A significant trend for increased risk of colorectal adenomas associated
with smoking was observed for each of the CYP1A1 MspI genotypes, and the
increasing trends did not differ by MspI genotype.
The positive association between smoking and colorectal adenomas did not
vary much with GSTM1 genotypes.
mong former and current smokers, adenoma risk did not differ according to
the combination of CYP1A1 MspI and GSTM1 genotypes.
CYP1A1 MspI and GSTM1 genotypes do not seem to modify the risk of colorectal
adenomas associated with cigarette smoking.  PMID: 10919645
**************************************************************

Acta Medica (Hradec Kralove) Suppl. 1999; 42(2): 65-9.
[Health status of persons occupationally exposed to chromium, nickel,
manganese and polycyclic aromatic hydrocarbons]
[Article in Czech]
Tejral J, Fiala Z, Bencko V, Smejkalova J, Srb V, Tmejova M, Borska L,
Andrys C, Kucera J.
Ustav hygieny a preventivniho lekarstvi, Univerzita Karlova v Praze,
Lekarska fakulta v Hradci Kralove. tejral at lfhk.cuni.cz

Occupational environment monitoring and biological-medical monitoring of
persons professionally exposed to welding fumes have been performed.
Chromium, manganese and polycyclic aromatic hydrocarbons in welding fumes
represents an important health risk.
Pollutant concentrations found in metal welding fumes represented only
fractions of those acceptable ones.
Polycyclic aromatic hydrocarbons have been reached the concentration found
in a busy road crossing in Hradec Kralove (compared with these as in Czech
Republic no maximum acceptable levels for PAHs having been declared).
Family, personal and occupational history have been taken.
Health state including total haematological count, biochemical and
cytogenetical changes of 19 stainless steel welders were checked-up.
The level of mercapturates in urine were examined as well.
The data were statistically compared with those of non exposed (control
group). No changes witnessing the above mentioned risk factors influence on
the haematological, biochemical and cytogenetical findings were ever proved.
In conclusion, our results did not confirm an increased professional risk in
this group of welders.   PMID: 10836077
**************************************************************

Mutat Res. 1997 Apr 24; 390(1-2): 59-68.
DNA adducts in human placenta as related to air pollution and to GSTM1
genotype.
Topinka J, Binkova B, Mrackova G, Stavkova Z, Benes I, Dejmek J, Lenicek J,
Sram RJ.
Laboratory of Genetic Ecotoxicology, Regional Institute of Hygiene of
Central Bohemia, Czech Academy of Sciences, Prague, Czech Republic.
jtopinka at biomed.cas.cz

DNA adducts in human placenta have been studied in relation to metabolic
genotype for glutathione S-transferase M1 (GSTM1) in 98 mothers living in
two regions with a different annual average air pollution levels:
Northern Bohemia-the district of Teplice as polluted industrial area (mines,
brown coal power plants) and
Southern Bohemia-the district of Prachatice as agricultural area without
heavy industry.
Forty-nine placenta samples (25 from the Teplice district and 24 from the
Prachatice district) from non-smoking mothers with the date of delivery in
the summer period and 49 placenta samples (25 from the Teplice district and
24 from Prachatice district) from mothers with the date of delivery in the
winter period were analysed.
The total DNA adduct levels were calculated as the sum of adducts in the
diagnoal radioactive zone (DRZ) and one distinct spot outside of the DRZ
(termed X), which was detected in almost all placenta samples.
We found total DNA adduct levels of 1.40 +/- 0.87 (0.04-3.65) and 1.04 +/-
0.63 (0.11-3.08) adducts per 10(8) nucleotides for the Teplice and
Prachatice districts, respectively.
The significant difference between both districts in placental DNA adduct
levels was found for the winter sampling period only (1.49 vs. 0.96 adducts
per 10(8) nucleotides; p = 0.023).
No seasonal variation was observed for DNA adduct levels in the overall
population studied.
A positive GSTM1 genotype was detected in 51 subjects, while GSTM1-null
genotype was found in 47 subjects.
Higher DNA adduct levels were detected in a group with GSTM1-null genotype
(p = 0.009).
This finding seems more significant for subjects in the Teplice district (p
= 0.047) than for those in the Prachatice district (p = 0.092).
Significant district and seasonal differences were found in subgroups
carrying the GSTM1-null genotype.
DNA adduct levels in placentas of mothers with GSTM1-null genotype living in
the polluted district of Teplice were higher than those in Prachatice (p =
0.050); also the adduct levels in placentas sampled in the summer period
were higher than those sampled in the winter period (p = 0.011).
Our results indicate that simultaneous analysis of DNA adducts and metabolic
genotypes could emphasize the use of DNA adduct measurements, particularly
in the case of the environmental exposure when the total doses of genotoxic
pollutants are very low.  PMID: 9150753
**************************************************************

