Yahoo! Groups Tips
Did you know...
Message search is now enhanced, find messages faster. Take it for a spin.
|
| hormesis: possible benefits of low-level aspartame (methanol, form |
Message List
|
From rmforall@... Tue Jan 27 20:20:49 2004
Return-Path: <rmforall@...>
Received: (qmail 15346 invoked from network); 28 Jan 2004 02:52:00 -0000
Received: from unknown (66.218.66.167)
by m8.grp.scd.yahoo.com with QMQP; 28 Jan 2004 02:52:00 -0000
Received: from unknown (HELO n21.grp.scd.yahoo.com) (66.218.66.77)
by mta6.grp.scd.yahoo.com with SMTP; 28 Jan 2004 02:51:57 -0000
X-eGroups-Return: rmforall@...
Received: from [66.218.67.139] by n21.grp.scd.yahoo.com with NNFMP; 28 Jan 2004 02:50:40 -0000
X-Sender: rmforall@...
X-Apparently-To: aspartameNM@yahoogroups.com
Received: (qmail 6374 invoked from network); 27 Jan 2004 23:39:20 -0000
Received: from unknown (66.218.66.166)
by m13.grp.scd.yahoo.com with QMQP; 27 Jan 2004 23:39:20 -0000
Received: from unknown (HELO mtiwmhc12.worldnet.att.net) (204.127.131.116)
by mta5.grp.scd.yahoo.com with SMTP; 27 Jan 2004 23:39:19 -0000
Received: from x7n3w0 (h-67-100-204-117.phndaz91.dynamic.covad.net[67.100.204.117])
by worldnet.att.net (mtiwmhc12) with SMTP
id <2004012723364711200otdpbe>
(Authid: rmforall@...);
Tue, 27 Jan 2004 23:36:52 +0000
Message-ID: <015d01c3e52e$74351cc0$dfaffea9@x7n3w0>
To: <aspartameNM@yahoogroups.com>,
<aspartame@yahoogroups.com>
Cc: "Harihara M. Mehendale" <mehendale@...>,
"A. R. B. Stebbing" <tony.stebbing@...>,
"Elaina M. Kenyon" <kenyon.elaina@...>,
<davis.jmichael@...>,
"J. Michael Davis" <Davis.Jmichael@...>,
"Joseph V. Rodricks" < jrodricks@...>,
"Ronald Mitchel" <mitchelr@...>,
"Suresh I. Rattan" <rattan@...>,
"William H. Farland" <farland.william@... >,
"George Gray" <ggray@...>,
"Christopher J. Portier" <christopher.portier@...>,
"Mark P. Mattson" <mark.mattson@...>,
"Edward J. Calabrese" <edwardc@...>,
"Thomas J. Goehl" <goehl@...>,
"Rebecca Renner" <applepie@...>,
"Linda A. Baldwin" <baldwinl@...>,
"M. A. Medinsky" <toxcon@...>,
"D.C. Dorman" <dorman@...>,
"Morando Soffritti" <crcfr@... >
Date: Tue, 27 Jan 2004 16:36:50 -0700
MIME-Version: 1.0
Content-Type: text/plain;
charset="iso-8859-1"
Content-Transfer-Encoding: 8bit
X-Priority: 3
X-MSMail-Priority: Normal
X-Mailer: Microsoft Outlook Express 6.00.2800.1158
X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2800.1165
X-eGroups-Remote-IP: 204.127.131.116
From: "Rich Murray" <rmforall@...>
Subject: hormesis: possible benefits of low-level aspartame (methanol, formaldehyde) use: Calabrese: Soffritti: Murray 1.27.4
X-Yahoo-Group-Post: member; u=116246628
X-Yahoo-Profile: rmforall
X-eGroups-Edited-By: rmforall <rmforall@...>
X-eGroups-Approved-By: rmforall <rmforall@...> via web; 28 Jan 2004 02:50:36 -0000
X-eGroups-Remote-IP: 66.218.66.77
http://groups.yahoo.com/group/aspartameNM/message/1055
hormesis: possible benefits of low-level aspartame (methanol, formaldehyde)
use: Calabrese: Soffritti: Murray 1.27.4
Edward J. Calabrese, 57, offers a profound insight, based on wide-ranging
evidence. Small doses of many toxins are actually beneficial. This complex
effect is called hormesis:
Hormesis as a Biological Hypothesis Feb 1998 review:
"The wide range of hormetic effects (e.g., increased growth, fecundity,
longevity, and decreased disease incidence) suggests that these changes are
fundamental and affect thousands of genes. This implies that hormetic
mechanisms are likely to be operational in a very upstream location.
Nevertheless investigators often focus on mechanisms more closely related to
biological protection. For example, substantial evidence exists in numerous
species that specific alterations in patterns of gene expression occur in
response to toxicant exposure. Such responses can be sorted into two
classes: those resulting in an enhanced metabolic capacity for
detoxification (e.g., the cytochrome P450 gene family) and those that offer
a more general protection against cellular damage caused by a wide variety
of agents (e.g., heat shock or stress proteins)."
[ Crit Rev Toxicol. 2003; 33(3-4): 407-24. Related Articles, Links
Ethanol and hormesis.
Calabrese EJ, Baldwin LA.
Department of Environmental Health Sciences, Morrill Science Center,
University of Massachusetts, Amherst, MA 01003, USA.
edwardc@...
This article provides a detailed assessment of the toxicological and
pharmacological literature concerning alcohol-induced biphasic dose-response
relationships. The assessment reveals that alcohol-induced hormetic-like
dose-response relationships are commonly observed, highly generalizeable
according to model and endpoint and quantitative feature of the dose
response. These findings have important implications affecting study design,
animal model, and endpoint selection as well as clinical applications.
Publication Types: Review Review, Tutorial PMID: 12809430
Crit Rev Toxicol. 2003; 33(3-4): 355-405.
Peptides and hormesis.
Calabrese EJ, Baldwin LA.
Department of Environmental Health Sciences, University of Massachusetts,
Amherst, MA 01003, USA. edwardc@...
The article provides a broad assessment of the occurrence of hormetic-like
biphasic dose-response relationships by over 30 peptides representing many
major peptide classes. These peptide-induced biphasic dose responses were
observed to occur in a extensive range of tissues, affecting an diverse
range of biological endpoints. Despite diversity of peptides, models and
endpoints, the quantitative features of the biphasic dose responses are
remarkably similar with respect to the amplitude and width of the
stimulatory response. These findings strongly suggest that hormetic-like
biphasic dose responses represent a broadly generalizable biological
phenomenon.
Publication Types: Review Review Literature PMID: 12809429 ]
The scientific information about aspartame is clear. It has an 11% methanol
(wood alcohol) component, which is immediately released into the GI tract,
and then made by the liver into formaldehyde and formic acid the same day.
About 30% of the methanol remains each day in all tissues as these toxic
products.
It is hardly surprising, then, that since its FDA approval in July, 1981,
there have been thousands of physician and citizen complaints about
aspartame reactions: headache, poor memory, impaired concentration,
irritability, fatigue, insomnia, aching joints and body pains, rashes,
dizziness, eye and vision problems, and even ideopathic seizures.
For the public service, I have worked tenaciously as a volunteer activist on
the world Net for five years, writing hundreds of polite, lucid, balanced,
lengthly, detailed, boring reviews of mainstream scientific research on the
issue of aspartame toxicty.
However, I admit that there are many users who operate at a high level of
competence in difficult careers, for instance, politicians, their staff, and
the media:
" http://www.mcall.com/features/all-hhtjan09.story
From The Morning Call frank.devlin@... 610-778-2235
Mainlining Diet Coke: Believe it or not - drinking Diet Coke makes dreams
come true.
By Frank Devlin of The Morning Call January 9, 2004
Don't believe it?
Then how do you explain the way Diet Coke keeps popping up as the celebrity
soda of choice? Surely there's some link between success and this
caffeinated, chemically sweetened serum.
Take Harvey Weinstein, head of the Miramax Pictures movie studio. U.S. News
and World Report reports Weinstein has a limousine ''outfitted with video
screens and seat pockets stocked with Diet Coke.'
Or presidential candidate John Edwards, who would ''chain-drink Diet Cokes''
when he was a hotshot personal injury lawyer, according to the Charlotte
Observer, and who's drinking about 10 cans a day now on the campaign trail.
