folic acid prevents neurotoxicity from formic acid, made by body from
methanol impurity in alcohol drinks [ also 11 % of aspartame ], BM
Bhushan, PL Carlen, DC Lehotay, AC Vandenbroucke, Y Adamchik, U. of
Toronto, 2007 Dec., Alcoholism Cl. Exp. Res.: Murray 2007.11.27
http://rmforall.blogspot.com/2007_11_01_archive.htm
Wednesday, November 27, 2007
http://groups.yahoo.com/group/aspartameNM/message/1495
http://www.faslink.org/Formic%20Acid%20Kapur.htm
Brief Summary:
Methanol in small amounts is present along with ethanol in beverage
alcohol. [Murray: and about the same amounts from aspartame diet sodas]
The body's natural enzymes preferentially metabolize ethanol while
methanol breaks down into highly neurotoxic Formic Acid.
Use of high levels of Folic Acid was found to inhibit brain damage
caused by the methanol.
The use of Folic Acid during pregnancy has been recommended for several
years to prevent neural tube defects.
However, this study indicates that even higher levels of Folic Acid can
be very beneficial to the developing baby, particularly where alcohol
exposure is a factor.
Folic Acid is mandated as an additive to all flour sold in Canada.
The debate has begun on its required addition to all beverage alcohol to
help mitigate damage caused to both infants and adults.
Formic Acid in the Drinking patient and the expectant mother
Dr. Bhushan M. Kapur
Departments of Laboratory Medicine,
St. Michael's Hospital , Toronto, Ontario, Canada
Abstract
Methanol is produced endogenously in the pituitary glands of humans and
is present as a congener in almost all alcoholic beverages.
Ethanol and methanol are both bio-transformed by alcohol dehydrogenase;
however, ethanol has greater affinity for the enzyme.
Since ethanol is preferentially metabolized by the enzyme, it is not
surprising that trace amounts of methanol, most likely originating from
both sources, have been reported in the blood of people who drink alcohol.
Toxicity resulting from methanol is very well documented in both humans
and animals and is attributed to its toxic metabolite formic acid.
To understand ethanol toxicity and Fetal Alcohol Spectrum Disorders, it
is important to consider methanol and its metabolite, formic acid, as
potential contributors to the toxic effects of alcohol.
Accumulation of methanol suggests that alcohol-drinking population
should have higher than baseline levels of formic acid.
Our preliminary studies do indeed show this.
Chronic low-level exposure to methanol has been suggested to impair
human visual functions.
Formic acid is known to be toxic to the optic nerve.
Ophthalmological abnormalities are a common finding in children whose
mothers used alcohol during pregnancy.
Formic acid, a low molecular weight substance, either crosses the
placenta or may be formed in-situ from the water soluble methanol that
crosses the placenta.
Embryo toxicity from formic acid has been reported in an animal model.
To assess neurotoxicity we applied low doses of formic acid to rat brain
hippocampal slice cultures.
We observed neuronal death with a time and dose response.
Formic acid requires folic acid as a cofactor for its elimination.
Animal studies have shown that when folate levels are low, the
elimination of formic acid is slower and formate levels are elevated.
When folic acid was added along with the formic acid to the brain slice
cultures, neuronal death was prevented.
Therefore, folate deficient chronic drinkers may be at higher risk of
organ damage.
Women who are folic acid deficient and consume alcohol may have higher
levels of formic acid and should they become pregnant, their fetus may
be at risk.
To our knowledge low level chronic exposure to formic acid and its
relationship to folic acid in men or women who drink alcohol has never
been studied.
Our hypothesis is that the continuous exposure to low levels of formic
acid is toxic to the fetus and may be part of the etiology of Fetal
Alcohol Spectrum Disorders.
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1530-0277.2007.00541.x
Alcoholism: Clinical and Experimental Research
Volume 31 Issue 12 Page 2114-2120, December 2007
Bhushan M. Kapur,
b.kapur@...,
Arthur C. Vandenbroucke, PhD, FCACB
Yana Adamchik,
Denis C. Lehotay,
dlehotay@...,
Peter L. Carlen
carlen@...,
(2007) Formic Acid, a Novel Metabolite of Chronic Ethanol Abuse, Causes
Neurotoxicity, Which Is Prevented by Folic Acid
Alcoholism: Clinical and Experimental Research 31 (12), 2114–2120.
doi:10.1111/j.1530-0277.2007.00541.x
From:
the Department of Clinical Pathology (BMK),
Sunnybrook Health Science Centre, Division of Clinical Pharmacology and
Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada;
St. Michael’s Hospital (ACV), Toronto, Canada; Department of Laboratory
Medicine and Pathobiology (BMK, ACV),
Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;
Departments of Medicine (Neurology) and Physiology (YA, PLC),
Toronto Western Research Institute, University of Toronto,
Toronto, Ontario, Canada;
and University of Saskatchewan (DLC), Saskatchewan, Canada.
Reprint requests: Dr. Bhushan M. Kapur, Department of Clinical
Pathology, Sunnybrook Health Science Centre, 2075 Bayview Ave,
Toronto, Ontario, M4N 3M5, Canada; Fax: 416-813-7562; E-Mail:
k.kapur@...,
Abstract
Background: Methanol is endogenously formed in the brain and is present
as a congener in most alcoholic beverages.
Because ethanol is preferentially metabolized over methanol (MeOH) by
alcohol dehydrogenase, it is not surprising that MeOH accumulates in the
alcohol-abusing population.
This suggests that the alcohol-drinking population will have higher
levels of MeOH’s neurotoxic metabolite, formic acid (FA).
FA elimination is mediated by folic acid.
Neurotoxicity is a common result of chronic alcoholism.
This study shows for the first time that FA, found in chronic
alcoholics, is neurotoxic
and this toxicity can be mitigated by folic acid administration.
Objective:
To determine if FA levels are higher in the alcohol-drinking population
and to assess its neurotoxicity in organotypic hippocampal rat brain
slice cultures.
Methods:
Serum and CSF FA was measured in samples from both ethanol abusing and
control patients, who presented to a hospital emergency department.
FA’s neurotoxicity and its reversibility by folic acid were assessed
using organotypic rat brain hippocampal slice cultures using clinically
relevant concentrations.
Results:
Serum FA levels in the alcoholics
(mean ± SE: 0.416 ± 0.093 mmol/l, n = 23) were significantly higher than
in controls (mean ± SE: 0.154 ± 0.009 mmol/l, n = 82) (p < 0.0002).
FA was not detected in the controls’ CSF (n = 20),
whereas it was >0.15 mmol/l in CSF of 3 of the 4 alcoholic cases.
Low doses of FA from 1 to 5 mmol/l added for 24, 48 or 72 hours to the
rat brain slice cultures caused neuronal death as measured by propidium
iodide staining.
When folic acid (1 micromol/l) was added with the FA, neuronal death was
prevented.
Conclusions:
Formic acid may be a significant factor in the neurotoxicity of ethanol
abuse.
This neurotoxicity can be mitigated by folic acid administration at a
clinically relevant dose.
http://www.uhnresearch.ca/researchers/profile.php?lookup=801
Peter L Carlen, FRCPC, MD
Head, Division of Fundamental Neurobiology
Toronto Western Research Institute (TWRI)
Senior Scientist, Division of Fundamental Neurobiology
Toronto Western Research Institute (TWRI)
Keywords: stroke, gap junctions, synaptic transmission, mitochondria,
calcium chelators, whole cell patch clamp recordings, fluorescence
imaging, epilepsy, dementia, fetal alcohol syndrome, brain state
classification
Research Interests:
Mechanisms of neural synchrony and entrainment (epilepsy), and
neurodegenerative processes
* We have several projects on cellular mechanisms of epilepsy,
particularly the synchronizing role of electrotonic coupling via gap
junctions.
Molecular biological and cellular electrophysiological recording
techniques are being used to measure the upregulation of gap junctional
function in several in vitro seizure models, including the use of the
intact mouse hippocampus preparation.
Also a project on the pathogenesis of hypoglycemic seizures is in progress.
* In collaboration with Drs. Berj Bardakjian and Frances Skinner,
the linear and nonlinear electrical and network properties of central
mammalian neurons in physiological and pathophysiological conditions
(e.g., epilepsy) are being described by neural modelling techniques.
We are developing nonlinear techniques for the identification different
brain states including those associated with anesthesia and epilepsy.
* In models of stroke and Alzheimer's disease, calcium homeostasis
and free radical production are under investigation, focusing on the
role of degenerating mitochondrial function in presynaptic terminals.
Fluorescence and confocal microscopic imaging of intracellular calcium
and mitochondrial function coupled with whole cell and field
electrophysiological recordings are being used.
* In collaboration with Drs. Bhushan Kapur, James Reynolds and
James Brien, we are examining the role of formic acid in the causation
of the brain damage in the fetal alcohol spectrum disorder and its
rescue by folate.
Peter L Carlen
Mailing Address
Primary Office
Toronto Western Hospital, McLaughlin Pavilion, 12th Floor Rm. 413
399 Bathurst St., Toronto, Ontario Canada M5T 2S8
Email
carlen@...,
Phone Numbers 416.603.5800 x5044
Staff and Trainees:
Yana Adamchik
Marija Cotic
Youssef El-Hayek
S Sabet Jahromi
Eunji (Ellen) Kang
Borna Kavousi
Philip Liang
Shanthi Mylvaganam
Marina Samoilova
Evan Sheppy
Damian Shim
Alexandre Tonkikh
Hui Ye
Wilson Yu
Zhang (Jane) Zhang
http://www.clinpharmtox.utoronto.ca/Page60.aspx
Dr. Bhushan Kapur
Selected Publications
Kapur BM. Drug Testing Methods and Clinical Interpretation of Test
Results. In: Carson-Dewitt R, ed. Encyclopedia of Drugs, Alcohol and
Addictive Behaviour. Vol 1. Macmillian Press; 2001, p. 450-461.
Kapur B, Hackman R, Selby P, Klein J, Koren G.
A randomized, double-blind placebo control trial of nicotine replacement
therapy in pregnancy. Current Therapeutic Research 2001; 62(4): 274-278.
Bailey B, Lalkin A, Kapur B, Koren G. Is chronic poisoning with
acetaminophen in children a frequent occurrence in Toronto?
Can J Clin Pharmacol 2001; 8(2): 96-101. [Read More]
Ho E, Collantes A, Kapur B, Moretti M, Koren G. Alcohol and breast
feeding: Calculation of time to reach zero-level in milk.
Biol Neonate 2001; 80(3): 219-222. [Read More]
[ Dr. Gideon Koren
Division of Clinical Pharmacology and Toxicology, Hospital for Sick
Children, 555 University Ave., Toronto, Ont. M5G 1X8 (Canada)
Tel. +1 416 813 5781, Fax +1 416 813 7562
E-Mail
gkoren@...,
pharmtox@..., ]
Kapur B, Koren G. Folic acid fortification of flour: three years later.
Can J Clin Pharmacol 2001; 8(2): 91-92. [Read More]
Ahn E, Kapur B, Koren G. Iron bioavailability in prenatal multivitamin
supplements with separated and combined iron and calcium.
J Obstet Gynaecol Can 2004; 26(9):809-14. [Read More]
Railton CJ, Kapur B, Koren G. Subtherapeutic risperidone serum
concentrations in an adolescent during hemodialysis: A pharmacological
puzzle.
Ther Drug Monit 2005; 27(5):558-561. [Read More]
Lehotay DC, George S, Etter ML, Graybiel K, Eichhorst JC, Fern B,
Wildenboer W, Selby P, Kapur B.
Free and bound enantiomers of methadone and its metabolite, EDDP in
methadone maintenance treatment: Relationship to dosage?
Clin Biochem 2005; 38(12): 1088-1094. [Read More]
Langman L, Kapur B. Toxicology-then and now.
Clin Biochem 2006; 39(5):498-510.
Kapur BM, Vandenbroucke A, Adamchik Y, Lehotay DC, Carlen PL.