Toxicology. 1996 May 3; 109(1): 31-8.
Immunotoxicity of a reconstituted polynuclear aromatic hydrocarbon mixture
in B6C3F1 mice.
Harper N, Steinberg M, Safe S.
Veterinary Physiology and Pharmacology, Texas A & M University, College
Station, 77843-4466, USA.

Previous studies on the immunotoxicity of a complex mixture of polynuclear
aromatic hydrocarbon (PAH) by-products from a manufactured gas plant
indicated possible synergistic interactions which were investigated by
determining the immunosuppressive effects of a reconstituted PAH mixture in
female B6C3F1 mice challenged with TNP-haptenated sheep red blood cells
(SRBCs) (T-cell-dependent) or trinitrophenyl-lipopolysaccharide (TNP-LPS)
(T-cell-independent) antigens.
The reconstituted PAH mixture contained the following 17 congeners: 2-rings
(indan, naphthalene, 1- and 2-methylnaphthalene), 3-rings (acenaphthylene,
acenaphthene, dibenzofuran, fluorene, phenanthrene and anthracene), and > or
= 4-rings (pyrene, fluoranthene, benz[a]anthracene, chrysene,
benzo[b]fluoranthene, benzo[k]fluoranthene and benzo[a]pyrene), and
resembled mixtures identified as by-products from manufactured gas plants.
The reconstituted mixture and the 2-, 3- and > or = 4-ring PAH fractions all
caused a dose-dependent decrease in the splenic plaque-forming cell (PFC)
response to SRBCs or TNP-LPS, and their ED50 values for the four treatment
groups were 86, 354, 145, and 23 or 163, 439, 637 and 31 mg/kg,
respectively.
The corresponding ED50 values for decreased serum anti-TNP IgM levels for
these same mixtures were (TNP-haptenated SRBCs, T-cell-dependent) 144, 231,
42 and 27 units, respectively, and (TNP-LPS, T-cell-independent) 161, 406,
312 and 69 units, respectively.
The suppression of anti-TNP IgM titers was similar to the suppression of the
PFC response and shows that antigen-specific immunoglobulin titer can be
used as a biomarker of PAH exposure.
A direct comparison of the immunotoxic responses of the reconstituted PAH
mixture and the corresponding dose of the > or = 4-ring PAHs indicated that
the latter fraction was primarily responsible for the activity of the
reconstituted mixture.   PMID: 8619250
**************************************************************

Carcinogenesis. 1995 Dec;16(12):2909-15.
A rapid and simple method for the analysis of 1-hydroxypyrene glucuronide: a
potential biomarker for polycyclic aromatic hydrocarbon exposure.
Singh R, Tucek M, Maxa K, Tenglerova J, Weyand EH.
Rutgers State University of New Jersey, College of Pharmacy, Department of
Pharmaceutical Chemistry, Piscataway 08855-0789, USA.