Bill Clinton, Donald Trump and Major League Baseball Commissioner Bud Selig
are also reported to be devoted Diet Coke drinkers...."
So, as truth consecrated scientists, we have to look for evidence that
formaldehyde exposure, surely disastrous at medium and high levels, may be
beneficial in some ways, at some low level for some types of people.
If such a person happens to be playing a public pro-aspartame role, then
their own personal experience will naturally make them resistant to the anti
point of view. Perhaps, more is involved than, say, vested corporate
interests, personal larceny, and ingrained professional arrogance, in the
perpetual, tenaciously polarized debate beween the pro side and the laymen,
amateurs, complainers, mavericks, fools, nut cases, fanatics, and rumor
mongers on the anti side, who have been rudely and exasperatedly talking
past each other for two decades.
Perhaps, both sides can join in a grudging admission that the research on
the actual biochemistry of formaldehyde and formic acid in humans from
methanol is strikingly skimpy, and may even lead to proving beneficial
effects for some people at low levels for some period of time.
That's just the sort of complex outcome that often results in many such
bitter, unresolvable scientific debates. The unstoppably exponential
advance of world toxicology renders breakthrough results impendingly
available, always far faster than expected. My goal is to provide extensive
information and suggestive leads to speed the process of fresh examination
and exploration of the complex facts of this contested case. Open-minded,
civil, cooperative communication is essential for the success of science in
ameliorating human pain.
[ re Ramazzini Foundation research, led by Morando Soffritti :
So this careful lifelong study by world class experts on total tumors in
hundreds of rats exposed almost lifelong to a wide range of formaldehyde
levels found evidence suggestive of hormesis at the levels of 10, 50, and
100 ppm, and then the usual toxic effect of increasing lifetime total tumors
at 500, 1,000, and 1,500 ppm in drinking water.
One possible hypothesis is that the low formaldehyde levels were enough to
eliminate tumor promoting contamination, virusus, or bacteria in the water
or even in the body tissues. This deserves to be checked out by careful
studies. Of course, much more complex, subtle biochemical possibilities
must exist. ]
European Ramazzini Foundation, led by Morando Soffritti, MD.
crcfr@... Cancer Research Center, European Ramazzini Foundation for
Oncology and Environmental Sciences, Bentivoglio Castle, 40010
Bentivoglio (BO), Italy. +39-051-6640460 fax +39-051-6640223
Annuals of the New York Academy of Science. 2002 Dec; Vol. 982.
I carefully examined the details of two long reports by Soffritti:
p. 56 Table 2. shows for groups of 100 rats, lifetime total tumors per 100
rats increasing with high (almost lifelong ) methanol in drinking water,
except that females have have the same lifelong tumor rate at 5,000 ppm as
at 500 ppm. Males have more tumors than females at all 3 high methanol
levels. Low levels were not tested.
The EPA limit for methanol in human drinking water is 7.8 mg daily, or 3.9
ppm for 2 L daily.
[ "Humans, due perhaps to the loss of two enzymes during evolution, are
more sensitive to methanol than any laboratory animal; even the monkey
is not generally accepted as a suitable animal model (42)."
42. Roe, O., Species Differences in Methanol Poisoning. CRC
Critical Rev. in Tox., pp. 275-286, October, (1982). In:
http://groups.yahoo.com/group/aspartameNM/message/870
Aspartame: Methanol and the Public Interest 1984:
Monte: Murray 9.23.2 rmforall
Dr. Woodrow C. Monte Aspartame: methanol, and the public health.
Journal of Applied Nutrition 1984; 36 (1): 42-54.
(62 references) Professsor of Food Science [retired 1992]
Arizona State University, Tempe, Arizona 85287 woodymonte@...
The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is
112 mg, 10% of the aspartame. The EPA limit for water is 7.8 mg daily
for methanol (wood alcohol), a deadly cumulative poison. Many users
drink 1-2 L daily. The reported symptoms are entirely consistent
with chronic methanol toxicity. (Fresh orange juice has 34 mg/L, but,
like all juices, has 16 times more ethanol, which strongly protects
against methanol.) ]
p. 95 Table 2. shows lifetime total tumors per 100 rats for groups of 100
rats fed formaldehyde almost lifelong in drinking water, at levels 0, 500,
5,000, and 20,000 ppm.
Males
0 ppm had 50, 10 ppm had 38 (24% less), 50 ppm had 30 (40% less).
Females
0 ppm had 49, 10 ppm had 44 (10 % less), 50 ppm had 52 ( 6% more).
Males
100 ppm had 46 ( 8% less)
Females
100 ppm had 85 (67% more)
Males were higher than females only for 500 ppm and 1,500 ppm, in contrast
with the results for methanol.
The combined sexes at 0 ppm had 49.5, while for methanol
the combined sexes at 0 ppm had 63.0 (27% more). The authors do not
comment on this large control group disparity. Both groups had 200 rats.
Comparing the methanol and formaldehyde results, we roughly estimate that in
drinking water for rats, lifelong total tumor rates are about the same,
about 100 lifetime tumors per 100 rats, for 20,000 ppm methanol and 1,500
ppm formaldehyde.
If about 3% of the aspartame remains in body tissues as formaldehyde and
formic acid products, then their similar lifetime rat studies already
carried out with
aspartame might show significantly more tumors for about 45,000 ppm in
nearly lifelong drinking water, which is 45,000 mg/L. Diet soda has 560
mg/L aspartame, so this would be about 80 times more concentrated.
The EPA limit for formaldehyde in human drinking water is 2 mg daily, or 1
ppm for 2 L daily. The EPA limit usually is established about a
hundred-fold less than any known toxic level.
[ http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall ]
So this careful lifelong study by world class experts on total tumors in
hundreds of rats exposed almost lifelong to a wide range of formaldehyde
levels found evidence suggestive of hormesis at the levels of 10, 50, and
100 ppm, and then the usual toxic effect of increasing lifetime total tumors
at 500, 1,000, and 1,500 ppm in drinking water.
One possible hypothesis is that the low formaldehyde levels were enough to
eliminate tumor promoting contamination, virusus, or bacteria in the water
or even in the body tissues. This deserves to be checked out by careful
studies. Of course, much more complex, subtle biochemical possibilities
must exist.
I discuss some of these with respect to aspartame, methanol, formaldehyde,
including more examples of possible hormesis, in:
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 1.28.4 rmforall
Note also that Yu F. Sasaki found probable genotoxicity in mice from a
single
aspartame dose of 2,000 mg/L [ ppm ]:
http://groups.yahoo.com/group/aspartameNM/message/934
24 recent formaldehyde toxicity [Comet assay] reports:
Murray 12.31.2 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 1.1.3 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 1.27.3 rmforall [A detailed look at the data]
*************************************************************
http://groups.yahoo.com/group/aspartameNM/message/1016
President Bush & formaldehyde (aspartame) toxicity: Ramazzini Foundation
carcinogenicity results Dec 2002: Soffritti: Murray 8.3.3 rmforall
p. 48 "The sweetening agent aspartame hydrolyzes in the gastrointestinal
tract to become free methyl alcohol. (25)"
"(25) Medinsky MA & Dorman DC. 1994; Assessing risks of low-level
methanol exposure. CIIT Act. 14: 1-7.
(30) Monte WC. 1984; Aspartame, methanol and the public health.
Journal Applied Nutrition. Vol 36: 42-54."
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
[ p. 56 Table 2. shows for groups of 100 rats, lifetime total tumors per
100 rats increasing with high (almost lifelong ) methanol in drinking water,
except that females have have the same lifelong tumor rate at 5,000 ppm as
at 500 ppm. Males have more tumors than females at all 3 high methanol
levels. Low levels were not tested. ]
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 & Dorman 1994]"
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 [ ppm ]
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. [ ppm ]
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
[ p. 95 Table 2. shows lifetime total tumors per 100 rats for groups of 100
rats fed formaldehyde almost lifelong in drinking water, at levels 0, 500,
5,000, and 20,000 ppm.
Males
0 ppm had 50, 10 ppm had 38 (24% less), 50 ppm had 30 (40% less).
Females
0 ppm had 49, 10 ppm had 44 (10 % less), 50 ppm had 52 ( 6% more).