Formic acid, a novel metabolite of chronic ethanol abuse: neurotoxicity
and its prevention by folic acid.
Submitted to Alcohol Clin Exp Res, April 30, 2007.
http://www.medicalnewstoday.com/articles/45698.php
Queen's-led Network Looks At FAS Aiming To Minimize Life-long Learning
Problems
Main Category: Pregnancy / Obstetrics News
Article Date: 24 Jun 2006 - 12:00 PDT
For the first time researchers are testing to see whether fetal exposure
to methanol, a contaminant found in many alcoholic beverages, plays an
important role in causing the life-long learning and behavioural
problems associated with Fetal Alcohol Spectrum Disorders (FASD).
By understanding fetal brain injury caused by exposure to methanol and
related toxins, an emerging team of researchers is laying the groundwork
for potential new therapeutic interventions to protect fetuses at risk
for FASD.
"The main goal will always be prevention of FASD," says lead researcher
James Reynolds, Queen's University professor of Toxicology and
Pharmacology, "but we also have to develop strategies to minimize injury
to the developing fetus and individualize earlier therapeutic
interventions for children with pre-natal exposure to alcohol."
The interdisciplinary research team, which also includes
James Brien and Doug Munoz from Queen's,
Peter Carlen (University Health Network),
Bhushan Kapur (Sunnybrook Hospital)
and Brenda Stade (St. Michael's Hospital) from Toronto,
received just under $1.5 million dollars in funding
from the Canadian Institutes of Health Research.
The Queen's researchers have found that simple eye movement tasks can be
used to assess brain function in children with FASD. Since this
technology is portable, the researchers plan to travel across the
country to bring the research program into affected communities. "It's
estimated that the incidence of FASD is about one per cent in the
general population," Dr. Reynolds says, "but there are regions and
communities in this country where the population affected by FASD
increases dramatically."
Using blood samples from at risk mother-baby pairs, the Toronto team
members hope to identify biological markers that may predict brain
injury in the child. At risk babies will be tracked for 24 months
following birth so researchers can identify early signs of FASD and
develop aggressive therapeutic interventions at earlier stages to
minimize the effects on a child's development.
To understand the underlying mechanisms of this novel hypothesis of
FASD, the Toronto team members are studying the effects of formic acid
and folic acid on the biological functions and survival of neurons in
isolated brain tissue. In parallel studies, the Kingston team will
assess the efficacy of folic acid supplementation as a potential
therapeutic intervention in preventing FASD.
For these researchers, an exciting opportunity has been created by
linking this study with Queen's University's state-of-the-art Magnetic
Resonance Imaging (MRI) facility. New experimental procedures being
developed at Queen's will link eye movement tasks to MRI images of the
brain, creating an objective and much more specific way to evaluate
brain function. By isolating individual brain responses, FASD
researchers hope to gain greater insight into the underlying brain
injury caused by prenatal exposure to alcohol, leading to more specific
intervention therapies designed to minimize the affects of FASD.
"Not all children exposed to alcohol during prenatal life develop FASD,"
adds Dr. Reynolds. "There are other contributing factors including
genetic predisposition and nutrition during gestation that make
important contributions to the ultimate outcome. We need a way to
identify the different sub-groups within the FASD spectrum. This
research will help us develop the standardized tools we need to evaluate
and treat children with FASD."
----------------------------
Article adapted by Medical News Today from original press release.
----------------------------
Contacts:
Lorinda Peterson, 613-533-3234,
lorinda.peterson@...,
Nancy Dorrance, 613-533-2869,
dorrance@...,
Contact: Lorinda Peterson
name: James N Reynolds
email:
jnr@...,
phone: 613 533 6946
campus_extension: 36946
department: Pharmacology and Toxicology
type: Faculty
name: James F Brien
email:
brienj@...,
phone: 613 533 6114
campus_extension: 36114
department: Pharmacology and Toxicology, School of Medicine, Psychiatry
type: Faculty
Dr. Douglas P. Munoz
doug@...,
Canada Research Chair in Neuroscience
Director, Centre for Neuroscience Studies
Professor of Physiology and Psychology
Member, CIHR Group in Sensory-Motor Systems
Queen's University, Kingston, Ontario, Canada K7L 3N6
Phone: (613) 533-2111 Fax: (613) 533-6840
Dr. Brenda Stade St. Michael’s Hospital Fetal Alcohol Spectrum Disorder
Diagnostic Clinic 61 Queen Street Toronto, Ontario M5B 1W8
Tel: (416) 867- 3655
stadeb@...,
http://www.faslink.org/toc2.htm
FASlink
2448 Hamilton Road, Bright's Grove, Ontario, Canada N0N 1C0
Phone: (519) 869-8026 E-mail:
info@...,
Fetal Alcohol Spectrum Disorders (FASD),
Fetal Alcohol Syndrome (FAS),
Fetal Alcohol Effects (FAE),
Partial Fetal Alcohol Syndrome (pFAS),
Alcohol Related Neurodevelopmental Disorders (ARND),
Static Encephalopathy (alcohol exposed) (SE)
and Alcohol Related Birth Defects (ARBD)
are all names for a spectrum of disorders
caused when a pregnant woman consumes alcohol
FASlink CD -- more than 170 MB of information.
While "officially" FASD is not a diagnosis but describes the broad range
of disorders caused by prenatal alcohol exposure, the reality is that
FASD IS the diagnosis and the other terms are sub-diagnoses describing
the specific effects on a specific patient.
"St. Michael's Hospital, Fetal Alcohol Spectrum Disorder Clinic is
pleased to support the work of FASlink.
St. Michael's FASD Clinic views FASlink as an essential service for our
clients.
We are fortunate to partner with FASlink in our attempt to improve the
lives of individuals and their families with FASD.
Dr. Brenda Stade, St. Michael's FASD Clinic" St. Michael's Hospital is a
teaching hospital affiliated with The University of Toronto.
FASD Overview
Invisible Disabilities -- An individual’s place, and success, in society
is almost entirely determined by neurological functioning.
A child with a brain injury is unable to meet the expectations of
parents, family, peers, school, career and can endure a lifetime of
failures.
The largest cause of brain injury in children is prenatal exposure to
alcohol.
Often the neurological damage goes undiagnosed, but not unpunished.
There are strategies that can work to help the child with an FASD
compensate for some difficulties.
Early diagnosis and intensive intervention and tutoring can do wonders,
but the need for a supportive structure is permanent.
Report on FASD -- Exposure Rates, Results of Prenatal Exposure to
Alcohol, and Incidence Markers -- Bruce Ritchie - February 2, 2007
(PDF download 1.2 MB)
37% of babies have been exposed to multiple episodes of binge drinking
(5+ drinks per session) during pregnancy.
An additional 42% have been multiply exposed to 1 to 4 drinks per
session during pregnancy.
Prenatal alcohol exposure has been linked to more than 60 disease
conditions, birth defects and disabilities.
Damage is a diverse continuum from mild intellectual and behavioural
issues to profound disabilities or premature death.
Prenatal alcohol damage varies due to volume ingested, timing during
pregnancy, peak blood alcohol levels, genetics and environmental factors.
For example, ethanol was found to interact with over 1000 genes and cell
events, including cell signalling, transport and proliferation.
Serotonin suppression causes loss of neurons and glia, inducing
excessive cell death during normal programmed death (apoptosis) or
triggering apoptosis at inappropriate times leading to smaller or
abnormal brain structures with fewer connections between brain cells,
leading to fewer cells for dopamine production, leading to problems with
addiction, memory, attention and problem solving, and more pronounced
conditions such as schizophrenia.
Approximately 20% of Canadian school age children are receiving special
education services, most for conditions of the types known to be caused
by prenatal alcohol exposure.
As FASD is a diverse continuum, issues range from almost imperceptible
to profound.
It is somewhere in the middle that the issues attract the attention of
parents, educators, medical and social work professionals, and
eventually the justice system.
Most of the issues that attract sufficient attention are behavioural and
performance issues.
It is probable that about 15% of children are significantly enough
affected by prenatal alcohol exposure to require special education.
As they become adults, FASD does not disappear but the issues of youth
translate into ongoing problems in family relationships, employment,
mental health and justice conflicts.
The cost to the individuals affected, their families and society are
enormous and as a society, we cannot afford to ignore them.
To ignore the facts does not change the facts.
Most girls are 2 to 3 months pregnant before they find out.
Maternal prenatal alcohol consumption even at low levels is adversely
related to child behavior.
The effect was observed at average exposure levels as low as 1 drink per
week.
FASD Prevention
Folic acid should be added to all beverage alcohol.
Break the cycle. Properly fund addiction intervention and rehabilitation
programs.
Identify women at risk of having children with FASD and intervene.
Meconium testing for Fatty Acid Ethyl Esters should be mandatory for
every birth.
Intensive family and social service supports for FASD and recovering
alcoholics.
Poverty is a result of, and breeds, substance abuse. Deal with it.
Alcohol Vendors
The beverage alcohol industry pays less than 1% of the total damages
caused by their products. Increase taxes on beverage alcohol.
All tax revenue to be returned to support rehabilitation programs and
victims of alcohol.
Remove all incentives for governments to promote alcohol.
End all government supports for beverage alcohol industry, including
"wine and beer tourism".
End all alcohol advertising
Alcohol must be served with food.
Breathalyzers in all alcohol establishments
Ban alcohol sales incentives, contests, games.
Ban "Happy Hour" discounted promotions. They encourage binge drinking.
Public Education
Educate the public that addiction is a medical issue not a moral failure.
Educate children from a very young age about dangers of alcohol.
Have youth design anti-alcohol programs targeting youth.
The ONLY purpose of beverage alcohol is to make your brain take a hike.
Research
Better diagnostic tools for the full range of FASD damage.
True incidence and scaling of FASD damage.
Chemically turn-off addiction center in brain.
FASlink began online in 1995.
FASlink's website contains more than 110,000 searchable FASD related
documents and serves more than 400,000 visitors annually.
The FASlink Discussion Forum shares 50 to 100 letters daily and compiles
the papers and discussions into the FASlink Archives.
Our membership is worldwide but most are in Canada and the USA, from the
most remote locations to urban centers.
http://www.faslink.org/faslink.htm
The FASlink Discussion Forum is a free Internet maillist for
individuals, families and professionals who deal with Fetal Alcohol
Spectrum Disorders.
FASlink provides support and information 24/7.
FASlink has the largest archive of FASD information in the world.
FASlink serves parents (birth, foster and adoptive), caregivers, adults
with FASD, doctors, teachers, social workers, lawyers, students and
government policy makers, etc.
Bruce Ritchie is the Moderator.
To join FASlink, go to
http://listserv.rivernet.net/mailman/listinfo/fas-link
Once you have subscribed, to send mail to the FASlink members, send it
to:
fas-link@...
info@... sends email directly to the Moderator, Bruce Ritchie
////////////////////////////////////////////////////////////
The aspartame content of two liters diet soda, 5.6 12-oz cans, is 1,120
mg, releasing 11 % as 123 mg methanol.
Usually, there is not a concurrent larger amount of ethanol taken, which
would prevent the production of formaldehyde.
So, the methanol from any aspartame is quickly turned into formaldehyde.
An expert review by a competent, unbiased team led by M. Bouchard, 2001,
cites references, many from aspartame industry funded studies, states
that about 30 - 40 % of the methanol remains in the body as unknown,
durable reaction products.
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 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.
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. "...the 14C in the feces was
negligible."
"That fraction not so excreted (about 31%) was converted to body
constituents through the one-carbon metabolic pool." "All radioactivity
measurements were counted to +-1 % accuracy..."
The abstract ends, "It was concluded that aspartame was digested to its
three constituents that were then absorbed as natural constituents of
the diet."
http://health.groups.yahoo.com/group/aspartameNM/message/1143
http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169
"Exposure to methanol also results from the consumption of certain
foodstuffs (fruits, fruit juices, certain vegetables, aspartame
sweetener, roasted coffee, honey) and alcoholic beverages (Health
Effects Institute, 1987; Jacobsen et al., 1988)."