The present study describes a simple method of analyzing metabolites of
pyrene in urine.
This method is capable of detecting the glucuronic acid and sulfate
conjugates of pyrene as well as free 1-hydroxypyrene in a single analysis.
In comparison to other analytical methods for detecting pyrene metabolites,
this new method does not require an overnight enzymatic hydrolysis step and
is much more rapid method of analysis.
The newly developed procedure involves solid phase extraction of pyrene
metabolites followed by separation using HPLC with a phenyl modified reverse
phase column and an acidic buffer and acetonitrile gradient elution system.
Metabolites were detected using a fluorescence detector with wavelength
conditions optimized for each metabolite.
This method resulted in baseline separation of the glucuronic acid (1-OH
P-GlcUA) and sulfate conjugate (1-OH P-Sul) of 1-hydroxypyrene and free
1-hydroxypyrene (1-OH P).
The potential of this method for use in monitoring human exposure to
mixtures of PAHs was evaluated by analyzing urine obtained from five
individuals working in a coal gasification plant.
1-OH P-GlcUA was detected as the major metabolite in the urine of all the
five workers.
This metabolite accounted for 80-100% of the total pyrene metabolites
excreted in urine.
1-OH P-GlcUA levels ranged from 0.31-0.94 microgram/g creatinine.
Low levels of the sulfate conjugate (0.002-0.06 microgram/g creatinine) were
detected in four of the samples while free 1-hydroxypyrene (0.07-0.2
microgram/g creatinine) was detected in two of the five urine samples.
Urine from occupationally exposed workers was also analyzed for
1-hydroxypyrene following enzymatic hydrolysis using the standard approach.
Levels of 1-hydroxypyrene ranged from 0.51-1.17 micrograms/g creatinine.
Comparison of the fluorescence intensities of 1-OH P-GlcUA and 1-OH P-Sul to
1-hydroxypyrene demonstrated that the glucuronide conjugate is 3-fold more
fluorescent and the sulfate conjugate is 4-fold more fluorescent than
1-hydroxypyrene.
These results indicate that conjugates of pyrene, specifically, 1-OH P-GlcUA
can potentially be used as a more sensitive biomarker of exposure to PAHs.
PMID: 8603463
**************************************************************

Carcinogenesis. 1995 May;16(5):1079-85.
Interindividual differences in the concentration of
1-hydroxypyrene-glucuronide in urine and polycyclic aromatic hydrocarbon-DNA
adducts in peripheral white blood cells after charbroiled beef consumption.
Kang DH, Rothman N, Poirier MC, Greenberg A, Hsu CH, Schwartz BS, Baser ME,
Groopman JD, Weston A, Strickland PT.
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene
and Public Health, Baltimore, MD 21205, USA.

Biological markers of internal dose and macromolecular dose from PAHs
provide a potential means of assessing environmental exposure to PAHs
through inhalation, ingestion and percutaneous absorption.
In this study we examined the time course and interindividual variation of
1-hydroxypyrene-glucuronide (1-OHP-gluc) excretion in urine and PAH-DNA
adduct formation in peripheral white blood cells (WBCs) after charbroiled
(CB) beef consumption.
As a marker of internal dose, 1-OHP-gluc was measured in human urine using
immunoaffinity chromatography and synchronous fluorescence spectroscopy.
PAH-DNA adducts were measured in WBCs by enzyme-linked immunosorbent assay
(ELISA) in order to assess macromolecular dose.
Ten healthy non-smoking males consumed identical amounts of CB beef on five
consecutive days.
Multiple blood and urine samples were collected before, during, and after
the feeding period.
The morning after the first day of CB beef consumption, individual urinary
concentrations of 1-OHP-gluc increased 10- to 80-fold (range: 2.0-16.6
pmol/ml urine) above pre-feed baseline concentrations (0.23 +/- 0.11
pmol/ml) in the 10 subjects.
1-OHP-gluc concentration decreased to near baseline levels by 24-72 h after
CB beef consumption ended.
In contrast, PAH-DNA adducts in WBCs increased markedly in only four of 10
subjects during or after CB beef consumption.
Significant interindividual variation was observed for both urinary
1-OHP-gluc concentration (P < 0.001 by Kruskal-Wallis) and PAH-DNA adduct
levels (P < 0.005) during the feeding period.
The mean urinary 1-OHP-gluc concentration for each subject during and
immediately after (days 2-8) the feeding period was significantly correlated
with their mean PAH-DNA adduct level in WBCs during the same time period
(Spearman r = 0.79, P < 0.01).
Evidence of segregation of the subjects into separate response groups based
on level of urinary 1-OHP-gluc was observed, suggesting that discrete
determinants may regulate the absorption, metabolism and/or excretion of
ingested pyrene.
PMID: 7767968
**************************************************************