Males
100 ppm had 46 ( 8% less)
Females
100 ppm had 85 (67% more) ]
Surely the authors deliberately emphasized that aspartame is well-known
to be a source of formaldehyde, which is an extremely potent, cumulative
toxin, with complex, multiple effects on all tissues and organs.
This is even more significant, considering that they have already tested
aspartame, but not yet released the results:
p. 29-32 Table 1: The Ramazzinni Foundation Cancer Program
Project of [200] Long-Term Carcinogenicity Bioassays: Agents Studied
No. No. of Bioassays Species No. Route of Exposure
108. "Coca-Cola" 4 Rat 1,999 Ingestion, Transplantal Route
109. "Pepsi-Cola" 1 Rat 400 Ingestion
110. Sucrose 1 Rat 400 Ingestion
111. Caffeine 1 Rat 800 Ingestion
112. Aspartame 1 Rat 1,800 Ingestion
http://members.nyas.org/events/conference/conf_02_0429.html
Soffritti said that Coca-Cola showed no carcinogenicity.
It may be time to disclose these important aspartame results.
*******************************************************************
In order to help those who may wish to attend to details, we summarize some
other studies on aspartame, methanol, and formaldehyde in rats.
This aspartame industry team found that in rats 50% of oral methanol or
aspartame remained in the body. Two other teams found that 4 to 11% of
injected formaldehyde in rats is retained after 48 hours.
J Toxicol Environ Health. 1976 Nov; 2(2): 441-51.
Comparative metabolism of aspartame in experimental animals and humans.
Ranney RE, Oppermann JA, Muldoon E, McMahon FG.
Aspartame [SC-18862; 3-amino-N-(alpha-carboxyphenethyl) succinamic acid,
methyl ester, the methyl ester of aspartylphenylalanine] is a sweetening
agent that organoleptically has about 180 times the sweetness of sugar.
The metabolism of aspartame has been studied in mice, rats, rabbits, dogs,
monkeys, and humans.
The compound was digested in all species in the same way as are natural
constituents of the diet.
Hydrolysis of the methyl group by intestinal esterases yielded methanol,
which was oxidized in the one-carbon metabolic pool to CO2.+
The resultant dipeptide was split at the mucosal surface by dipeptidases and
the free amino acids were absorbed.
The aspartic acid moiety was transformed in large part to CO2 through its
entry into the tricarboxylic acid cycle.
Phenylalanine was primarily incorporated into body protein either unchanged
or as its major metabolite, tyrosine. PMID: 827618
This 1976 study by a G.D. Searle & Co. laboratory proved, using an
undisclosed number of rats, that by 8 hours, fully 50% of oral methanol or
oral aspartame was no longer being eliminated in exhaled air, as shown on
Figure 2: Cumulative 14-CO2 excretion by rats.
They did not specify any detailed numbers, or mention urine and feces,
although in 1973 in their similar study on 3 to 4 small monkeys, they gave
numbers like 73.0+- 3.1% for methanol excretion in exhaled air, 3.17+- .31%
in urine, and "little" in feces.
They did not point out that in rats this meant that fully 50% of the
methanol or aspartame must therefore accumulate daily as unspecified
products, almost certainly highly toxic formaldehyde and formic acid
products.
Two other teams found that about 4 to 11% of injected formaldehyde in rats
is retained in the body.
Life Sci 1991;48(11):1031-41
The toxicity of methanol.
Tephly TR. [a notable pro-aspartame scientist]
Department of Pharmacology, University of Iowa, Iowa City 52242.
p. 1033 "The effects of methanol in lower animals are quite different from
those seen in humans and primates in that metabolic acidosis and ocular
toxicity are normally not seen (13). This makes it impossible to
extrapolate results obtained from experiments using non-human animals to
humans....Monkeys are susceptible to methanol toxicity and serves as the
only model of intoxiction (14)."
p. 1036 "About 85% of a low dose of 14C-formaldehyde [radioactive label] is
excreted as pulmonary 14CO2 (49,50)....."
49. Biochem. Pharmacol. 13: 1137-1142 (1964).
The metabolic fate of formaldehyde-C14 intraperitoneally administered
to the rat.
W. Brock Neely
Biochemical Research Labs, Dow Chemical Co., Midland, Michigan
In one rat, a 60.5 mg/kg dose = 2,000 mmol/kg was injected, and by 48
hours, 82.0% was in the exhaled air as CO2 and 13.9 % was in the urine
= total 95.9% excreted, so 4 % was retained in the body.
50. Xenobiotica 1982 Feb;12(2):119-24
Formaldehyde metabolism by the rat: a re-appraisal.
Mashford PM, Jones AR.
Dept. of Biochemistry, University of Sidney, Australia
(grant from Geistlich Sons Ltd, Pharmaceuticals, Chester, UK)
Six rats were injected with a 4 mg/kg dose = 133 mmol/kg, and by 48 hours,
82% was in the exhaled air as CO2, and 7.5% in the urine = total
89.5% excreted, so 10.5% was retained in the body.
*******************************************************************
http://hdlighthouse.org/research/general/updates/0080toxin.phtml
the HD lighthouse: Huntington's Disease: information and community
Toxin 3NPA and Huntington's Disease
HD Lighthouse Editor's Comment: Edward J. Calabrese has over 500
publications in peer reviewed journals. He is professing radical new
treatment ideas. At least one Huntington's researcher is listening.
Calabrese's expertise on toxins may lead to treatments to delay the onset of
Huntington's disease (HD).
Sugar cane workers sometimes developed a disease that mimics HD. The cause
is the toxin 3-nitropropionic acid (3NPA) found in sugar cane mold. 3NPA is
used to make a HD mouse model. To my knowledge every agent that treats the
3NPA HD mouse also treats the genetic HD mouse.
As a striking fact genetic HD mice are resistant to 3NPA damage. What ever
the mouse does to defend against HD also defends against the toxin 3NPA. A
treatment for HD may be found in sugar cane because sugar cane probably
defends against 3NPA. Such a candidate agent has been recently found in
sugar cane (ref).
In plants, insects and humans 3NPA is a powerful mitochondrial toxin. 3NPA
has been found in peanuts and corn. 3NPA is produced by some plants as a
defense against insects or competing plants. Finding out how plants defend
against 3NPA could bring treatments for HD. As an environmental toxin 3NPA
is not measured by the Environmental Protection Agency. We may all be
exposed to low doses of 3NPA.
The following suggests that low doses of 3NPA may increase defences against
HD to delay onset. Some good science has to be done before any human dare
take 3NPA. --Jerry Posted to the HDL: 12 Dec 2003
A New Idea For Treatment
HD researcher Mark Mattson recently invited Calabrese to visit his lab to
discuss the possibility of experiments that would test whether low doses of
otherwise toxic chemicals strengthen the brain's defenses against diseases
like Alzheimer's, Parkinson's, or Huntington's.
A scientist finds benefit in small doses of toxins
By Gareth Cook, Globe Staff, 12/12/2003
AMHERST -- Edward J. Calabrese, a gray-haired man who works in a rundown
office surrounded by documents on highly toxic chemicals, has an explosive
idea.
For more than a decade, Calabrese, a respected professor of toxicology at
the University of Massachusetts, endured ridicule as he gathered evidence
showing that small amounts of poisons, even cancer-causing chemicals like
dioxin, can be good for you.
His research threatens to overturn a key principle of environmental
regulation, which assumes that if a large quantity of a chemical causes
cancer, then a small quantity is still dangerous, and that the ideal amount
is zero. Calabrese's work suggests that for many chemicals, exposure to a
low level may be healthier than no exposure at all.
Though long relegated to the scientific fringe, Calabrese's idea is suddenly
being taken seriously. He has landed several papers in prestigious research
journals. Other scientists are citing his work, the invitations to speak at
universities and scientific meetings are flooding in, and the concept has
been added to two leading toxicology textbooks.
All of this has put Calabrese at the center of a politically charged debate
with broad implications for health. If the regulations that protect the
nation's air, water, and soil are not stringent enough to keep toxins below
hazardous levels, Americans will die. Yet if Calabrese is correct, and small
quantities of many toxins can actually be beneficial, then it could bring
innovative drug therapies, save billions by relaxing overly strict
environmental standards, and fundamentally change the way scientists and the
public think about poisons.
"I think he is shaking us all up in a way that is really useful," said
George Gray, a toxicologist who is executive director of the Harvard Center
for Risk Analysis.