"Experimental studies on the detailed time profiles following controlled
repeated exposures to methanol are lacking."
"Thus, in monkeys and plausibly humans, a much larger fraction of body
formaldehyde is rapidly converted to unobserved forms rather than passed
on to formate and eventually CO2."
"However, the volume of distribution of formate was larger than that of
methanol, which strongly suggests that formate distributes in body
constituents other than water, such as proteins."
http://groups.yahoo.com/group/aspartameNM/message/1143
methanol (formaldehyde, formic acid) disposition: Bouchard M et al, full
plain text, 2001: substantial sources are degradation of fruit pectins,
liquors, aspartame, smoke: Murray 2005.04.02
http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169
Toxicological Sciences 64, 169-184 (2001) Copyright © 2001 by the
Society of Toxicology BIOTRANSFORMATION AND TOXICOKINETIC A Biologically
Based Dynamic Model for Predicting the Disposition of Methanol and Its
Metabolites in Animals and Humans
Michèle Bouchard *, ^,1,
bouchmic@...,
Robert C. Brunet, ^^
brunet@...,
Pierre-Olivier Droz, ^
and Gaétan Carrier *
gaetan.carrier@...,
* Department of Environmental and Occupational Health, Faculty of
Medicine,
Université de Montréal, P.O. Box 6128, Main Station, Montréal, Québec,
Canada, H3C 3J7;
^ Institut Universitaire romand de Santé au Travail, rue du Bugnon 19,
CH-1005, Lausanne, Switzerland, and
^^ Département de Mathématiques et de Statistique and Centre de
Recherches Mathématiques, Faculté des arts et des sciences, Université
de Montréal, P.O. Box 6128, Main Station, Montréal, Québec, Canada, H3C 3J7
1 To whom correspondence should be addressed at Département de santé
environnementale et santé au travail, Université de Montréal, P.O. Box
6128, Main Station, Montréal, Québec, H3C 3J7, Canada. Fax: (514) 343-2200.
Received May 10, 2001; accepted August 28, 2001
"However, the severe toxic effects are usually associated with the
production and accumulation of formic acid, which causes metabolic
acidosis and visual impairment that can lead to blindness and death at
blood concentrations of methanol above 31 mmol/l (Røe, 1982; Tephly and
McMartin, 1984; U.S. DHHS, 1993).
Although the acute toxic effects of methanol in humans are well
documented, little is known about the chronic effects of low exposure
doses, which are of interest in view of the potential use of methanol as
an engine fuel and current use as a solvent and chemical intermediate.
Gestational exposure studies in pregnant rodents (mice and rats) have
also shown that high methanol inhalation exposures (5000 or 10,000 ppm
and more, 7 h/day during days 6 or 7 to 15 of gestation) can induce
birth defects (Bolon et al., 1993; IPCS, 1997; Nelson et al., 1985)."
"The corresponding average elimination half-life of absorbed methanol
through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and
1.7 h."
"Inversely, in monkeys and in humans, a larger fraction of body burden
of formaldehyde is rapidly transferred to a long-term component.
The latter represents the formaldehyde that (directly or after oxidation
to formate) binds to various endogenous molecules..."
"Animal studies have reported that systemic methanol is eliminated
mainly by metabolism (70 to 97% of absorbed dose) and only a small
fraction is eliminated as unchanged methanol in urine and in the expired
air (< 3-4%) (Dorman et al., 1994; Horton et al., 1992).
Systemic methanol is extensively metabolized by liver alcohol
dehydrogenase and catalase-peroxidase enzymes to formaldehyde, which is
in turn rapidly oxidized to formic acid by formaldehyde dehydrogenase
enzymes (Goodman and Tephly, 1968; Heck et al., 1983; Røe, 1982; Tephly
and McMartin, 1984).
Under physiological conditions, formic acid dissociates to formate and
hydrogen ions.
Current evidence indicates that, in rodents, methanol is converted
mainly by the catalase-peroxidase system whereas monkeys and humans
metabolize methanol mainly through the alcohol dehydrogenase system
(Goodman and Tephly, 1968; Tephly and McMartin, 1984).
Formaldehyde, as it is highly reactive, forms relatively stable adducts
with cellular constituents (Heck et al., 1983; Røe, 1982)."
"The whole body loads of methanol, formaldehyde, formate, and unobserved
by-products of formaldehyde metabolism were followed.
Since methanol distributes quite evenly in the total body water,
detailed compartmental representation of body tissue loads was not
deemed necessary."
"According to model predictions, congruent with the data in the
literature (Dorman et al., 1994; Horton et al., 1992), a certain
fraction of formaldehyde is readily oxidized to formate, a major
fraction of which is rapidly converted to CO2 and exhaled, whereas a
small fraction is excreted as formic acid in urine.
However, fits to the available data in rats and monkeys of Horton et al.
(1992) and Dorman et al. (1994) show that, once formed, a substantial
fraction of formaldehyde is converted to unobserved forms.
This pathway contributes to a long-term unobserved compartment.
The latter, most plausibly, represents either the formaldehyde that
(directly or after oxidation to formate) binds to various endogenous
molecules (Heck et al., 1983; Røe, 1982) or is incorporated in the
tetrahydrofolic-acid-dependent one-carbon pathway to become the building
block of a number of synthetic pathways (Røe, 1982; Tephly and McMartin,
1984).
That substantial amounts of methanol metabolites or by-products are
retained for a long time is verified by Horton et al. (1992) who
estimated that 18 h following an iv injection of 100 mg/kg of
14C-methanol in male Fischer-344 rats, only 57% of the dose was
eliminated from the body.
From the data of Dorman et al. (1994) and Medinsky et al. (1997), it
can further be calculated that 48 h following the start of a 2-h
inhalation exposure to 900 ppm of 14C-methanol vapors in female
cynomolgus monkeys, only 23 % of the absorbed 14C-methanol was
eliminated from the body.
These findings are corroborated by the data of Heck et al. (1983)
showing that 40 % of a 14C-formaldehyde inhalation dose remained in the
body 70 h postexposure.
In the present study, the model proposed rests on acute exposure data,
where the time profiles of methanol and its metabolites were determined
only over short time periods (a maximum of 6 h of exposure and a maximum
of 48 h postexposure).
This does not allow observation of the slow release from the long-term
components.
It is to be noted that most of the published studies on the detailed
disposition kinetics of methanol regard controlled short-term (iv
injection or continuous inhalation exposure over a few hours) methanol
exposures in rats, primates, and humans (Batterman et al., 1998; Damian
and Raabe, 1996; Dorman et al., 1994; Ferry et al., 1980; Fisher et al.,
2000; Franzblau et al., 1995; Horton et al., 1992; Jacobsen et al.,
1988; Osterloh et al., 1996; Pollack et al., 1993; Sedivec et al., 1981;
Ward et al., 1995; Ward and Pollack, 1996).
Experimental studies on the detailed time profiles following controlled
repeated exposures to methanol are lacking."
"Thus, in monkeys and plausibly humans, a much larger fraction of body
formaldehyde is rapidly converted to unobserved forms rather than passed
on to formate and eventually CO2."
"However, the volume of distribution of formate was larger than that of
methanol, which strongly suggests that formate distributes in body
constituents other than water, such as proteins.
The closeness of our simulations to the available experimental data on
the time course of formate blood concentrations is consistent with the
volume of distribution concept (i.e., rapid exchanges between the
nonblood pool of formate and blood formate)."
"Also, background concentrations of formate are subject to wide
interindividual variations (Baumann and Angerer, 1979; D'Alessandro et
al., 1994; Franzblau et al., 1995; Heinrich and Angerer, 1982; Lee et
al., 1992; Osterloh et al., 1996; Sedivec et al., 1981)."
http://groups.yahoo.com/group/aspartameNM/message/1286
methanol products (formaldehyde and formic acid) are main cause of
alcohol hangover symptoms [same as from similar amounts of methanol, the
11% part of aspartame]: YS Woo et al, 2005 Dec: Murray 2006.01.20
Addict Biol. 2005 Dec;10(4): 351-5. Concentration changes of methanol in
blood samples during an experimentally induced alcohol hangover state.
Woo YS, Yoon SJ, Lee HK, Lee CU, Chae JH, Lee CT, Kim DJ. Chuncheon
National Hospital, Department of Psychiatry, The Catholic University of
Korea, Seoul, Korea. [ Han-Kyu Lee ]
A hangover is characterized by the unpleasant physical and mental
symptoms that occur between 8 and 16 hours after drinking alcohol.
After inducing experimental hangover in normal individuals, we measured
the methanol concentration prior to and after alcohol consumption and we
assessed the association between the hangover condition and the blood
methanol level.
A total of 18 normal adult males participated in this study.
They did not have any previous histories of psychiatric or medical
disorders.
The blood ethanol concentration prior to the alcohol intake
(2.26+/-2.08) was not significantly different from that 13 hours after
the alcohol consumption (3.12+/-2.38).
However, the difference of methanol concentration between the day of
experiment (prior to the alcohol intake) and the next day (13 hours
after the alcohol intake) was significant (2.62+/-1.33/l vs.
3.88+/-2.10/l, respectively).
[ So, the normal methanol level was 2.62 mg per liter, and increasing
that by 50% = 1.3 mg per liter to 3.88 mg per liter caused hangover
symptoms.
The human body has about 5.6 liters blood, so adding 1.3 mg per liter
gives an estimate of 7.3 mg added methanol, as much as 4 oz diet soda.
Diet soda is about 200 mg aspartame per 12 oz can, which is 22 mg (11%
methanol), 1.83 mg methanol per ounce.
Also, this 50 % increase in blood methanol that caused roughly similar
symptoms in South Koreans, Woo YS, 2005, as in men in Swedem who had a
6-fold increase in urine methanol, confirms many studies that show that
specific genetic differences make Asians and American Indians much more
vulnerable to inebriation, hangover, and addiction than Europeans.
Bendtsen P, Jones AW, Helander A. 1998 ]
A significant positive correlation was observed between the changes of
blood methanol concentration and hangover subjective scale score
increment when covarying for the changes of blood ethanol level
(r=0.498, p<0.05).
This result suggests the possible correlation of methanol as well as its
toxic metabolite to hangover. PMID: 16318957
[ The "toxic metabolite" of methanol is formaldehyde, which in turn
partially becomes formic acid -- both potent cumulative toxins that are
the actual cause of the toxicity of methanol.]
Int J Neurosci. 2003 Apr; 113(4): 581-94. The effects of alcohol
hangover on cognitive functions in healthy subjects. Kim DJ, Yoon SJ,
Lee HP, Choi BM, Go HJ. Department of Psychiatry, College of Medicine,
Catholic University of Korea, Buchon City, Kyunggi Do, Korea.
A hangover is characterized by the constellation of unpleasant physical
and mental symptoms that occur between 8 and 16 h after drinking alcohol.
We evaluated the effects of experimentally-induced alcohol hangover on
cognitive functions using the Luria-Nebraska Neuropsychological Battery.
A total of 13 normal adult males participated in this study.
They did not have any previous histories of psychiatric or medical
disorders.
We defined the experimentally-induced hangover condition at 13 h after
drinking a high dose of alcohol (1.5 g/kg of body weight).
We evaluated the changes of cognitive functions before drinking alcohol
and during experimentally-induced hangover state.
The Luria-Nebraska Neuropsychological Battery was administrated in order
to examine the changes of cognitive functions.
Cognitive functions, such as visual, memory, and intellectual process
functions, were decreased during the hangover state.
Among summary scales, the profile elevation scale was also increased.
Among localization scales, the scores of left frontal, sensorimotor,
parietal-occipital dysfunction, and right parietal-occipital scales were
increased during the hangover state.
These results indicate that alcohol hangovers have a negative effect on
cognitive functions, particularly on the higher cortical and visual
functions associated with the left hemisphere and right posterior
hemisphere. Publication Types: Clinical Trial PMID: 12856484
Alcohol Alcohol. 1998 Jul-Aug; 33(4): 431-8. Urinary excretion of
methanol and 5-hydroxytryptophol as biochemical markers of recent
drinking in the hangover state.