Immunobiology. 1994 Jun;190(4-5):333-45.
Characterization of a chemically induced tumor model and the effects of
natural killer cell depletion by antiasialo GM-1.
Mather GG, Talcott PA, Exon JH.
University of Idaho, Moscow.

A tumor model in the Sprague-Dawley rat has been developed and characterized
in our laboratory using the polycyclic aromatic hydrocarbon
3-methylcholanthrene (3MC).
Interactions between the tumorigenic process and the natural killer cell
(NK) response were investigated in this study.
Rats given a single injection of 1.5 mg 3MC had reduced NK activity the
first three weeks after injection when compared to vehicle treated controls.
Tumor incidence in this group reached 45% and 76% 12 and 20 weeks,
respectively, after the 3MC injection.
Cell lines were established from six of these tumors and were tested for in
vitro lysis by NK cells.
Sensitivity of these cells ranged from 2.9 to 12.2% compared to 32.3 to
37.5% for the NK sensitive YAC-1 target cells.
Rabbit antiasialo GM-1 antibody (ASGM-1) was used to effect in vivo
reductions of NK function at arbitrarily selected times after 3MC injection.
Tumor incidence in the group of rats treated to reduce NK activity at the
time of initiation (0-2 weeks) reached 100% in 20 weeks compared to 67% in
the companion 3MC treated controls.
The number of days to tumor was also decreased from 93 to 77 days in this
group.
Rats treated to reduce NK activity at other times (5-7 weeks or 10-12 weeks)
did not have alterations in tumor incidence or latency that were different
from controls.
The study supports a role for NK cells in the early detection and removal of
transformed cells and points out the dangers of transient immunosuppression.
PMID: 7982719
*************************************************************

Int Arch Occup Environ Health. 1994;65(5):329-38.
Determinants of urinary thioethers, D-glucaric acid and mutagenicity after
exposure to polycyclic aromatic hydrocarbons assessed by air monitoring and
measurement of 1-hydroxypyrene in urine: a cross-sectional study in workers
of coke and graphite-electrode-producing plants.
Ferreira M Jr, Buchet JP, Burrion JB, Moro J, Cupers L, Delavignette JP,
Jacques J, Lauwerys R.
Industrial Toxicology and Occupational Medicine Unit, Catholic University of
Louvain, Brussels, Belgium.

A cross-sectional epidemiological study was performed on 286 workers from
two coke oven and one graphite electrode plants.
The aim was to evaluate the usefulness of monitoring 1-hydroxypyrene (1-HOP)
in urine for assessing exposure to polycyclic aromatic hydrocarbons (PAHs),
and that of the urinary excretion of thioethers and D-glucaric acid, and the
mutagenic activity of urine as indicators or biological effects of PAHs.
The results confirm that 1-HOP determination in urine probably reflects
exposure to PAHs by all routes and is not significantly influenced by the
smoking habit.
In comparison with the total PAHs in the air and 1-hydroxypyrene in urine,
taken as reference exposure parameters, the results indicate that urinary
D-glucaric acid excretion is not positively influenced by PAHs exposure;
thioethers determination in urine is of poor value, since the smoking habit
is a strong confounding factor.
The determination of urinary mutagenicity might contribute to the detection
of groups of workers exposed to potentially genotoxic PAHs.   PMID: 8175189
**************************************************************

Arch Biochem Biophys. 1989 May 1; 270(2): 662-71.
Selective oxidation of mitochondrial glutathione in cultured rat adrenal
cells and its relation to polycyclic aromatic hydrocarbon-induced
cytotoxicity.
Hallberg E, Rydstrom J.
Department of Biochemistry, Arrhenius Laboratory, University of Stockholm,
Sweden.