The concept underlying Calabrese's work is called "hormesis." In the broad
sense it is hardly controversial. Vitamins are healthy in the right dose;
toxic in larger ones. A glass of red wine a day can be good for you; a
gallon is not. But this is not how scientists have traditionally thought
about the risks posed by environmental chemicals. One of toxicology's most
important tools is to observe the effects of large doses of a chemical on
laboratory animals, and then use that data to estimate the effects of much
lower doses on humans over longer periods.
In the case of cancer-causing agents, toxicologists assume that the harmful
effects decrease as the dosage goes down, but that they do not hit zero
until the exposure is zero. For threats not involving cancer, the model is
only slightly different; scientists also assume that smaller doses cause
less harm, and the harmful effects hit zero as soon as the dose hits a
certain low threshold.
These two ideas form the bedrock of modern toxicology, but Calabrese began
to suspect that they were wrong when he discovered, as a college student,
that spraying peppermint plants with very low doses of a growth retardant
made the plants grow larger. So at low doses, the growth inhibitor didn't
just stop working -- it had the opposite of its intended effect.
Other scientists have noticed unexpected effects like this, Calabrese said.
At low doses, both dioxin and DDT have been shown to reduce some cancers in
lab animals. Low doses of cadmium, which can be highly toxic, reduces liver
cancer in rats.
In his research, Calabrese, 57, has shown that these effects may be very
common.
Calabrese and a colleague searched through the toxicology literature,
looking for all examples where scientists had measured the response to doses
below the threshold at which the chemical is thought to have no effect.
Their statistical analysis, published this year in the journal Toxicological
Sciences, showed that, on average, these low doses had a measurable
effect -- itself a surprise -- and that the effect was the opposite of the
large-dose effect. Chemicals that had a bad effect at high doses tended to
have a beneficial one at small doses.
Their analysis included a wide variety of life forms -- including plants,
animals, and microbes -- and of effects -- such as growth, reproduction, and
behavior.
"What I think is going on here is a revolution in thought to a bunch of
people who are not used to a revolution," Calabrese said.
Before hormesis could be used to justify changes in regulations, scientists
would need a better understanding for exactly how it works, said William H.
Farland, acting deputy assistant administrator for science in the Office of
Research and Development at the Environmental Protection Agency. A chemical
that is beneficial in one way may cause problems in other areas, he said. Or
levels of a chemical that may be healthy for some people, or even positive,
may be harmful for children, pregnant women, or others.
And even when unexpected things happen at small doses, they are not always
positive. Several researchers have found that certain chemicals that act
like hormones can cause damage at much lower levels than anyone had
expected.
As the science improves, Farland said, researchers are seeing more and more
surprises at low levels of exposure.
This "most likely represents very complex biology," Farland said, "and what
we have to do now is understand that biology."
One mechanism behind hormesis is that small amounts of chemicals can evoke a
stress response from cells, causing them to devote resources to defending
themselves.
For example, laboratory animals forced to fast periodically, and thereby put
stress on their entire system, develop neurons that are more resistant to
diseases like Parkinson's, according to research done by Mark P. Mattson,
chief of the Laboratory of Neuroscience at the National Institute on Aging.
Other experiments have shown that chemicals can evoke the same stress
responses.
Mattson recently invited Calabrese to visit his lab to discuss the
possibility of experiments that would test whether low doses of otherwise
toxic chemicals strengthen the brain's defenses against diseases like
Alzheimer's, Parkinson's, or Huntington's.
"The idea would be to identify a treatment that could be given long term and
delay the onset of disease," Mattson said. "This is a long way from
something that could be applied in humans, but it is worth pursuing.
Calabrese's work, said Farland and other scientists, is part of a dramatic
rethinking of the biological effects of low-level exposures. New scientific
tools and the explosion of detailed genetic information is allowing
scientists to move from the standard animal toxicity tests, which use
massive doses, to a more detailed looks at how individual molecules interact
with living cells. This has led to a growing recognition that effects can
differ in kind, not just degree, as the concentration changes.
Indeed, the National Toxicology Program, the government's clearinghouse for
toxicology research, just began an expansive, year-long review to change its
approach, given the developing scientific approaches.
"The idea is, what are we going to do to change this discipline," said
Christopher J. Portier, the program's associate director. "I am sure that
hormesis will be a part of the discussion as we move through this."
# # #
Trached on the HDL: Mark Matson
Edward Calabrese
Source: Adopted from:The Boston Globe 12 Dec 2003
*******************************************************************
Huntington's Disease And Calorie Restriction
... HD Lighthouse Editor's Comment: Mark Matson, researcher at the National
Institute of Health, found that lowering calories forestalls Huntington's
disease in
...
hdlighthouse.org/treatment-care/care/hdltriad/
diet/updates/0062sirtuins.phtml - 22k -
Not Skipping Meals May Damage Brain
... Edition the week of April 28, 2003 . All about professor Mark P. Matson.
# # #. Source: NIH/National Institute on Aging, 28 Apr 2003 ...
hdlighthouse.org/treatment-care/care/hdltriad/diet/updates/0053skipmeal.phtm
l - 20k -
Toxin 3NPA and Huntington's Disease
... I am sure that hormesis will be a part of the discussion as we move
through this." # # #. Trached on the HDL: Mark Matson.
Edward Calabrese. ...
hdlighthouse.org/research/general/ updates/0080toxin.phtml - 22k
New Drugs Protect Nerve Cells In Parkinson Mice
... Would these mice develop cancer tumors or HD symptoms? The new drugs
being investigated by researcher Matson are P53 suppressors. ...
hdlighthouse.org/research/general/ updates/0056p53.shtml - 19k
********************************************************************
http://www.sciam.com/article.cfm?articleID=00019A70-0C1C-1F41-B0B980A841890000
In Depth August 18, 2003 HORMESIS
Nietzsche's Toxicology; Whatever doesn't kill you might make you stronger
By Rebecca Renner
Image: RALPH WHITE Corbis
POLLUTION STANDARDS that factories--such as this chemical plant on Lake
Baikal, Russia--must meet may change if hormesis proves to be a
widespread phenomenon.
If dioxin and ionizing radiation cause cancer, then it stands to reason that
less exposure to them should improve public health. If mercury, lead and
PCBs impair intellectual development, then less should be more. But a
growing body of data suggests that environmental contaminants may not always
be poisonous--they may actually be good for you at low levels.
Called hormesis, this phenomenon appears to be primarily an adaptive
response to stress, says toxicologist Edward J. Calabrese of the University
of Massachusetts at Amherst. The stress triggers cellular repair and
maintenance systems. A modest amount of overcompensation then produces the
low-dose effect, which is often beneficial.
This idea may sound bizarre, but such adaptation to stress is common, says
physiologist Suresh Rattan of Århus University in Denmark. Exercise, for
instance, plays biochemical havoc with the body: starving some cells of
oxygen and glucose, flooding others with oxidants, and depressing immune
functions. "At first glance, there is nothing good for the body about
exercise," he notes. But even couch potatoes know that moderate exercise is
worthwhile. Rattan says that the cellular insults from exercise prompt the
defense system to work more efficiently.
Over the past decade, Calabrese has compiled thousands of examples of
hormesis from published scientific literature. Many findings challenge and
even flout established theories about what is harmful. For example, the
prevailing theory is that any increase in radiation exposure increases the
risk of cancer. But biologist Ronald Mitchel of Atomic Energy of Canada has
shown that a single low dose of ionizing radiation stimulates DNA repair,
delaying the onset of cancer in mice; high doses produced the opposite
effect, as expected. Prolonged exposure to extreme temperatures is also
harmful, but Rattan has found that heating up human skin cells to 41 degrees
Celsius (106 degrees Fahrenheit) twice a week for an hour slows aging in the
cells.
Even well-established environmental headaches display some hormesis. The
definitive rat study that linked high doses of dioxin to cancer, published
in 1978 by Richard Kociba of Dow Chemical and his colleagues, also found
that low doses reduced the incidence of tumors.
Image: LUCY READING; ADAPTED FROM J. R. MAISIN ET AL. IN RADIATION RESEARCH,
FEBRUARY 1988 (top) AND
TETSUYA ABE ET AL. IN BIOCHEMICAL PHARMACOLOGY, JULY
1, 1999 (bottom), AS REPRODUCED BY EDWARD J. CALABRESE AND LINDA A. BALDWIN
IN TRENDS IN PHARMACOLOGICAL SCIENCES, JUNE 2001
A PINCH OF POISON seems beneficial in some cases when compared with control
groups, as shown by the effects of gamma rays on the emergence of
mouse tumors (top) and of cadmium exposure on human ovarian cells (bottom).