Bendtsen P,
prebe@...,
Jones AW,
Helander A.
Anders.Helander@...,
Drug Dependence Unit, University Hospital, Linkoping, Sweden.
Twenty healthy social drinkers (9 women and 11 men) drank either 50 g of
ethanol (mean intake 0.75 g/kg) or 80 g (mean 1.07 g/kg) according to
choice as white wine or export beer in the evening over 2 h with a meal.
After the end of drinking, at bedtime, in the following morning after
waking-up, and on two further occasions during the morning and early
afternoon, breath-alcohol tests were performed and samples of urine were
collected for analysis of ethanol and methanol and the
5-hydroxytryptophol (5-HTOL) to 5-hydroxyindol-3-ylacetic acid (5-HIAA)
ratio.
The participants were also asked to quantify the intensity of hangover
symptoms (headache, nausea, anxiety, drowsiness, fatigue, muscle aches,
vertigo) on a scale from 0 (no symptoms) to 5 (severe symptoms).
The first morning urine void collected 6-11 h after bedtime as a rule
contained measurable amounts of ethanol, being 0.09 ± 0.03 g/l (mean ±
SD) after 50 g and 0.38 ± 0.1 g/l after 80 g ethanol.
The corresponding breath-alcohol concentrations were zero, except for
three individuals who registered 0.01-0.09g/l.
Ethanol was not measurable in urine samples collected later in the
morning and early afternoon.
The peak urinary methanol occurred in the first morning void, when the
mean concentration after 80 g ethanol was approximately 6-fold higher
than pre-drinking values.
[ This is a much greater increase of methanol than the 50 % increase
that cause roughly similar symptoms in South Koreans, Woo YS, 2005,
confirming many studies that show that specific genetic differences make
Asians and American Indians much more vulnerable to inebriation,
hangover, and addiction. ]
This compares with a approximately 50-fold increase for the
5-HTOL/5-HIAA ratio in the first morning void.
Both methanol and the 5-HTOL/5-HIAA ratio remained elevated above
pre-drinking baseline values in the second and sometimes even the third
morning voids.
Most subjects experienced only mild hangover symptoms after drinking 50
g ethanol (mean score 2.4 ± 2.6), but the scores were significantly
higher after drinking 80 g (7.8 ± 7.1).
The most common symptoms were headache, drowsiness, and fatigue.
A highly significant correlation (r = 0.62-0.75, P <0.01) was found
between the presence of headache, nausea, and vertigo and the urinary
methanol concentration in the first and second morning voids, whereas
5-HTOL/5-HIAA correlated with headache and nausea.
These results show that analysing urinary methanol and 5-HTOL furnishes
a way to disclose recent drinking after alcohol has no longer been
measurable by conventional breath-alcohol tests for at least 5-10 h.
The results also support the notion that methanol may be an important
factor in the aetiology of hangover. PMID: 9719404
////////////////////////////////////////////////////////////
http://groups.yahoo.com/group/aspartameNM/message/1067
eyelid contact dermatitis by formaldehyde from aspartame, AM Hill & DV
Belsito, Nov 2003: Murray 4.4.4 rmforall [ 150 KB ]
[ Extracts ]
McMartin, KE et al 1979, put 3,000 mg/kg methanol in the stomachs of
small monkeys and, 18 hours later found accumulation of formate in
liver, kidney, optic nerve, cerebrum, and midbrain in 2 of three monkeys.
Biochemical Pharmcacology 1979: 28; 645-649.
Lack of a role for formaldehyde in methanol poisoning in the monkey.
Kenneth E. McMartin, Gladys Martin-Amat, Patricia E. Noker
and Thomas R. Tephly
The Toxicology Center, Dept. of Pharmacology,
University of Iowa, Iowa City, Iowa 52242
K.E. McMartin and T.R. Tephly, authors of many pro-aspartame studies, in
Biochemical Pharmacology (1979) remarked, "It is now generally accepted
that the toxicity of methanol is due to the formation of toxic
metabolites, either formaldehyde or formic acid."
They put damage doses of methanol into the stomachs of three monkeys,
and, using insensitive tests, found no formaldehyde in many tissues --
except for a single datum in the midbrain,
1.5 times their detection limit.
They did report widespread accumulation of formic acid in five tissues.
The use of inadequate tests is common in industry research that is
funded to claim the safety of profitable toxins.
Since then, industry scientists have been very wary of doing studies on
primates, which all too easily show the dangers to humans.
"Abstract [ not given in PubMed ]: [ My briefer comments are in square
brackets. ]
Methanol was administered [ by nasogastric tube ] either to untreated
cynomolgus monkeys [ 2-3.5 kg ] or to a folate-deficient cynomolgus
monkey which exhibits exceptional sensitivity to the toxic effects of
methanol.
Marked formic acid accumulation in the blood and in body fluids and
tissues was observed.
No formaldehyde accumulation was observed in the blood and no
formaldehyde was detected in the urine, cerebrospinal fluid, vitreous
humor, liver, kidney, optic nerve, and brain in these monkeys at a time
when marked metabolic acidosis and other characteristics of methanol
poisoning were observed.
Following intravenous infusion into the monkey, formaldehyde was rapidly
eliminated from the blood with a half-life of about 1.5 min and formic
acid levels promptly increased in the blood.
Since formic acid accumulation accounted for the metabolic acidosis and
since ocular toxicity essentially identical to that produced in methanol
poisoning has been described after formate treatment, the predominant
role of formic acid as the major metabolic agent for methanol toxicity
is certified.
Also, results suggest that formaldehyde is not a major factor in the
toxic syndrome produced by methanol in the monkey."
"It is now generally accepted that the toxicity of methanol is due to
the formation of toxic metabolites (1,2), either formaldehyde or formic
acid."
So, this is an acute toxicity study, with little relevance for chronic
long-term, low-level exposure.
Monkeys, like people, are susceptible to methanol toxicity.
This team cites their six previous methanol in monkey studies,
from 1975 to 1977.
The report is difficult to understand, since the three monkeys were
treated differently, and different assays were used.
For the methanol sensitive, folate-deficient monkey A, the assay used
was the chromatropic acid method, with a detection limit of .025 mmol/L.
None of the five tissues showed any formaldehyde with this assay, except
the midbrain, 0.14 mmol/kg wet weight tissue [ units converted from
their 0.14 micromole/gm -- just 1.5 times the detection limit of .09
mmol/kg wet tissue weight (given on p. 648).
[ Since 1 kg of water is 1 L, 1 mmol/kg is equivalent to 1 mmol/L. ]
Meanwhile, in the methanol sensitive, folate-deficient monkey A, the
blood formate level rose by 18 hours from 0.18 to 10.02 mEq/L. [ I
assume that a mEq is equivalent to a mmol -- let me know if I'm wrong. ]
The formate detection limits for the assays were not given in this report.
The formate level in the vitreous humor of the eye of monkey A was 7.90
mEq/L.
It is well known that formate is extremely damaging to the eye.
For unexplained reasons, formate levels in the five tissues and
cerebrospinal fluid were not measured in the methanol sensitive,
folate-deficient monkey A., in the cerebrospinal fluid of monkey B,
or in the optic nerve of monkey C.
Formaldehyde was not measured in the optic nerve of Monkey A.
The kidney formate level for monkey B was 6.33 and for C was only 0.44,
with no comment or explanation given.
The experiment seems arbitrary, capricious, and erratic.
For monkey A, after 18 hours, the urine formaldehyde level was below
detection level, while urine formate was 115.80 mEq/L -- so much of the
formaldehyde had been converted into formic acid, another cumulative,
potent toxin.
"In the presence of high formate values and definitive evidence of
toxicity in methanol-poisoned monkeys, no measurable formaldehyde was
found in the body tissues that were tested."
It is reasonable to surmise that more sensitive assays would have found
formaldehyde and formate bound to and reacted with a variety of cellular
substances in all tissues -- just as the 1998 Trocho study confirmed.
(Appendix E)
Monkeys B and C were normal, not extra vulnerable to methanol, and were
given 3,000 mg/kg methanol, and samples taken at 18 hr.
Formaldehyde was detected only in the blood of Monkey B, while formate
was found in 8 and 10, respectively, of the 10 fluid and tissue samples
in Monkeys B and C.
For instance, the lowest value of formate, except for zero-time blood,
for each monkey was in the midbrain, 2.16 mmol/kg for Monkey B (24 times
the detection limit for the chromatropic acid method) and 1.02 mmol/kg
(1.3 times the detection for the dimedon method) for Monkey C.
This shows accumulation of formate in liver, kidney, optic nerve,
cerebrum, and midbrain.
"Thus, whereas one can associate formate intimately with ocular toxicity
in the monkey, no association of formaldehyde with ocular toxicity can
be made at this time.
It is not possible to completely eliminate formaldehyde as a toxic
intermediate because formaldehyde could be formed slowly within cells
and interfere with normal cellular function without ever obtaining
levels that were detectable in body fluids..."
"Acknowledgements-- This research was supported by NIH grant GM 19420
and GM 12675." [not funded by the industry]
Life Sci 1991; 48(11): 1031-41. The toxicity of methanol. Tephly TR.
Department of Pharmacology, University of Iowa, Iowa City 52242.
"Abstract:
Methanol toxicity in humans and monkeys is characterized by a latent
period of many hours followed by a metabolic acidosis and ocular toxicity.
This is not observed in most lower animals.
The metabolic acidosis and blindness is apparently due to formic acid
accumulation in humans and monkeys, a feature not seen in lower animals.
The accumulation of formate is due to a deficiency in formate metabolism
which is, in turn, related, in part, to low hepatic tetrahydrofolate (H4
folate).
An excellent correlation between hepatic H4 folate and formate oxidation
rates has been shown within and across species.
Thus, humans and monkeys possess low hepatic H4 folate levels, low rates
of formate oxidation and accumulation of formate after methanol.
Formate, itself, produces blindness in monkeys in the absence of
metabolic acidosis.
In addition to low hepatic H4 folate concentrations, monkeys and humans
also have low hepatic 10-formyl H4 folate dehydrogenase levels, the
enzyme which is the ultimate catalyst for conversion of formate to
carbon dioxide.
This review presents the basis for the role of folic acid-dependent
reactions in the regulation of methanol toxicity.
Publication Types: Review Review, Academic PMID: 1997785"
p. 1035 "In the past, formaldehyde has often been suggested as the
methanol metabolite which produces toxicity (34,35).
Today, a great deal of information is available concerning its lack of
such a role.
The presence of elevated formaldehyde levels in body fluids or tissues
following methanol administration has not been observed.
No formaldehyde has been detected in blood, urine or tissues obtained
from methanol-treated animals (36,37) and,
in methanol-poisoned humans, formaldehyde increases have not been
observed....
About 85% of a low dose of 14C-formaldehyde [radioactive label] is
excreted as pulmonary 14CO2 (49,50)....."
[ This suggests that 15% of the formaldehyde is indeed retained in the
body, a very significant result, considering its extreme and complex
toxicity. ]
49. W.B. Neely, Biochem. Pharmacol. 13: 1137-1142 (1964).
50. Xenobiotica 1982 Feb; 12(2): 119-24.
Formaldehyde metabolism by the rat: a re-appraisal.
Mashford PM, Jones AR.
1. The metabolism of [14C]formaldehyde has been investigated in the male
Sprague-Dawley rat.
It is extensively oxidized to CO2 and formate, which is excreted in the
urine.
2. Two radioactive compounds isolated from the urine of rats dosed with
[14C]formaldehyde have been identified as N-(hydroxymethyl)urea and
N,N'-bis-(hydroxymethyl)urea, and shown to be urinary artefacts.
3. Previous studies of the metabolism of formaldehyde by rats have been
re-appraised.
Differences in the rate of oxidation of formaldehyde in various strains
of rats result in the excretion of different urinary metabolites and, in
some cases, formaldehyde.