Primary cultures of rat adrenal cells, as well as rat adrenals in vivo, are
sensitive to the potent carcinogen 7,12-dimethylbenz[a]anthracene and its
liver metabolite 7-hydroxymethyl-12-methylbenz[a]anthracene, whereas
unmethylated polycyclic aromatic hydrocarbons like benzo[a]pyrene or
benzo[a]anthracene are ineffective.
The adrenocorticolytic potencies of the hydrocarbons are affected by
adrenocorticotrophic hormone and various steroids, cytochrome P450
inhibitors, and antioxidants.
In the present investigation digitonin was used to fractionate cultured rat
adrenal cells.
It was found that the mitochondria and cytosol of the cells contained 3-5
nmol/10(6) cells (approximately 15%) and 20-30 nmol/10(6) cells
(approximately 85%) of the total soluble cellular glutathione equivalents,
respectively.
After exposing the cells to 7-hydroxymethyl-12-methylbenz[a]anthracene in
the culture medium, a time- and concentration-dependent selective oxidation
of mitochondrial glutathione was observed, whereas the effect on the
cytosolic glutathione was negligible.
Under the same conditions, 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene
were unable to alter the redox levels of the subcellular pools of
glutathione. Omission of adrenocorticotrophic hormone lowered the oxidation
of mitochondrial glutathione induced by
7-hydroxymethyl-12-methylbenz[a]anthracene about twofold.
The results suggest that rat adrenal cells contain two separate pools of
glutathione, one cytosolic and one mitochondrial, of which the latter is
selectively influenced by 7-hydroxymethyl-12-methylbenz[a]anthracene.
Moreover, it is concluded that rat adrenal cells offer a unique model system
for general studies of the effects of a selective oxidation of mitochondrial
glutathione on various cell functions.
These effects may constitute early changes in cytotoxicity, preceding, e.g.,
membrane damage and loss of cytosolic components.   PMID: 2539778
**************************************************************

Vet Hum Toxicol. 1987 Feb; 29(1): 25-30.
Toxicity of polycyclic aromatic hydrocarbons. II. Effect of NO2-nitrated
phenanthrene and pyrene on blood chemistry in rats.
Yoshikawa T, Flory W, Ruhr LP, Giamalva D, Church DF, Pryor WA.

Male Sprague-Dawley rats were treated with a single ip injection of dimethyl
sulfoxide (DMSO), phenanthrene, nitrated products of phenanthrene, pyrene,
or nitrated products of pyrene.
Phenanthrene, pyrene and their nitrated products were dissolved in DMSO.
Phenanthrene produced a significant elevation of serum aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) levels relative to
DMSO-injected rats 24 hr after injection.
Gamma-glutamyl transpeptidase (GGTP) levels were significantly increased for
groups treated with phenanthrene when compared with the DMSO group 72 hr
after injection.
Nitrated products of phenanthrene produced a significant elevation of serum
AST, ALT, sorbitol dehydrogenase (SDH), and GGTP levels when compared with
groups treated with DMSO and phenanthrene 24 hr after injection.
Four of six rats in the nitrated phenanthrene treatment group died between
48 and 72 hr after the injection.
Injection of pyrene caused no significant increases in serum enzyme
activities. Significant changes in the serum AST, SDH and LDH levels were
observed with the nitrated products of pyrene at 24 hr.
Only SDH levels were significantly different when pyrene and its nitrated
products were compared.
No significant differences were detected at 72 hr with the nitrated products
of pyrene.
As supported by serum chemistry, this study suggests that the products of
the reaction of NO2 with two model polynuclear aromatic hydrocarbons (PAH)
are hepatotoxic.
Both pyrene and phenanthrene form nitrated products that are more toxic than
the parent PAH, but the nitrated products of phenanthrene appear to be more
toxic than the nitration products of pyrene.  PMID: 3824871
**************************************************************