"Adaptation to such stresses is absolutely essential," Mitchel remarks. "If
we couldn't adapt to changes in our environment, we would die." Such
adaptation at the molecular level is seen in most primitive forms of life
and has been evolutionarily conserved all the way up to humans, he adds.
Hormesis challenges the existing hazard-assessment process underlying
environmental regulations, Calabrese says. Toxicologists usually determine
the relation between exposure to contaminants and health risks by conducting
animal experiments. They start out by giving lab animals a high dose that
produces clear adverse effects. Then they work downward until they can
estimate a concentration that doesn't cause harmful effects. For chemicals
that don't cause cancer, they obtain a safe dose for humans by applying
uncertainty factors to account for differences between mice and men and
among individual people. The resulting safe dose for humans is then usually
deemed to be about 0.01 to 0.001 the safe dose for mice. For carcinogens,
toxicologists assume that exposure to any amount increases the risk.
But Calabrese suspects that in many cases, the benefits of hormesis may
occur at levels higher than the recommended safe doses for humans. Thus, it
might be possible to refine pollution standards so that we can reap the
benefits of hormesis while still being protected against adverse effects in
the environment. Or at the very least, it might be reasonable to stop
worrying about exceedingly low exposures.
Researchers investigating adaptive stress responses aren't the only ones
interested in effects at low doses. Scientists studying endocrine disruption
are also joining in. They are concerned that contaminants that mimic
hormones can have significant harmful effects at very low doses if exposure
occurs during a susceptible developmental window. In some sense, endocrine
disruption appears to be the opposite of hormesis, in which low doses could
have unsuspected harmful effects because of the contaminant's chemical
similarity to hormones.
Advances in molecular biology are giving toxicologists the tools to
investigate low-dose phenomena, according to Joseph V. Rodricks, health
sciences director at Environ, environmental consultants in Arlington, Va.
Instead of monitoring the onset of disease or cancer, toxicologists are
beginning to use modern molecular biology tools to identify the critical
early precursors to illness. They then monitor how the precursors vary at
low doses.
Hormesis has much to prove if it is to revolutionize toxicology, Rodricks
notes. Many of the hormetic dose-response relations that Calabrese has
compiled raise more questions than answers, he says. For example, the dioxin
study looks like hormesis if all types of cancer are combined, but hormesis
doesn't show for individual types of cancer. Despite such skepticism,
Rodricks is one of many toxicologists calling for a National Research
Council review of this phenomenon.
Rebecca Renner writes about environmental issues from Williamsport, Pa.
*******************************************************************
Harihara M. Mehendale mehendale@...;
A. R. B. Stebbing tony.stebbing@...;
Elaina M. Kenyon kenyon.elaina@...;
davis.jmichael@...;
J. Michael Davis Davis.Jmichael@...;
Joseph V. Rodricks < jrodricks@...>;
Ronald Mitchel mitchelr@...;
Suresh I. Rattan rattan@...;
William H. Farland farland.william@... ;
George Gray ggray@...;
Christopher J. Portier christopher.portier@...;
Mark P. Mattson mark.mattson@...;
Edward J. Calabrese edwardc@...;
Thomas J. Goehl <goehl@...>;
Rebecca Renner <applepie@...>;
Linda A. Baldwin <baldwinl@...>;
M. A. Medinsky" <toxcon@...>;
D.C. Dorman <dorman@...>
*******************************************************************
Toxicological Defense Mechanisms and the Shape of Dose-Response
Relationships
Environmental Health Perspectives 106, Supplement 1, February 1998
Hormesis as a Biological Hypothesis
Edward J. Calabrese and Linda A. Baldwin
Department of Environmental Health Sciences, School of Public Health,
University of Massachusetts, Amherst, Massachusetts
Abstract
A comprehensive effort was undertaken to identify articles demonstrating
chemical hormesis.
Nearly 4000 potentially relevant articles were retrieved from preliminary
computer database searches by using various key word descriptors and
extensive cross-referencing.
A priori evaluation criteria were established including study design
features (e.g., number of doses, dose range), statistical analysis, and
reproducibility of results.
Evidence of chemical hormesis was judged to have occurred in approximately
350 of the 4000 studies evaluated.
Chemical hormesis was observed in a wide range of taxonomic groups and
involved agents representing highly diverse chemical classes, many of
potential environmental relevance.
Numerous biological end points were assessed; growth responses were the
most prevalent, followed by metabolic effects, longevity, reproductive
responses, and survival.
Hormetic responses were generally observed to be of limited magnitude.
The average low-dose maximum stimulation was approximately 50% greater
than controls.
The hormetic dose-response range was generally limited to about one order of
magnitude, with the upper end of the hormetic curve approaching the
estimated no observable effect level for the particular end point.
Based on the evaluation criteria, high to moderate evidence of hormesis was
observed in studies comprised of>6 doses; with>3 doses in the hormetic zone.
The present analysis suggests that chemical hormesis is a reproducible and
relatively common biological phenomenon.
A quantitative scheme is presented for future application to the
database. -- Environ Health Perspect 106(Suppl 1):357-362 (1998).
http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-1/357-362calabrese/abstract.html
Key words: hormesis, [beta]-curve, stimulation, low dose, U-shaped
This paper is based on a presentation at The Third BELLE Conference on
Toxicological Defense Mechanisms and the Shape of Dose-Response
Relationships held 12-14 November 1996 in Research Triangle Park, NC.
Manuscript received at EHP 29 April 1997; accepted 17 July 1997.
This report was sponsored in part by an award to the University of
Massachusetts (E.J. Calabrese, Principal Investigator) by the Texas
Institute for Advancement of Chemical Technology, Inc.
Address correspondence to Dr. E.J. Calabrese, Department of Environmental
Health Sciences, School of Public Health, University of Massachusetts,
Amherst, MA 01003. Telephone: (413) 545-3164. Fax: (413) 545-4692.
E-mail: edwardc@...
Abbreviations used: LOEL, lowest observable effect level; NOEL, no
observable effect level.
[Table of Contents] [Full Article] [Citation in PubMed] [Related Articles]
Last Update: March 11, 1998
Introduction
The concept of chemical hormesis has a long history, originating over a
century ago from the research of Schulz (1), who noted that many chemicals
were able to stimulate growth and respiration of yeast at low doses but were
inhibitory at higher levels. This concept of a generalized low-dose
stimulation-high-dose inhibition was gradually supported by similar
observations with other chemicals and eventually became known as the
Arndt-Schulz law. Although Schulz (1) ushered in the so-called modern
concept of hormesis, Paracelsus (2), writing in the 16th century, likewise
noted that various toxic substances may be beneficial in small quantities.
Despite the widespread recognition of apparent hormetic effects, which
continued into the early decades of the 20th century, Stebbing (2) argues
that the Arndt-Schulz law gradually fell into disuse because it did not
provide an adequate explanatory (i.e., mechanism-based) capacity.
Nonetheless, over the years a continuing stream of observations has been
reported (2) in toxicological publications and the broader biological
literature that document low-dose stimulations.
Although there has been long-standing interest in the concept of chemical
hormesis few attempts have been made to summarize the extent of its
occurrence in biological systems and its potential to generalize with
respect to animal models, biological end points, or chemical class. Previous
limited summaries have been reported (2-6). In addition, Davis and
Svendsgaard (7) attempted to assess the statistical likelihood of low-dose
stimulation among a random sample of experimental studies published in
prominent toxicological journals. The goal of this research was to extend
the findings of these previous reports by attempting to evaluate in a
comprehensive manner those studies that are believed or alleged to display
evidence of chemical hormesis. These findings would then be employed to
assess the scientific basis of the hypothesis that hormesis is induced by
chemical agents and is a generalized biological phenomenon.