Excretion of formaldehyde leads to the formation of several artefacts
depending on the components present in the urine. PMID: 6806997
////////////////////////////////////////////////////////////
details on 6 epidemiological studies since 2004 on diet soda (mainly
aspartame) correlations, as well as 14 other mainstream studies on
aspartame toxicity since summer 2005: Murray 2007.11.27
http://rmforall.blogspot.com/2007_11_01_archive.htm
Wednesday, November 14, 2007
http://groups.yahoo.com/group/aspartameNM/message/1490
"Of course, everyone chooses, as a natural priority, to enjoy peace,
joy, and love by helping to find, quickly share, and positively act upon
evidence about healthy and safe food, drink, and environment."
Rich Murray, MA Room For All
rmforall@...
505-501-2298 1943 Otowi Road, Santa Fe, New Mexico 87505
http://RMForAll.blogspot.com new primary archive
http://groups.yahoo.com/group/aspartameNM/messages
group with 113 members, 1,495 posts in a public archive
http://rmforall.blogspot.com/2007_09_01_archive.htm
Saturday, September 15, 2007
http://groups.yahoo.com/group/aspartameNM/message/1472
bias, omissions, incuriosity = opportunity, aspartame safety evaluation,
Magnuson BA, Burdock GA, Williams GM, 7 more, 2007 Sept, Ajinomoto
funded 98 pages html [$ 32 781888262_content.pdf]: Murray 2007.09.15
////////////////////////////////////////////////////////////
http://groups.yahoo.com/group/aspartameNM/message/1491
industry scientists praise aspartame safety and benefits in Paris on
2006.05.30, Herve Nordmann, Andrew G. Renwick, Carlo La Vecchia, Tommy
Visscher, Jaap Seidell, France Bellisle, Adam Drewnowski, Margaret
Ashwell, Anne de la Hunty, Sigrid A. Gibson, Alan R. Boobis: Murray
2007.11.18
[ This layman review gives detailed access to the gist of six
epidemiological studies since 2004, two in 2007, that show correlations
of diet soda (largely aspartame) with health issues.
Probably studies of the correlations at the top 0.1 to 1.0 % level of
use over periods of years by people in vulnerable groups are needed.
http://groups.yahoo.com/group/aspartameNM/message/1141
Nurses Health Study can quickly reveal the extent of aspartame
(methanol, formaldehyde, formic acid) toxicity: Murray 2004.11.21
The Nurses Health Study is a bonanza of information about the health of
probably hundreds of nurses who use 6 or more cans daily of diet soft
drinks -- they have also stored blood and tissue samples from their
immense pool of subjects, over 100,000 for decades.
In total, there are 20 mainstream studies about negative effects with
aspartame since summer, 2005, listed in this review, included many about
the detailed biochemistry involved. ]
////////////////////////////////////////////////////////////
http://RMForAll.blogspot.com September 21, 2007
http://groups.yahoo.com/group/aspartameNM/message/1475
19,000 people, the 4% of users of aspartame who drink average 5 cans
daily, have more problems in NIH AARP study of 474,000 people: Murray
2007.09.21
This is the first good data about the percentage of aspartame users who
use over 3 cans daily, averaging 5 cans daily at 200 mg per 12 oz can
diet soda.
About 4% of 473,984 is 19,000 people, with a peak intake of 17 cans
daily, and average 5 cans daily.
It would be worthwhile to investigate a wide variety of symptoms for the
0.1% of highest level users, about 500 people.
For about 200 million USA aspartame users, this would be 200,000 people.
Table 1 reveals consistent increase in problems from
--------------------- zero to (400 - 600) to (over 600) mg/d
aspartame intake:
% of cohert ---------- 46 -------- 5 -------- 4 %
mean aspartame mg/d --- 0 -------441 ------ 986
16+ education -------- 37 ------- 40 ------- 34 %
diabetes history ------ 3 ------- 22 ------- 26 %
alcohol g/d ---------- 14 ------- 11 ------- 13
never smoke ---------- 36 ------- 31 ------- 29 %
Body Mass Index ------ 26 ------- 29 ------- 29
18.5 - 25 ------------ 42 ------- 21 ------- 19 %
30 - 35 -------------- 13 ------- 23 ------- 26 %
over 35 --------------- 4 ------- 10 ------- 13 %
Physical activity %:
under 3-4/mo --------- 32 ------- 32 ------- 37 %
under 1-2/wk --------- 22 ------- 21 ------- 19 %
over 3-4/wk ---------- 45 ------- 45 ------- 43 %
Calories kcal ----- 1,919 ---- 1,855 ---- 2,044 %
Caffeine mg/d ------- 393 ------ 364 ------ 424
There do seem to be many increases of problems
from the second to third row, as mean aspartame use doubles.
Granted, this is cherry picking the data, selecting interesting patterns.
Correlations alone do not prove any direction of causation.
Nevertheless, it may be of value to study the correlations for
increasing aspartame intake among the 4 % using over 600 mg, the
equivalent of 3 cans 12-oz cans diet soda daily.
The average use for this group is 5 cans daily.
For instance, are a minority of these heavy users displaying the great
majority of the problems that are reflected in the mean for each level
of use, with most users only having little or no increase in problems?
This is a group of about 20,000 people.
"We cannot exclude the possibility that higher aspartame consumption
than that observed in this study may be associated with an elevated risk
of hematopoietic or brain cancers."
http://cebp.aacrjournals.org/cgi/content/full/15/9/1654 free full text
http://cebp.aacrjournals.org/cgi/reprint/15/9/1654 free full text pdf
Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1654-1659,
September 2006
© 2006 American Association for Cancer Research
Consumption of Aspartame-Containing Beverages and Incidence of
Hematopoietic and Brain Malignancies
Unhee Lim 1,
Amy F. Subar 2,
subara@...,
Traci Mouw 1,
Patricia Hartge 1,
Lindsay M. Morton 1,
Rachael Stolzenberg-Solomon 1,
David Campbell 3,
Albert R. Hollenbeck 4
and Arthur Schatzkin 1
1 Division of Cancer Epidemiology and Genetics,
2 Division of Cancer Control and Population Sciences, National Cancer
Institute, NIH, Department of Health and Human Services;
3 Information Management Services, Inc., Rockville, Maryland; and
4 AARP, Washington, District of Columbia
Requests for reprints: Amy Subar,
Division of Cancer Control and Population Sciences,
National Cancer Institute,
6130 Executive Boulevard, EPN 4005, Rockville, MD 20852-7344.
Phone: 301-594-0831; Fax: 301-435-3710. E-mail:
subara@...,
BACKGROUND:
In a few animal experiments, aspartame has been linked to hematopoietic
and brain cancers.
Most animal studies have found no increase in the risk of these or other
cancers.
Data on humans are sparse for either cancer.
Concern lingers regarding this widely used artificial sweetener.
OBJECTIVE:
We investigated prospectively whether aspartame consumption is
associated with the risk of hematopoietic cancers or gliomas (malignant
brain cancer).
METHODS:
We examined 285,079 men and 188,905 women ages 50 to 71 years in the
NIH-AARP Diet and Health Study cohort
Daily aspartame intake was derived from responses to a baseline
self-administered food frequency questionnaire that queried consumption
of four aspartame-containing beverages (soda, fruit drinks, sweetened
iced tea, and aspartame added to hot coffee and tea) during the past year.
Histologically confirmed incident cancers were identified from eight
state cancer registries.
Multivariable-adjusted relative risks (RR) and 95% confidence intervals
(CI) were estimated using Cox proportional hazards regression that
adjusted for age, sex, ethnicity, body mass index, and history of diabetes.
RESULTS:
During over 5 years of follow-up (1995-2000), 1,888 hematopoietic
cancers and 315 malignant gliomas were ascertained.
Higher levels of aspartame intake were not associated with the risk of
overall hematopoietic cancer
(RR for >/=600 mg/d, 0.98; 95% CI, 0.76-1.27),
glioma (RR for >/=400 mg/d, 0.73; 95% CI, 0.46-1.15;
P for inverse linear trend = 0.05),
or their subtypes in men and women.
CONCLUSIONS:
Our findings do not support the hypothesis that aspartame increases
hematopoietic or brain cancer risk. PMID: 16985027
"We cannot exclude the possibility that higher aspartame consumption
than that observed in this study may be associated with an elevated risk
of hematopoietic or brain cancers.
In the laboratory study with positive findings, animals were fed doses
starting from 4 mg up to 5,000 mg per kg body weight.
Significantly elevated lymphomas and leukemias were observed in female
rats fed 20 mg of aspartame and higher (e.g., 1,200 mg for humans
weighing 60 kg or 132 lb; refs. 13, 14).
The reported aspartame intake in our data ranged from 0 to 3,400 mg/d
with sparse numbers in the upper intake categories
(1,200 or 2,000 mg/d, which is equivalent to ~7 to 11 cans of soft
drinks daily) compared with the lowest categories,
and the associations were similarly null in both men and women."
////////////////////////////////////////////////////////////
http://RMForAll.blogspot.com October 12, 2007
http://groups.yahoo.com/group/aspartameNM/message/1479
13,620 seniors using more than 1 can/week artificially sweetened
[aspartame] soft drinks had 8% higher death risk, 1981-2004,
Paganini-Hill A, Kawas CH, Corrada MM, U. Southern Cal., Prev. Med. 2007
April 44(4) 305-10: Murray 2007.10.12
"Individuals who drank more than 1 can/week of artificially sweetened
(but not sugar-sweetened) soft drink (cola and other) had an 8 %
increased risk (95 % CI: 1.01-1.16)."
"The increased death risk with consumption of artificially sweetened,
but not sugar-sweetened, soft drinks suggests an effect of the sweetener
rather than other components of the soft drinks, although residual
confounding remains a possibility."
Prev Med. 2007 Apr; 44(4): 305-10. Epub 2006 Dec 29.
Non-alcoholic beverage and caffeine consumption and mortality: the
Leisure World Cohort Study.
Paganini-Hill A,
annliahi@...,
Kawas CH,
ckawas@...,
Corrada MM.
mcorrada@...,
Department of Preventive Medicine, Keck School of Medicine of the
University of Southern California, CA, USA.
OBJECTIVE:
To examine the effects of non-alcoholic beverage and caffeine
consumption on all-cause mortality in older adults.
METHODS:
The Leisure World Cohort Study is a prospective study of residents of a
California retirement community.
A baseline postal health survey included details on coffee, tea, milk,
soft drink, and chocolate consumption.
Participants were followed for 23 years (1981-2004).
Risk ratios (RRs) of death were calculated using Cox regression for 8644
women and 4980 men (median age at entry, 74 years) and adjusted for age,
gender, and multiple potential confounders.
RESULTS:
Caffeine consumption exhibited a U-shaped mortality curve.
Moderate caffeine consumers had a significantly reduced risk of death
(multivariable-adjusted RR = 0.94, 95 % CI: 0.89, 0.99 for 100-199 mg/day
and RR = 0.90, 95 % CI: 0.85, 0.94 for 200-399 mg/day
compared with those consuming <50 mg/day).
Individuals who drank more than 1 can/week of artificially sweetened
(but not sugar-sweetened) soft drink (cola and other) had an 8 %
increased risk (95 % CI: 1.01-1.16).
Neither milk nor tea had a significant effect on mortality after
multivariable adjustment.
CONCLUSIONS:
Moderate caffeine consumption appeared beneficial in reducing risk of death.
Attenuation in the observed associations between mortality and intake of
tea and milk with adjustment for potential confounders suggests that
such consumption identifies those with other mortality-associated
lifestyle and health risks.
The increased death risk with consumption of artificially sweetened, but
not sugar-sweetened, soft drinks suggests an effect of the sweetener
rather than other components of the soft drinks, although residual
confounding remains a possibility. PMID: 17275898
Age Ageing. 2007 Mar; 36(2): 203-9.
Type of alcohol consumed, changes in intake over time and mortality: the
Leisure World Cohort Study.