Toxicol Appl Pharmacol. 1985 Jun 30; 79(2): 218-26.
Toxicity of polycyclic aromatic hydrocarbons. I. Effect of phenanthrene,
pyrene, and their ozonized products on blood chemistry in rats.
Yoshikawa T, Ruhr LP, Flory W, Giamalva D, Church DF, Pryor WA.

Male Sprague-Dawley rats were treated with a single ip injection of
physiological saline (3.0 ml/kg), dimethyl sulfoxide (DMSO, 3.0 ml/kg),
phenanthrene (150 mg/kg), ozonized products of phenanthrene (150 mg/kg),
pyrene (150 mg/kg), or ozonized products of pyrene (150 mg/kg).
Phenanthrene, pyrene, and their ozonized products were dissolved in DMSO (50
mg/ml).
Serum aspartate aminotransferase (AST) activity was increased significantly
24 hr after ip administration of DMSO when compared with physiological
saline. Phenanthrene produced a significant elevation of serum AST and
gamma-glutamyl transpeptidase (GGTP) levels related to physiological saline
and DMSO-injected rats 24 hr after injection.
However, GGTP levels for groups treated with DMSO or phenanthrene were not
significantly increased when compared with saline groups 72 hr after
injection.
Ozonized products of phenanthrene produced a significant elevation of serum
AST, alanine aminotransferase (ALT), GGTP, and bilirubin levels when
compared with groups treated with physiological saline, DMSO, and
phenanthrene 24 or 72 hr after injections.
The ozonized products of phenanthrene also produced significant elevation of
serum creatinine levels compared with physiological saline, DMSO, and
phenanthrene groups at 24 hr after treatment and of blood urea nitrogen
(BUN) levels at 24 and 72 hr.
Although pyrene caused a small but significant increase in the serum AST and
bilirubin levels 24 hr after treatment, no significant change in the serum
AST, ALT, GGTP, BUN, and creatine levels were observed with the ozonized
products of pyrene at 24 or 72 hr.
This study demonstrates significant alterations in serum chemistry induced
by reaction products of ozone with phenanthrene.
No such effect was observed when the products of pyrene ozonation were
administered.
Although the ozonation products of pyrene were not toxic under the
conditions of this study, phenanthrene products were more hepatotoxic than
was phenanthrene itself.
Nephrotoxicity was also an apparent effect of ozonized phenanthrene.
Since ozone-polycyclic aromatic hydrocarbon (PAH) reactions may occur in the
atmosphere, these reactions might produce compounds that are more toxic than
either ozone or the PAH alone.  PMID: 2860738
**************************************************************

Adv Exp Med Biol. 1986; 206: 5-10.
Brief history of the role of nutrition in carcinogenesis.
Poirier LA.

That diet exerts an influence on the development of tumors in humans and in
experimental animals has been recognized for over 60 years.
>From 1940 to 1960, a number of essential nutrients were shown to
significantly alter the carcinogenic activities of specific polycyclic
aromatic hydrocarbon and aromatic amine and aminoazo dye carcinogens.
Diet has been shown to modify the carcinogenic process at many stages.
Since 1970, the number of known interactions between carcinogens and
essential nutrients has increased markedly.
It is hoped that this volume will provide a comprehensive evaluation
increasing our understanding of the multiple effects of the essential
nutrients on carcinogenesis.  PMID: 3591536
**************************************************************

http://groups.yahoo.com/group/aspartameNM/message/1071
research on aspartame (methanol, formaldehyde, formic acid) toxicity:
Murray 2004.05.14 rmforall