Criteria for Evaluating Hormesis
To conduct this investigation it was necessary to define chemical hormesis
and develop a priori criteria to evaluate its possible occurrence in
experimental or empirical investigations. The definition derived from
Stebbing (2) is low-dose stimulation followed by higher-dose inhibition; the
most common form of hormesis follows the widely recognized ß-curve (Figure
1). The use of the ß-curve follows principally from the widespread use of
growth as a principal end point in hormesis research. However, the term U
shaped, as emphasized by Davis and Svendsgaard (8), would most
appropriately be applied when the end point relates to a traditional
toxicologically based health end point such as cancer incidence. The
criteria applied in the present methodology were the same for the ß-curve
and U-shaped relationships.
Figure 1. The most common dose-response curve showing hormesis--the ß-curve.
Because hormesis is a scientific hypothesis the question of whether it is
beneficial is often contextual. To eliminate subjective decisions concerning
beneficial versus harmful effects, the decision was made to evaluate model-
and end point-specific responses with respect to stimulation and inhibition.
For example, stimulation of detoxifying enzyme levels observed in the larval
form of a species would be evaluated for its hormetic potential even though
this increased metabolic activity, although beneficial in the short-term,
may have a detrimental effect on other end points. Likewise the stimulation
of microbial reproduction by antibiotics was evaluated for its hormetic
potential even though these low dose effects are harmful to the host
organism.
This assessment of chemical hormesis has been restricted to those
dose-response relationships most conforming to the ß-curve and would be
affected by the magnitude of the low-dose stimulatory response, the number
of doses establishing the reliability of the ß-curve, the presence of
statistical analysis, and the reproducibility of the findings. Within this
category only the well-known types of dose-response relationships exhibiting
ß- or U-shaped curves (represented by nutritionally essential substances,
with the exception of copper) were excluded, as this phenomenon is generally
accepted.
The capacity to evaluate high conformity to the ß-curve ideally requires the
establishment of an end point-specific lowest observable effect level (LOEL)
and no observable effect level (NOEL), with multiple doses within two orders
of magnitude immediately below the NOEL. This suggests that to be a relevant
study for the evaluation of chemical hormesis, an experiment would be
expected to have four or more doses distributed in a highly specific manner
relative to the NOEL. Therefore, highly restrictive study design
requirements must be satisfied to adequately assess chemical hormesis. Most
toxicological studies do not satisfy these design criteria and would be
classified as nonrelevant, as they are unable to demonstrate no evidence or
some evidence (i.e., equal to or greater than low evidence) of hormesis.
Similarly, data from epidemiological studies, with the exception of reports
on ethanol and cardiovascular disease, were difficult to conform to these
criteria. Within this evaluative context judgment on the evidence supporting
consistency of data from an individual experiment with the definition of
chemical hormesis was made by a weight-of-evidence procedure. It should be
noted that upward-curving ß- or U-shaped dose-response curves (e.g.,
characteristic of certain studies where low doses reduce mortality) were
included in the analysis. In addition many studies contain multiple
dose-response relationships for the same or different end points. In these
cases all end points within a study showing low-dose stimulation were
evaluated.
To facilitate an appreciation of weight-of-evidence evaluation methodology,
several graphic examples are presented that illustrate how such judgments
concerning chemical hormesis may be made (Figure 2A-E).
Figure 2. Dose-response curves illustrating various data sets evaluated for
chemical hormesis.
Figure 2A depicts a hypothetical study with a dose range of 10-fold that
displays a modest statistically insignificant increase (i.e., stimulation)
in response at the lowest dose followed by a more definitive decrease (i.e.,
inhibition). Using the criteria applied in the present methodology this
study would be judged as a) displaying an extremely limited dosage range
probably inadequate for assessment of the dynamics of the dose-response
continuum, b) inadequately describing the dose-response relationship in the
hypothetical hormetic zone, and c) having inadequate statistical power to
conclude that the stimulatory effort was treatment related. An initial
screen of such an experiment would most likely result in a designation of
not highly relevant to assess the hormesis hypothesis. However, the study
would be retained for further evaluation within a weight-of-evidence
context, based on the observation of the low-dose stimulation. At present
this experiment would be most consistent with either a low or not relevant
evidence designation of hormesis. Neither categorical placement is
convincing.
Figure 2B likewise depicts a study with a limited dose range (10-fold) with
a limited number of doses. However in contrast to Figure 2A, a more striking
stimulatory response is seen at the lowest dose, which is highly
statistically significant. However, this study is limited by having only one
dose showing a stimulatory response even though the response was impressive.
A case can be made for either a low or moderate evidence classification of
hormesis.
Figure 2C depicts a study with a markedly larger dose range (500-fold) and
number of doses (seven), with three doses in the hypothetical hormetic zone
(i.e., doses less than the NOEL). However, the magnitude of stimulation is
very limited and the observed increases are not statistically significant.
This experiment would probably be considered as no or low evidence of
hormesis. It would of course be a relevant study because of the wide dosage
range, the substantial number of doses, the inclusion of doses below the
LOEL, and the observation, although inconclusive, of stimulation at low
dose.
Figure 2D depicts a study with a very broad dose range (>1000-fold) and a
large number of doses (11), with a low-dose stimulatory response observed in
seven doses in the hypothetical hormetic zone. In addition the results
display considerable statistical power. This type of study would receive a
high evidence ranking.
Figure 2E depicts a study with a wide range of doses (>500) and a large
number of concentrations with adequate statistical power. However the data
do not show any evidence of a low-dose stimulation. This study would receive
a not relevant designation because it does not establish a NOEL nor does it
have any doses below the NOEL.
Nature and Yield of Search Strategy
Table 1 summarizes the search strategy and yield. Computerized library
searches were conducted on BIOSIS (Knight-Ridder Information, Mountain
View, CA; 1969-1996), Chemical Abstracts (Knight-Ridder Information;
1967-1996), and Medline (Knight-Ridder Information; 1966-1996) using
hormesis and the combination of U shaped plus dose response as key word
descriptors. One
hundred fifty-two publications were retrieved using hormesis as the key word
descriptor; 165 publications were retrieved using the combination of U
shaped plus dose response. Radiation hormesis was the subject of 104 of the
317 publications.
Based on information obtained from the initial searches described above,
additional search strategies were employed using the same three databases
and the following key word descriptors: low dose plus stimulation, beta
curve plus dose response, adaptation plus pollution, and homeopathy. A total
of 4058 articles was identified then reduced to 3272 following elimination
of database replication of articles. Manual review of the 3272 abstracts
revealed approximately 172 potentially relevant publications, the majority
of which were chemically oriented. Radiation studies comprised approximately
25% of the 172 articles.
A computerized library search conducted on the database Agricola
(Knight-Ridder Information; 1970-September 1995) using the key word
descriptors hormesis, U shaped plus dose response, and low dose plus
stimulation revealed very few articles not already identified in the
previous searches.
To include the most recent articles, computerized searches of the Current
Contents Life Sciences and Agricultural, Biological, and Environmental
Sciences databases (Institute for Scientific Information, Philadelphia, PA)
for the time period 15 May 1995 through 5 June 1996 were conducted using
the key word descriptors hormesis, U shaped plus dose response, low dose
plus stimulation, adaptation plus pollution, and beta curve.
Only a small number of new articles not included in the prior searches was
identified.
Potentially relevant articles not included in the computerized library
searches were obtained from extensive cross-referencing of primary sources.
Most recently additional search strategies were employed using BIOSIS,
Medline, and Chemical Abstracts and the following key word descriptors:
doses plus sublethal, doses plus subtoxic, doses plus subthreshold,
responses plus sublethal, responses plus subtoxic, and responses plus
subthreshold. A total of 5569 articles was identified then reduced to 3776
following elimination of database replication of articles. Manual review of
the 3776 abstracts revealed approximately 67 potentially relevant
publications.
A computerized library search using the same key word descriptors listed
above and the database Agricola (1970-September 1996) identified 230
articles. When reviewed approximately 25 were considered potentially
relevant. The same key word descriptors were also used in computerized
searches of the Current Contents Life Sciences and Agricultural, Biological,
and Environmental Sciences databases for the time period 16 October 1995
through 7 October 1996 to include the most recent articles. Of the 214
abstracts identified, 27 new articles were considered potentially relevant.
Finally, computer searches of Science Citations (Institute for Scientific
Infor-mation; 1990-1996) were conducted using authors' names Stebbing ARD
and Luckey TD. Approximately 400 articles were identified, of which 149 were
considered potentially relevant.