Paganini-Hill A, Kawas CH, Corrada MM.
Department of Preventive Medicine,
Keck School of Medicine of University of Southern California, USA.
annliahi@...
BACKGROUND:
modifiable behavioural risk factors including smoking and alcohol
consumption are major contributing or actual causes of mortality.
OBJECTIVE:
to examine the effect of alcohol intake on all-cause mortality in older
adults.
Design and SETTING:
prospective population-based cohort study of residents of a California,
United States retirement community.
SUBJECTS:
8,877 women and 5,101 men (median age, 74 years) who in the early 1980s
completed a postal health survey incluing details on alcohol consumption.
METHODS:
participants were followed for 23 years (1981-2004) including two
follow-up questionnaires (in 1992 and 1998) asking about current alcohol
intake.
Age-adjusted and multivariate-adjusted risk ratios of death and 95 %
confidence intervals were calculated separately for men and women, using
proportional hazard regression.
RESULTS:
of the 8,644 women and 4,980 men with complete information on the
variables of interest and potential confounders,
6,930 women and 4,456 men had died (median age, 87 years).
Both men and women who drank alcohol had decreased mortality compared
with non-drinkers.
Those who drank two or more drinks per day had a 15 % reduced risk of death.
The reduced risk was not limited to one type of alcohol.
Stable drinkers (those who reported drinking both at baseline and
follow-up) had a significantly decreased risk of death compared with
stable non-drinkers.
Those who started drinking at follow-up also had a significantly lower risk.
Women who quit drinking were at increased risk of death.
CONCLUSION:
in elderly men and women, moderate alcohol intake exhibits a beneficial
effect on mortality.
Those who quit may do so for health reasons that affect mortality.
PMID: 17350977
////////////////////////////////////////////////////////////
" Analyses that used food frequency questionnaire data suggested that
intake of over 1 drink per day of either regular or diet soft drinks was
associated with a over 50% higher incidence of metabolic syndrome
compared with intake of under 1 soft drink per week.
" Although the association of high fructose corn syrup intake and
insulin resistance may be a contributory mechanism, 31 in the present
study, both regular and diet soft drinks appeared to pose similar
metabolic hazards,
which suggests that other factors may be operational. "
" The caramel content of both regular and diet drinks may be a potential
source of advanced glycation end products, 5 which may promote insulin
resistance 36 and can be proinflammatory. 37 "
" It is conceivable, though,
that there may be residual confounding caused by lifestyle factors not
adjusted for in the present analyses. "
" As noted above, it is conceivable that residual confounding by
lifestyle/dietary factors not adjusted for may have contributed to the
metabolic risks associated with soft drink intake. "
" The similar metabolic hazard posed by both regular and diet soft
drinks is noteworthy given the lack of calories in the latter; however,
other studies have also reported associations of diet soft drinks with
weight gain in boys 29 and with hypertension in adult women. 7 "
29. Berkey CS, Rockett HRH, Field AE, Gillman MW, Colditz GA.
Sugar-added beverages and adolescent weight change.
Obesity Res. 2004; 12: 778–788.[Abstract/Free Full Text]
7. Winkelmayer WC, Stampfer MJ, Willett WC, Curhan GC.
Habitual caffeine intake and the risk of hypertension in women.
JAMA. 2005; 294: 2330–2335.[Abstract/Free Full Text]
http://circ.ahajournals.org/cgi/content/full/116/5/480 free full text
[ Extracts ]
doi:10.1161/CIRCULATIONAHA.107.689935
CLINICAL PERSPECTIVE
Circulation. 2007; 116: 480-488.
© 2007 American Heart Association, Inc.
Epidemiology
Circulation. 2007 Jul 31; 116(5): 480-8. Epub 2007 Jul 23.
Soft drink consumption and risk of developing cardiometabolic risk
factors and the metabolic syndrome in middle-aged adults in the community.
Ravi Dhingra, MD;
Lisa Sullivan, PhD;
Paul F. Jacques, PhD;
Thomas J. Wang, MD;
Caroline S. Fox, MD;
foxca@...,
James B. Meigs, MD, MPH;
Ralph B. D’Agostino, PhD;
J. Michael Gaziano, MD, MPH;
Ramachandran S. Vasan, MD
vasan@...,
From the National Heart, Lung, and Blood Institute’s Framingham Heart
Study (R.D., T.J.W., C.S.F., R.S.V.), Framingham, Mass;
Massachusetts Veterans Epidemiology Research and Information Center
(R.D., J.M.G.), VA Boston Healthcare System, Boston, Mass;
Division of Aging (R.D., J.M.G.), Brigham and Women’s Hospital, Harvard
Medical School, Boston, Mass; Alice Peck Day Memorial Hospital (R.D.),
Lebanon, NH;
Department of Biostatistics (L.S., R.B.D.), Boston University School of
Public Health, Boston, Mass;
Jean Mayer USDA Human Nutrition Research Center on Aging (P.F.J.), Tufts
University, Boston, Mass; Division of Cardiology (T.J.W.) and Department
of Medicine (J.B.M.), Massachusetts General Hospital, Harvard Medical
School, Boston, Mass;
National Heart, Lung, and Blood Institute (C.S.F.), Bethesda, Md;
Divisions of Preventive Medicine and Cardiovascular Medicine (J.M.G.),
Brigham and Women’s Hospital, Boston, Mass;
and Cardiology Section and the Department of Preventive Medicine and
Epidemiology (R.S.V.), Boston University School of Medicine, Boston, Mass.
Correspondence to Ramachandran S. Vasan, MD, Framingham Heart Study, 73
Mount Wayte Ave, Suite 2, Framingham, MA 01702-5803.
vasan@...,
Received January 12, 2007; accepted May 15, 2007.
BACKGROUND:
Consumption of soft drinks has been linked to obesity in children and
adolescents, but it is unclear whether it increases metabolic risk in
middle-aged individuals.
METHODS AND RESULTS:
We related the incidence of metabolic syndrome and its components to
soft drink consumption in participants in the Framingham Heart Study
(6,039 person-observations, 3,470 in women; mean age 52.9 years) who
were free of baseline metabolic syndrome.
Metabolic syndrome was defined as the presence of over of the following:
waist circumference over 35 inches (women) or over 40 inches (men);
fasting blood glucose over 100 mg/dL;
serum triglycerides over 150 mg/dL;
blood pressure over 135/85 mm Hg;
and high-density lipoprotein cholesterol under 40 mg/dL (men)
or under 50 mg/dL (women).
Multivariable models included adjustments for age, sex, physical
activity, smoking, dietary intake of saturated fat, trans fat, fiber,
magnesium, total calories, and glycemic index.
Cross-sectionally, individuals consuming over 1 soft drink per day had a
higher prevalence of metabolic syndrome
(odds ratio [OR], 1.48; 95 % CI, 1.30 to 1.69)
than those consuming under 1 drink per day.
On follow-up (mean of 4 years), new-onset metabolic syndrome developed
in 765 (18.7 %) of 4095 participants consuming under 1 drink per day and
in 474 (22.6 %) of 2059 persons consuming over 1 soft drink per day.
Consumption of over 1 soft drink per day
was associated with increased odds of developing
metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74),
obesity (OR, 1.31; 95 % CI, 1.02 to 1.68),
increased waist circumference (OR, 1.30; 95 % CI, 1.09 to 1.56),
impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48),
higher blood pressure (OR, 1.18; 95 % CI, 0.96 to 1.44),
hypertriglyceridemia (OR, 1.25; 95 % CI, 1.04 to 1.51), and
low high-density lipoprotein cholesterol
(OR, 1.32; 95 % CI 1.06 to 1.64).
CONCLUSIONS:
In middle-aged adults, soft drink consumption is associated with a
higher prevalence and incidence of multiple metabolic risk factors.
PMID: 17646581
Key Words: diabetes mellitus • metabolic syndrome • epidemiology •
obesity • risk factors • carbonated beverages
* Introduction
Several reports from the United States and Europe indicate increasing
consumption of soft drinks among children, adolescents, and adults over
the past 3 decades. 1,2
Many clinical studies have linked the rising consumption of soft drinks
to the present epidemic of obesity and diabetes mellitus among children
and adolescents 3–6 and to the development of hypertension in adults. 7
Furthermore, added sweeteners in soft drinks have been linked to an
increase in serum triglycerides levels in some reports 8,9 but not in
others. 10,11
The association of soft drink consumption with obesity and higher
insulin resistance has been attributed to multiple factors, including
greater caloric intake, the high fructose corn syrup content, 12 less
satiety and compensation, and a general effect of consuming refined
carbohydrates (see review by Drewnowski and Bellisle 13).
The aforementioned data raise the possibility that the consumption of
soft drinks can fuel metabolic derangements, including insulin
resistance, that can translate into a greater risk of developing
abdominal obesity, high triglyceride levels, low levels of high-density
lipoprotein cholesterol (HDL-C), elevated blood pressure, and impaired
glucose tolerance; this constellation of metabolic traits has been
collectively referred to as the metabolic syndrome. 14
Higher prevalence of the metabolic syndrome poses greater risk for
cardiovascular disease in the community, 15 although the independent
contribution of this entity to vascular risk beyond its components has
been questioned 16
In the present prospective investigation, we tested the hypothesis that
greater soft drink consumption increases the risk of developing
metabolic risk factors (alone and in combination [metabolic syndrome])
in middle-aged adults in the community.
Additionally, we evaluated whether metabolic risk varied on the basis of
consumption of sugar-sweetened ("regular") versus artificially sweetened
("diet") soft drinks.
* Methods
Study Sample
The Framingham Heart Study began in 1948 with the enrollment of 5,209
participants into the original study cohort. 17
In 1971, children of the original cohort participants and the spouses of
the children were enrolled into the Framingham Offspring Study (n=5,124). 18
Offspring study participants are evaluated approximately every 4 years.
Information on daily consumption of soft drinks was collected via a
physician-administered questionnaire at each study visit from the fourth
(1987–1991) through the sixth (1995–1998) examination cycles.
That examination questionnaire did not elicit information regarding
consumption of regular versus diet soft drinks; however, such
information was available from the self-administered food frequency
questionnaires (FFQ; Willett questionnaire) 19 completed by participants
at the fifth (1992–1995) and sixth examination cycles (see below).
For the present investigation, we selected offspring cohort participants
who attended any 2 consecutive examinations from the fourth through the
seventh (1998–2001) examination cycles.
We excluded participants with missing data on covariates (n = 207) and
those with prevalent cardiovascular disease (n = 926).
After exclusions, a total of 8997 person-observations (4871 in women)
were eligible for the cross-sectional analyses.
For prospective analyses, we excluded individuals with baseline
metabolic syndrome (n = 2897 person-observations; metabolic syndrome as
defined below) and those with any missing metabolic syndrome components
on follow-up (n = 61 person-observations).
The schema for selection of individuals eligible for cross-sectional and
longitudinal analyses is displayed in the Figure.
All participants provided written informed consent, and the protocol for
the study was approved by institutional review board of Boston Medical
Center.
Figure 1185095
Selection of study sample from baseline examinations using the
examination cola questionnaire and from the sample with available FFQ
data (within parentheses, for examinations 5 and 6).
Eligible participants and exclusions are indicated in the Figure.
CVD indicates cardiovascular disease.
Measurement of Covariates
At each Framingham Heart Study examination, participants provided a
medical history and underwent a complete standardized physical
examination that included anthropometry, blood pressure measurements,
and laboratory assessment of vascular risk factors.
Fasting levels of blood glucose, triglycerides, and HDL-C were measured
with standard assays.
Blood pressure was measured by a physician using a mercury
sphygmomanometer and with the participant resting in a seated position
for 5 minutes; the average of 2 readings obtained on the participant’s
left arm constituted the examination blood pressure.
Physical activity was assessed by calculating a "physical activity
index"; participants were asked specific questions regarding how many
hours in a typical day they spent sitting, sleeping, or performing
light-moderate or heavy physical activities. 20
Alcohol intake was assessed by averaging the number of alcoholic
beverages consumed per week.