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

Thrasher (2001): "The major difference is that the Japanese demonstrated
the incorporation of FA and its metabolites into the placenta and fetus.
The quantity of radioactivity remaining in maternal and fetal tissues
at 48 hours was 26.9% of the administered dose." [ Ref. 14-16 ]

Arch Environ Health 2001 Jul-Aug; 56(4): 300-11.
Embryo toxicity and teratogenicity of formaldehyde. [100 references]
Thrasher JD, Kilburn KH.  toxicology at drthrasher.org
Sam-1 Trust, Alto, New Mexico, USA.
http://www.drthrasher.org/formaldehyde_embryo_toxicity.html   full text

http://www.drthrasher.org/formaldehyde_1990.html  full text   Jack Dwayne
Thrasher, Alan Broughton, Roberta Madison. Immune activation and
autoantibodies in humans with long-term inhalation exposure to formaldehyde.
Archives of Environmental Health. 1990; 45: 217-223.  "Immune activation,
autoantibodies, and anti-HCHO-HSA antibodies are associated with long-term
formaldehyde inhalation."  PMID: 2400243

Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 2002.12.09 rmforall

Environ Health Perspect. 2003 Sep; 111(12): 1461-4.
Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity:
central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.
Pall ML.
School of Molecular Biosciences, 301 Abelson Hall, Washington State
University, Pullman, WA 99164, USA. martin_pall at wsu.edu

The elevated nitric oxide/peroxynitrite and the neural sensitization
theories of multiple chemical sensitivity (MCS) are extended here to propose
a central mechanism for the exquisite sensitivity to organic solvents
apparently induced by previous chemical exposure in MCS.
This mechanism is centered on the activation of N-methyl-D-aspartate (NMDA)
receptors by organic solvents producing elevated nitric oxide and
peroxynitrite, leading in turn to increased stimulating of and
hypersensitivity of NMDA receptors.
In this way, organic solvent exposure may produce progressive sensitivity to
organic solvents.
Pesticides such as organophosphates and carbamates may act via muscarinic
stimulation to produce a similar biochemical and sensitivity response.

Accessory mechanisms of sensitivity may involve both increased blood-brain
barrier permeability, induced by peroxynitrite, and cytochrome P450
inhibition by nitric oxide.
The NMDA hyperactivity/hypersensitivity and excessive nitric
oxide/peroxynitrite view of MCS provides answers to many of the most
puzzling aspects of MCS while building on previous studies and views of this
condition.   PMID: 12948884

Prof. Pall describes processes by which an initial trigger exposure, such as
carbon monoxide or formaldehyde, can generate hypersensitivity to many
substances.  He himself had recovered from a sudden, debilitating attack of
multiple chemical sensitity in June/July 1997.

http://groups.yahoo.com/group/aspartameNM/message/1055
hormesis: possible benefits of low-level  aspartame (methanol, formaldehyde)
use: Calabrese: Soffritti:  Murray 2004.03.11 rmforall

http://groups.yahoo.com/group/aspartameNM/message/1056
disorders of NMDA glutamate receptors in brain range from high activity
(MCS, CF, PTSD, FM, from carbon monoxide or formaldehyde (methanol,
aspartame)-- Pall)
to low activity (schizophrenia-- Coyle, Goff, Javitts):
Murray 2004.03.13 rmforall

Finally, an intripid and much published team in Japan has found DNA damage
in 8 tissues from single non-lethal doses of aspartame (near-significant
high levels of DNA damage in 5 tissues) and many other additives in groups
of 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.
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
additives.
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 (2000mg/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

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

http://groups.yahoo.com/group/aspartameNM/message/935
Comet assay finds DNA damage from sucralose, cyclamate, saccharin in
mice: Sasaki YF & Tsuda S  Aug 2002: Murray 2003.01.01 rmforall
[ Also 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.]

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 rmforall   [A detailed look at the data]     ]
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