Results of Article Evaluation
Those studies placed within a high evidence category of chemical hormesis
had the greatest number of total study doses (i.e., 6.3 on average) and
doses in the so-called hormetic zone (i.e., 3.4 on average), followed by
studies demonstrating moderate evidence and more distantly by studies
demonstrating low evidence (Table 2).
The types of chemicals that induce hormetic effects represent a broad range
of chemical classes (Table 3). The most studied agents were metals, followed
by alcohols, antibiotics, auxin-related compounds, and numerous biocidal
agents. The range of hormetic responses is listed in Table 4 and indicates
that the principal end point is growth, followed by metabolic changes (e.g.,
enzyme activity), longevity, and various reproductive indices.
Characteristics of the Chemical Hormetic Zone
To assess the characteristics of the chemical hormetic dose-response zone,
experimental data were evaluated with respect to a) the dosage range of the
hormetic zone (i.e., from the estimated dosage where the response starts to
deviate from the control to the estimated dosage where the response begins
to dip below the controls); b) the maximum stimulatory response (as a
percentage greater than the control response); and c) the magnitude of
dosage difference from the maximum stimulatory response and the estimated
NOEL (Figure 3).
Figure 3. Dose-response curve depicting characteristics of the chemical
hormetic zone. ZEP, zero equivalent point.
In general the hormetic dose-response range is usually within a 10-fold
range. Stimulatory effects, however, have been reported over dosage ranges
of two or more orders of magnitude as well as over a more narrow range of
dosages depending on the agent, end point, and model assessed. The magnitude
of stimulatory responses has been observed as high as several-fold but the
majority of low-dose stimulations are 30 to 60% greater than the controls.
The distance from the maximum stimulatory response to the NOEL is difficult
to discern as it is a function of the number of doses employed, their
variability in response, and the estimated value of the NOEL. Nonetheless,
the distance between the maximum stimulatory response and the estimated
NOEL is typically observed in the 3- to 6-fold range (i.e., the NOEL is
about 3- to 6-fold greater than the maximum stimulatory response).
Hormesis as a General Biological Phenomenon
Hormetic responses are observed in numerous species from a broad range of
taxonomic groups including microbes, plants, and animals (Table 5). These
responses occur with a large number of chemicals representing a broad range
of chemical classes (Table 3). Although Stebbing (2) focused principally on
growth hormesis, the present report indicates that hormetic effects are
observed in a broad range of biological end points that involve not only
growth but survival, longevity, reproduction, and numerous metabolic and
physiological responses (e.g., metallothionein synthesis, DNA synthesis, RNA
synthesis, mitosis, oxygen consumption, altered hepatic foci, photosynthesis
rate, tissue regeneration, immune response, stress protein synthesis,
germination of seeds, etc.). Thus hormesis appears relatively common with
respect to species, chemical, and biological end point.
The ability to generalize hormetic responses also extends to the descriptive
nature of the dose-response phenomenon itself. As Stebbing (2) noted
earlier, when the data are precise and comprehensive, the points appear to
fit a ß-curve and have remarkable similarity with respect to the range and
amplitude of response. However it should be emphasized that the
developmental dynamics of the hormetic dose response over time have not been
widely or systematically studied. For example, while Stebbing (2) found that
the form of the curve varied during the course of the experiment with hydra,
Calabrese and Howe (9) observed a consistent shape of the ß-curve over 4 to
6 weeks in plant growth experiments.
Why is Hormesis Infrequently Observed?
If hormesis is believed to be relatively common, questions arise as to why
it is not reported more frequently and why the Arndt-Schulz law failed to
become established. The infrequent reports of hormesis are most likely
attributable to a combination of factors, predominantly the issue of
appropriate study design, along with the influence on safety evaluation,
which emphasizes the upper end of the dose-response continuum (i.e., where
higher concentrations establish toxic responses that can be used in chemical
evaluation and risk assessment). The present conclusions support this
assessment; a direct relationship has been shown between the strength of the
evidence supporting hormesis and the number of doses, including both overall
experimental number of doses and the number of doses in the hormetic zone.
Furthermore, because the average range of the hormetic zone is about one
order of magnitude this phenomenon is difficult to discern when wide dose
intervals (e.g., >10-fold) are used.
Predictive insight into the number of published articles potentially
displaying hormesis may be derived as follows. Assuming 500,000 toxicology
studies have been published this century (based on searches of Chemical
Abstracts, Index Medicus, and BIOSIS), it is estimated that approximately
350,000 toxicology articles have been published since 1966. Thus we assume
for the sake of argument that 500,000 toxicology papers comprise the
available pool for evaluation. If we also assume that 2% of these studies
include six or more doses (10) then 10,000 studies may contain dose ranges
adequate for hormesis evaluation. Of these 10,000 studies, based on the
characteristics defining hormetic studies, approximately 10% (i.e., 1000)
have three or more doses below the estimated NOEL. Further refinement of
this estimation can be made by assuming that 90% of these 1000 studies have
doses in the low-dose range within one to two orders of magnitude and close
to the estimated NOEL (10).
These figures suggest that mammalian toxicologists may have had only limited
direct interaction with the concept of hormesis, as only an estimated 900
potentially relevant studies exist. Therefore it is not surprising that
toxicologists may view hormesis more as a belief than a phenomenon and that
the Arndt-Schulz law (i.e., hormesis) fell into general disuse.
In addition to the low number of hormetic observations reported, Stebbing
(2) suggested that the Arndt-Schulz Law fell into disuse because it lacked
an explicit mechanism component. However, the concept of adaptation, a
potentially important explanatory component for hormesis, has evolved for
the most part independent of hormesis. Although numerous studies of
adaptation exist, only a limited number address specific mechanisms
applicable to chemically induced hormetic dose-response relationships.
Nonetheless there are studies that have sought to mechanistically explain
specific hormetic dose-response relationships.
Perhaps the most systematically assessed mechanism-based research has been
in the area of herbicide-induced stimulatory effects. Hormetic responses
have long been recognized by herbicide researchers who have conducted
studies assessing not only the molecular basis for the response but also the
effect of the plant species and age on the response.
A growing number of mammalian examples also exists where plausible
explanatory mechanisms have been put forth to account for specific hormetic
dose-response relationships (11-15).
The wide range of hormetic effects (e.g., increased growth, fecundity,
longevity, and decreased disease incidence) suggests that these changes are
fundamental and affect thousands of genes. This implies that hormetic
mechanisms are likely to be operational in a very upstream location.
Nevertheless investigators often focus on mechanisms more closely related to
biological protection. For example, substantial evidence exists in numerous
species that specific alterations in patterns of gene expression occur in
response to toxicant exposure. Such responses can be sorted into two
classes: those resulting in an enhanced metabolic capacity for
detoxification (e.g., the cytochrome P450 gene family) and those that offer
a more general protection against cellular damage caused by a wide variety
of agents (e.g., heat shock or stress proteins).
Proposed Quantitative Evaluation Scheme
A quantitative scheme has been developed to provide a more objective and
reproducible methodology for ranking studies with respect to hormetic
potential. Criteria have been established and assigned point values based
on: the number of experimental doses below the NOEL, experimental
determination or estimation of the high NOEL, the statistical significance
of the stimulatory response, the magnitude (percentage of control value) of
the stimulatory response, and the reproducibility of data by other studies
(Tables 6 and 7). Evidence of hormesis will be assessed by comparing the
summation of point values to point ranges established for six evidence
categories: high, moderate-high, moderate, low-moderate, low, and no-low
(Table 8). Results of the application of this methodology and comparison
with the current qualitative findings will be published elsewhere (16).
Summary
A goal of the present research is to create a database of studies
demonstrating objective evidence of hormesis. It is hoped that this
database, when complete, will enable the scientific community to evaluate
more rigorously and efficiently the concept of hormesis with respect to its
status as a biological hypothesis, its potential to be generalized, and its
impact on environmental and human health.
The findings to date indicate that examples of low-dose stimulation
consistent with ß-curve characteristics are copious, diverse, independently
derived, and reproducible. Yet despite the large number of such observations
no long-term systematic effort has been made to uncover explanatory
mechanisms, except in limited cases (e.g., herbicidal agents).
A more objective and reproducible evaluation methodology for ranking studies
with respect to hormetic potential is needed. The development of
quantitative criteria based on study design, response, and reproducibility
of findings is proposed and will be applied to the current database.