Participants who reported smoking 1 or more cigarettes per day in the
year before the Framingham Heart Study examination were considered
current smokers.
Assessment of Soft Drink Consumption and Dietary Intake of Other Foods
At the index examinations, participants reported the average number of
12-oz servings of soft drinks (Coke, Pepsi, Sprite, or other carbonated
soft drinks, separately categorized into caffeinated or decaffeinated
drinks) consumed per day in the year preceding the examination.
The responses to the questions were entered as integers (0 or more)
separately for caffeinated and decaffeinated soft drinks.
This questionnaire (referred to as the "examination cola questionnaire")
did not separate nondrinkers from infrequent drinkers (<1 drink per day).
Accordingly, we compared individuals who reported consuming 1, over 1,
or over 2 soft drinks per day with attendees who reported consuming
under 1 soft drink per day (infrequent drinkers and nondrinkers, who
served as the referent).
Intake of regular and diet soft drinks was assessed from FFQs 19 that
were administered at the fifth and sixth examinations.
We also assessed the dietary information on consumption of total
calories, saturated fat, trans fat, fiber, magnesium, and glycemic index
from the FFQ. 19
Because a FFQ was not administered at the fourth examination cycle,
dietary covariate data from the fifth examination cycle were used for
analyses using information from the examination cola questionnaire at
all 3 examinations.
Data from the FFQ were considered valid only if total energy intakes
reported were over 2.51 MJ/d (600 kcal/d) for men and women but under
17.54 MJ/d (4200 kcal/d) for men or under 16.74 MJ/d (4000 kcal/d) for
women and if fewer than 13 food items were left blank.
Each food item was categorized in 9 categories that ranged from never or
under 1 serving per month to over 6 servings per day.
For assessment of saturated fat, trans fat, or dietary fiber, the
nutrient intakes from all specific food items were multiplied by the
frequency of consumption.
The validity of the FFQ has been demonstrated previously. 21
Definition and Components of the Metabolic Syndrome
The metabolic syndrome was considered present if 3 or more of the
following individual components were present 14,22:
waist circumference over 35 inches (88 cm) for
or over 40 inches (102 cm) for men;
fasting blood sugar over 100 mg/dL (5.5 mmol/L) or treatment with oral
hypoglycemic agents or insulin;
blood pressure over 135/85 mm Hg or treatment for hypertension;
serum triglycerides over 150 mg/dL (1.7 mmol/L)
or treatment for hypertriglyceridemia (with niacin or fibrates);
and HDL-C under 40 mg/dL (1.03 mmol/L) in men
or under 50 mg/dL (1.3 mmol/L) in women.
Statistical Analyses
Age- and sex-adjusted baseline characteristics of the participant groups
defined according to the number of soft drinks consumed in 1 day
(under 1, 1, or over 2 per day) were compared by multiple linear and
multiple logistic regression analysis for continuous and categorical
characteristics, respectively.
Data on consumption of soft drinks at each of the 3 eligible baseline
examinations (examination cola questionnaire) were used for this purpose.
Tests for trend in baseline characteristics across soft drink
consumption categories were performed with multiple regression.
We also assessed the baseline characteristics after excluding
participants with prevalent metabolic syndrome at baseline
examinations (sample used for incidence analyses; see below).
Soft Drink Consumption and Prevalence of the Metabolic Syndrome
We used data from examinations 4, 5, and 6 (examination cola
questionnaire) and generalized estimating equations to compare the
prevalence of metabolic syndrome in participants who consumed over 1
soft drink per day with those who consumed under 1 soft drink per day
(referent).
Each participant could contribute up to 3 person-examinations of data
for analysis.
We also evaluated a dose response by comparing individuals
who consumed 1 soft drink per day and those who consumed over 2 soft
drinks per day with the referent group.
We constructed multivariable models in hierarchical fashion with
adjustment for age and sex (model I)
and for age, sex, physical activity index, smoking, dietary consumption
of saturated fat, trans fat, fiber, magnesium, total calories, and
glycemic index (model II).
We used soft drink consumption data from FFQs at examinations 5 and 6,
which yielded a smaller sample (Figure), to relate the prevalence of
metabolic syndrome across the following categories of intake of regular
versus diet soft drinks using generalized estimating equations:
(1) under 1 diet or regular soft drink per week (referent),
(2) 1 to 6 diet soft drinks per week,
(3) over 1 diet soft drink per day,
(4) 1 to 6 regular soft drinks per week,
(5) 1 to 6 regular or diet soft drinks per week,
and (6) over 1 regular soft drink per day.
Individuals reporting consumption of both diet and regular soft drinks
over 1/d (n = 16) were grouped into the last category empirically.
We evaluated the 2 sets of models (I and II) noted above.
Soft Drink Consumption and Incidence of the Metabolic Syndrome
To assess the relations of soft drink consumption to the incidence of
metabolic syndrome, we excluded participants with prevalent metabolic
syndrome at each of examination cycles 4, 5, and 6 (n = 2,897
person-observations).
Then, we used pooled logistic regression analyses
by combining each 4-year follow-up period of observations to relate the
number of soft drinks consumed per day (examination cola questionnaire)
to the incidence of metabolic syndrome (from examination cycles 4 to 5,
5 to 6, and 6 to 7).23
The eligible participants were free of metabolic syndrome
at each baseline examination,
and in this setting, pooled logistic regression has been shown to
provide risk estimates similar to time-dependent Cox models.24
We compared the consumption of soft drinks over 1 per day with
infrequent drinkers (under 1 per day; referent) and also
tested for a dose response by comparing groups consuming 1 and over 2
soft drinks per day with the referent group.
We evaluated 2 sets of models
(covariates as in models I and II above),
which paralleled the analyses of prevalence of metabolic syndrome.
Consumption of soft drinks varies with age and by sex.25
It has also been suggested that the effects of soft drinks and
carbohydrates on metabolic traits may vary according to age, sex,26
and baseline body weight.27
Therefore, we assessed for effect modification by age (modeled
as a continuous variable), sex, and body mass index
(under 30 versus over 30 kg/m2) by incorporating appropriate interaction
terms in the multivariable models.
We repeated analyses with additionally adjustment
for alcohol consumption and baseline levels of systolic and diastolic
blood pressure, blood glucose, serum triglycerides, and HDL-C.
These models were constructed to account for baseline levels of
metabolic traits.
Additionally, we repeated analyses to examine the association
between consumption of caffeinated and decaffeinated soft drinks,
considered separately, and incidence of the metabolic syndrome.
Because individuals with diabetes mellitus are a particularly high-risk
group for developing metabolic abnormalities, we also repeated our
analyses after excluding those with prevalent diabetes mellitus at baseline.
To compare the risk of new-onset metabolic syndrome according to the
type of soft drink consumed (regular versus diet),
we used data from the FFQs at examinations 5 and 6
and evaluated the incidence of the metabolic syndrome across categories
of soft drinks consumed.
The 6 categories of regular and diet soft drinks were those noted above
(for the analyses of the prevalence of metabolic syndrome),
and 2 sets of models were evaluated
(models I and II, as described above).
Incidence of Individual Components of Metabolic Syndrome
We used multivariable logistic regression to evaluate the relations of
soft drink consumption to the incidence of each individual component of
metabolic syndrome using data from the examination cola questionnaire.
We excluded participants who had the specific metabolic trait prevalent
at baseline; for example, we excluded individuals with blood glucose
over 100 mg/dL (5.5 mmol/L) from the "at-risk" group for analysis that
examined the incidence of impaired fasting glucose.
Thus, we examined the incidence of increased waist circumference,
impaired fasting glucose, high blood pressure, hypertriglyceridemia, and
low HDL-C (all defined as above) according to the number of soft drinks
consumed per day.
We evaluated 2 sets of models (I and II, as noted above) and compared
the risk of developing metabolic traits associated with consumption of
over 1 soft drinks per day
with that in infrequent drinkers (under 1 soft drinks per day).
We also evaluated for a dose response as detailed above.
We did not perform analyses of development of individual metabolic
syndrome components in relation to regular versus diet soft drink intake
using the FFQ data at examinations 5 and 6 because the grouping of
incident events into 6 categories resulted in modest numbers of events
in each category.
All analyses were performed with SAS software version 9.0 (SAS
Institute, Cary, NC). A 2-sided probability value of under 0.05 was
considered statistically significant.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the manuscript
as written.
Results
The baseline characteristics of participants according to the categories
of soft drinks consumed per day are presented in Table 1.
Approximately 35 % of the participants reported consuming over 1 soft
drink per day in response to the examination cola questionnaire
(data based on all 3 examinations).
In comparison, only 22 % of participants reported intake of at least 1
soft drink (diet or regular) per day in response to the FFQ (data
available for examinations 5 and 6 only).
The lower proportion reporting daily intake on the FFQ may be related to
the greater number of options available to indicate soft drink intake;
participants drinking 1 to 6 soft drinks per week (also 22 % on the FFQ)
may have rounded their responses on the examination cola questionnaire
to the nearest integer.
View this table:
TABLE 1. Baseline Characteristics of Participants According to
Soft Drink Consumption (n = 8997)
In age- and sex-adjusted models, the prevalence of obesity (assessed
both by body mass index and by waist circumference), high blood
pressure, glucose intolerance, low HDL-C, and hypertriglyceridemia was
significantly higher in those who consumed a greater number of soft
drinks per day.
Serum total cholesterol, low-density lipoprotein cholesterol, physical
activity index, and alcohol consumption did not vary across categories
of soft drinks consumed.
Similar trends were obtained when we excluded individuals with prevalent
metabolic syndrome (Data Supplement, Table I).
Prevalence of the Metabolic Syndrome
There was a 48 % higher adjusted prevalence of metabolic syndrome among
those who consumed 1 or more soft drinks per day relative to individuals
with infrequent soft drink consumption (Table 2).
We observed a rising prevalence of metabolic syndrome across categories
of 1 and over 2 soft drinks per day
In parallel analyses with the data from the FFQ (Table 2), participants
who consumed over 1 diet or regular soft drink per day had nearly a
1.8-fold adjusted prevalence of metabolic syndrome compared with
infrequent drinkers (under 1 per week).
TABLE 2. Cross-Sectional Relationships of Soft Drink Consumption With
Prevalence of Metabolic Syndrome
Incidence of the Metabolic Syndrome
Individuals who consumed at least 1 soft drink per day had a 44 % higher
adjusted risk (95 % CI, 20 % to 74 %) of developing metabolic syndrome
compared with infrequent drinkers in multivariable-adjusted analyses
(Table 3).
There was no effect modification by age, body mass index, or sex
(interaction terms were not statistically significant).
After additional adjustment for baseline levels of covariates (blood
sugar, systolic and diastolic blood pressure, triglycerides, and HDL-C)
and alcohol consumption in our models, the association of consumption of
over 1 soft drink per day with incidence of metabolic syndrome remained
robust (odds ratio [OR], 1.44; 95 % CI, 1.19 to 1.74).
Further exclusion of individuals with diabetes mellitus at baseline (n =
138) attenuated the association (OR for over 1 soft drink per day, 1.16;
95% CI 1.00 to 1.34).
After stratification of analyses by caffeinated versus decaffeinated
drinks, results were consistent with the primary analyses; consumption
of over 1 soft drink per day was associated with incident metabolic
syndrome for both types of beverages (Data Supplement, Table II).
TABLE 3. Multiple Logistic Regression Examining Soft Drink Consumption
and Incidence of Metabolic Syndrome (n = 6154)
In analyses with FFQ data (Table 3), intake of at least 1 regular or
diet soft drink per day was associated with a over 50 % higher incidence
of metabolic syndrome than among those who drank under 1 soft drink per
week, although the association was borderline significant for intake of
over 1 regular soft drink per day ( P = 0.07 ).
We also observed a graded increase in the risk of metabolic syndrome
from those who were consuming 1 to 6 diet or regular soft drinks per
week to those who drank over 1 soft drinks per day (diet or regular).