Furthermore, statistical simulations of dose-response relationships given
various types of variability in control groups can provide important insight
into the establishment of more quantifiable criteria in the evaluation of
possible hormetic findings. The area of hormesis and its evaluation as a
biological hypothesis has striking similarities to the evolving mathematical
area of meta-analysis in epidemiology. In fact the application of
meta-analysis techniques to the evaluation of hormetic response data is
likely to yield significant advances.
References
1. Schulz H. Ueber Hefegifte. Pfluegers Arch Gesamte Physiol Menschen Tiere
42: 517 (1888).
2. Stebbing ARD. Hormesis--the stimulation of growth by low levels of
inhibitors. Sci Total Environ 22: 213-234 (1982).
3. Townsend JF, Luckey TD. Hormoligosis in pharmacology. J Am Med Assoc
173: 44-48 (1960).
4. Luckey TD. Hormology with inorganic compounds. In: Heavy Metal Toxicity,
Safety, and Hormology, Supplement Volume 1 (Coulston F, Korte F, eds).
Stuttgart:George Thieme, 1975; 83-118.
5. Calabrese EJ, McCarthy M, Kenyon E. The occurrence of chemical
hormesis. Health Phys 57: 531-54 (1987).
6. Calabrese EJ. Primer on BELLE. In: Biological Effects of Low Level
Exposures: Dose-Response Relationships (Calabrese EJ, ed). Boca Raton,
FL:CRC/Lewis Publishers, 1994; 27-42.
7. Davis JM, Svendsgaard DJ. Nonmonotonic dose-response relationships in
toxicological studies. In: Biological Effects of Low Level Exposures:
Dose-Response Relationships (Calabrese EJ, ed). Boca Raton, FL:CRC/Lewis
Publishers, 1994; 67-86.
8. Davis JM, Svendsgaard DJ. U-shaped dose-response curves: their
occurrence and implications for risk assessment. J Toxicol Environ Health
30: 71-83 (1990).
9. Calabrese EJ, Howe KJ. Stimulation of growth of peppermint (Mentha
piperita) by phosfon, a growth retardant. Physiol Plant 37: 163-165 (1976).
10. Calabrese EJ. Unpublished data.
11. Calabrese EJ, Baldwin LA, Mehendale HM. Contemporary issues in
toxicology: G2 subpopulation in rat liver induced into mitosis by low level
exposure to carbon tetrachloride: an adaptive response. Toxicol Appl
Pharmacol 121: 1-7 (1993).
12. Calabrese EJ, Mehendale HM. A review of the role of tissue repair as an
adaptive strategy: why low doses are often non-toxic and why high doses can
be fatal. Food Chem Toxicol 34: 301-311 (1996).
13. Hart RW, Frame LT. Toxicological defense mechanisms and how they may
affect the nature of dose-response relationships. BELLE Newslett 5: 1-16
(1996).
14. Mukherjee SN, Rawal SK, Ghumare SS, Sharma RN. Hormetic
concentrations of azadirachtin and isoesterase profiles in Tribolium
castraneum (Herbst) (Coleoptera:Tenebrionidae). Experientia 49: 557-560
(1993).
15. Vichi P, Tritton TR. Stimulation of growth in human and murine cells by
adriamycin. Cancer Res 49: 2679-2682 (1989).
16. Calabrese EJ, Baldwin LA. Quantitatively-based methodology for the
evaluation of chemical hormesis. Hum Ecol Risk Assess 4: 545-554 (1997).
*******************************************************************
Rich Murray, MA Room For All rmforall@...
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-986-9103
http://groups.yahoo.com/group/aspartameNM/message/1039
three-page review: aspartame (methanol, formaldehyde) toxicity:
Murray 11.22.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1026
brief aspartame review: formaldehyde toxicity: Murray 9.11.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/989 On 4.10.2003
the European Union Parliament voted 440 to 20 to approve sucralose,
limit cyclamates & reevaluate aspartame & stevia: Murray 4.12.3 rmforall
http://google.com gives 221,000 websites for "aspartame" , with the top
9 of 10 listings being anti-aspartame, while
http://groups.google.com finds on 700 MB of posts from 20 years of
Usenet groups, 83,800 posts, the top 10 being anti-aspartame.aspartame
(methanol, formaldehyde) toxicity: Murray 1.24.4 rmforall
http://news.google.com 28 recent aspartame items from 4500 sources.
http://www.AllTheWeb.com gives 291,700, the top 7 of 10 being
leading and very well informed volunteer anti-aspartame sites.
http://teoma.com/index.asp gives 85,700 websites, top 8 of 10 anti.
http://www.ncbi.nlm.nih.gov/PubMed lists 742 aspartame items.
http://groups.yahoo.com/group/aspartameNM/message/1025
aspartame & formaldehyde toxicity: Murray 9.9.3 rmforall
http://groups.yahoo.com/group/aspartameNM/messages
for 1056 posts in a public searchable archive 125 members
http://groups.yahoo.com/group/aspartame/messages 759 with 16,425 posts
http://groups.yahoo.com/group/aspartameNM/message/1047
Avoiding Hangover Hell 12.31.3 Mark Sherman, AP writer: Robert Swift, MD:
[formaldehyde from methanol in aspartame]: Murray 1.16.4 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1048
hangovers from formaldehyde from methanol (aspartame?):
Schwarcz: Linsley: Murray 1.18.4
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 7.12.1: Murray 1.22.4 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1024
aspartame review: methanol, formaldehyde, formic acid toxicity:
Murray 9.5.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall
It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time are partially eliminated as carbon dioxide and water.
However, about 30% of the methanol remains in the body as cumulative
durable toxic metabolites of formaldehyde and formic acid-- 37 mg daily,
a gram every month. [Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
J. Nutrition 1973 Oct; 103(10): 1454-1459.]
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA daily limit for formaldehyde in water.
Bear in mind that the EPA limit for formaldehyde in drinking water is
1 ppm, or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and
leading to vision and eye problems, and even seizures. In many cases
there is addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.
http://groups.yahoo.com/group/aspartameNM/message/872
immune system reactions due to formaldehyde from the 11% methanol in
aspartame: Thrasher: Tephly: Monte: Murray 9.27.2 rmforall
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
They found that about 70% of the radioactive methanol in aspartame put
into the stomachs of 3 to 7 kg monkeys was eliminated within 8 hours,
with little additional elimination, as carbon dioxide in exhaled air
and as water in the urine. They did not mention
that this meant that about 30% of the methanol must transform
into formaldehyde and then into formic acid, both of which must remain
as toxic products in all parts of the body. They did not report any
studies on the distribution of radioactivity in body tissues, except
that blood plasma proteins after 4 days held 4% of the initial
methanol. This study did not monitor long-term use of aspartame.
The low oral dose of aspartame and for methanol was 0.068 mmol/kg,
about 1 part per million [ppm] of the acute toxicity level of 2,000
mg/kg, 67,000 mmol/kg, used by McMartin (1979). Two L daily use of
diet soda provides 123 mg methanol, 2 mg/kg for a 60 kg person, a dose
of 67 mmole/kg, a thousand times more than the dose in this study.
By eight hours excretion of the dose in air and urine had leveled off
at 67.1 +-2.1% as CO2 in the exhaled air and 1.57+-0.32% in the urine,
so 68.7 % was excreted, and 31.3% was retained. [This data is the
average of 4 monkeys.]
http://groups.yahoo.com/group/aspartameNM/message/915
formaldehyde toxicity: Thrasher & Kilburn: Shaham: EPA: Gold: Murray:
Wilson: CIIN: 12.12.2 rmforall
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.
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: 12.9.2 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1016
President Bush & formaldehyde (aspartame) toxicity: Ramazzini Foundation
carcinogenicity results Dec 2002: Soffritti: Murray 8.3.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1037
Joe Trippi, heavy user of Diet Pepsi (aspartame toxicity), Dean's campaign
manager: Murray 11.16.3 rmforall
http://groups.yahoo.com/group/aspartameNM/message/927
Rumsfeld, 1977 head of Searle Corp., got aspartame FDA approval:
Turner: Murray 12.23.2 rmforall
********************************************************************
|
Tue Jan 27, 2004 11:36 pm
"Rich Murray" <rmforall@...>
rmforall
 Offline
 Send Email
|
|
Having problems with message search?
Fill out this form to ensure your group is one of the first to be migrated to the new message search system.