Incidence of Individual Components of the Metabolic Syndrome
Compared with infrequent drinkers, individuals who consumed over 1 soft
drink per day had a 25 % to 32 % higher adjusted risk of incidence of
each individual metabolic trait (Table 4), with the exception of
development of high blood pressure, for which there was a borderline
significant 18 % higher adjusted odds ( P = 0.10).
TABLE 4. Multiple Logistic Regression Analysis Examining the Relations
of Incidence of Individual Components of Metabolic Syndrome According to
Soft Drink Consumption (Data From All 3 Examinations [4, 5, and 6])
Discussion
In the present study, we observed a significantly higher prevalence of
metabolic syndrome among middle-aged adults who consumed over 1 soft
drink per day.
This association was consistent for intake of both regular and diet soft
drinks.
Our prospective analyses corroborated the cross-sectional findings;
we observed an increase in the incidence of metabolic syndrome among
adults consuming at least 1 soft drink per day, regardless of whether it
was of the regular or diet type.
Additionally, consumption of soft drinks daily was associated with a
higher incidence of each metabolic syndrome component.
The present study extends results from prior studies that reported that
a greater intake of soft drinks is associated with increased prevalence
of metabolic syndrome, 28 higher risk of obesity, 4–6 high blood
pressure, 7 and diabetes mellitus. 5
The similar metabolic hazard posed by both regular and diet soft drinks
is noteworthy given the lack of calories in the latter; however, other
studies have also reported associations of diet soft drinks with weight
gain in boys 29 and with hypertension in adult women. 7
Mechanisms
There are several mechanisms that can explain the higher risk of
metabolic abnormalities associated with greater consumption of soft drinks.
These can be broadly grouped under physiological effects, dietary
behavior, and the economics of food choice. 13
There are several physiological effects of soft drinks that may pose an
adverse metabolic risk.
Larger consumption of added nutritive sweeteners such as high fructose
corn syrup (the primary sweetener in soft drinks) can lead to weight
gain, increased insulin resistance, 30,31 a lowering of HDL-C, 32 and an
increase in triglyceride levels. 27
Typically, in the United States, the high fructose corn syrup added to
the beverages contains about 55 % fructose. 30,31
Although the association of high fructose corn syrup intake and insulin
resistance may be a contributory mechanism, 31 in the present study,
both regular and diet soft drinks appeared to pose similar metabolic
hazards, which suggests that other factors may be operational.
Consumption of liquids is associated with a lesser degree of dietary
compensation (the adjustment in energy intake made in subsequent meals
in response to food intake).
Some investigators believe that intake of sugar-sweetened beverages
induces less compensation than intake of artificially sweetened soft
drinks, 33 but others disagree. 34
The high sweetness of diet or regular soft drinks may lead to
conditioning for a greater preference for intake of sweetened items, 35
although this explanation also has been questioned by some experts. 13
The caramel content of both regular and diet drinks may be a potential
source of advanced glycation end products, 5 which may promote insulin
resistance 36 and can be proinflammatory. 37
Dietary behavior among individuals consuming soft drinks may account in
part for the clustering of metabolic risk factors in these people. 13
Individuals with greater intake of soft drinks also have a dietary
pattern characterized by greater intake of calories and saturated and
trans fats, lower consumption of fiber 38 and dairy products, 39 and a
sedentary life. 40
These observations were corroborated by the our findings of increased
consumption of saturated and trans fat, lower consumption of dietary
fiber, and higher rates of smoking in those with greater intake of soft
drinks.
Nonetheless, in the present investigation, we adjusted for saturated fat
and trans fat intake, dietary fiber consumption, smoking, and physical
activity in multivariable analyses and still observed a significant
association of soft drink consumption with the risk of developing
metabolic syndrome and its component traits.
It is conceivable, though, that there may be residual confounding caused
by lifestyle factors not adjusted for in the present analyses.
Last, it has been suggested that the obesity-promoting effects of soft
drinks may be related in part to their costs, with less expensive drinks
being associated with greater hazard by virtue of their preferential
selection for economic reasons. 13
The present investigation could not explore this explanation.
Strengths and Limitations
The strengths of the present study include the large community-based
sample of men and women and the adjustments for potential confounders;
however, several limitations merit comment.
We chose to use the modified definition of metabolic syndrome
recommended by the National Cholesterol Education Program 14 and did not
use other criteria for the syndrome (such as those suggested by the
World Health Organization 41 or the European panel).
Researchers have found high correlation between these guidelines. 42
Given the observational nature of the present study, we cannot infer
that the observed associations are causal.
As noted above, it is conceivable that residual confounding by
lifestyle/dietary factors not adjusted for may have contributed to the
metabolic risks associated with soft drink intake.
Finally, participants in the present study were all white Americans,
which may limit the generalizability of our results to nonwhites.
Conclusions
In our large community-based sample of middle-aged adults, soft drink
consumption was associated with higher risk of developing adverse
metabolic traits and the metabolic syndrome.
The present observational data raise the possibility that public health
policy measures to limit the rising consumption of soft drinks in the
community may be associated with a lowering of the burden of metabolic
risk factors in adults.
Acknowledgments
Sources of Funding
This work was supported through National Institutes of Health/National
Heart, Lung, and Blood Institute contracts N01-HC-25195, 1R01HL67288,
and 2K24HL04334 (Dr Vasan) and K23HL74077 (Dr Wang) and by a career
development award from the American Diabetes Association (Dr Meigs).
Disclosures
None.
References
1. Nielsen SJ, Popkin BM. Changes in beverage intake between 1977
and 2001. Am J Prev Med. 2004; 27: 205–210.[CrossRef][Medline] [Order
article via Infotrieve]
2. Vereecken CA, Inchley J, Subramanian SV, Hublet A, Maes L. The
relative influence of individual and contextual socio-economic status on
consumption of fruit and soft drinks among adolescents in Europe. Eur J
Public Health. 2005; 15: 224–232.[Abstract/Free Full Text]
3. James J, Thomas P, Cavan D, Kerr D. Preventing childhood obesity
by reducing consumption of carbonated drinks: cluster randomised
controlled trial (published correction appears in BMJ. 2004;328:1236).
BMJ. 2004; 328: 1237.[Abstract/Free Full Text]
4. Ludwig DS, Peterson KE, Gortmaker SL. Relation between
consumption of sugar-sweetened drinks and childhood obesity: a
prospective, observational analysis. Lancet. 2001; 357:
505–508.[CrossRef][Medline] [Order article via Infotrieve]
5. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ,
Willett WC, Hu FB. Sugar-sweetened beverages, weight gain, and incidence
of type 2 diabetes in young and middle-aged women. JAMA. 2004; 292:
927–934.[Abstract/Free Full Text]
6. Troiano RP, Briefel RR, Carroll MD, Bialostosky K. Energy and fat
intakes of children and adolescents in the United States: data from the
National Health and Nutrition Examination Surveys. Am J Clin Nutr. 2000;
72: 1343S–1353S.[Abstract/Free Full Text]
7. Winkelmayer WC, Stampfer MJ, Willett WC, Curhan GC. Habitual
caffeine intake and the risk of hypertension in women. JAMA. 2005; 294:
2330–2335.[Abstract/Free Full Text]
8. Parks EJ, Hellerstein MK. Carbohydrate-induced
hypertriacylglycerolemia: historical perspective and review of
biological mechanisms. Am J Clin Nutr. 2000; 71: 412–433.[Abstract/Free
Full Text]
9. Smith JB, Niven BE, Mann JI. The effect of reduced extrinsic
sucrose intake on plasma triglyceride levels. Eur J Clin Nutr. 1996; 50:
498–504.[Medline] [Order article via Infotrieve]
10. Surwit RS, Feinglos MN, McCaskill CC, Clay SL, Babyak MA,
Brownlow BS, Plaisted CS, Lin PH. Metabolic and behavioral effects of a
high-sucrose diet during weight loss. Am J Clin Nutr. 1997; 65:
908–915.[Abstract/Free Full Text]
11. Swanson JE, Laine DC, Thomas W, Bantle JP. Metabolic effects of
dietary fructose in healthy subjects. Am J Clin Nutr. 1992; 55:
851–856.[Abstract/Free Full Text]
12. Jurgens H, Haass W, Castaneda TR, Schurmann A, Koebnick C,
Dombrowski F, Otto B, Nawrocki AR, Scherer PE, Spranger J, Ristow M,
Joost HG, Havel PJ, Tschop MH. Consuming fructose-sweetened beverages
increases body adiposity in mice. Obes Res. 2005; 13:
1146–1156.[Abstract/Free Full Text]
13. Drewnowski A, Bellisle F. Liquid calories, sugar, and body
weight. Am J Clin Nutr. 2007; 85: 651–661.[Abstract/Free Full Text]
14. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin
BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F.
Diagnosis and management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute scientific
statement. Circulation. 2005; 13: 322–327.
15. Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB.
Metabolic syndrome as a precursor of cardiovascular disease and type 2
diabetes mellitus. Circulation. 2005; 112: 3066–3072.[CrossRef][Medline]
[Order article via Infotrieve]
16. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome:
time for a critical appraisal: joint statement from the American
Diabetes Association and the European Association for the Study of
Diabetes. Diabetes Care. 2005; 28: 2289–2304.[Abstract/Free Full Text]
17. Dawber TR, Meadors GF, Moore FE. Epidemiologic approaches to
heart disease: the Framingham Study. Am J Public Health. 1951; 41:
279–286.[Free Full Text]
18. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An
investigation of coronary heart disease in families: the Framingham
Offspring Study. Am J Epidemiol. 1979; 110: 281–290.[Abstract/Free Full
Text]
19. Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J,
Hennekens CH, Speizer FE. Reproducibility and validity of a
semiquantitative food frequency questionnaire. Am J Epidemiol. 1985;
122: 51–65.[Abstract/Free Full Text]
20. Kannel WB, Belanger A, D’Agostino R, Israel I. Physical activity
and physical demand on the job and risk of cardiovascular disease and
death: the Framingham Study. Am Heart J. 1986; 112:
820–825.[CrossRef][Medline] [Order article via Infotrieve]
21. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB,
Willett WC. Reproducibility and validity of an expanded
self-administered semiquantitative food frequency questionnaire among
male health professionals. Am J Epidemiol. 1992; 135:
1114–1126.[Abstract/Free Full Text]
22. Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. Executive Summary of the Third Report of
the National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). JAMA. 2001; 285: 2486–2497.[Free Full Text]
23. Cupples LA, D’Agostino RB, Anderson K, Kannel WB. Comparison of
baseline and repeated measure covariate techniques in the Framingham
Heart Study. Stat Med. 1988; 7: 205–222.[Medline] [Order article via
Infotrieve]
24. D’Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K,
Kannel WB. Relation of pooled logistic regression to time dependent Cox
regression analysis: the Framingham Heart Study. Stat Med. 1990; 9:
1501–1515.[Medline] [Order article via Infotrieve]
25. Storey ML, Forshee RA, Anderson PA. Beverage consumption in the
US population. J Am Diet Assoc. 2006; 106: 1992–2000.[CrossRef][Medline]
[Order article via Infotrieve]
26. Vartanian LR, Schwartz MB, Brownell KD. Effects of soft drink
consumption on nutrition and health: a systematic review and
meta-analysis. Am J Public Health. 2007; 97: 667–675.[Abstract/Free Full
Text]
27. Willett W, Manson J, Liu S. Glycemic index, glycemic load, and
risk of type 2 diabetes. Am J Clin Nutr. 2002; 76:
274S–280S.[Abstract/Free Full Text]
28. Yoo S, Nicklas T, Baranowski T, Zakeri IF, Yang SJ, Srinivasan
SR, Berenson GS. Comparison of dietary intakes associated with metabolic
syndrome risk factors in young adults: the Bogalusa Heart Study. Am J
Clin Nutr. 2004; 80: 841–848.[Abstract/Free Full Text]
29. Berkey CS, Rockett HRH, Field AE, Gillman MW, Colditz GA.
Sugar-added beverages and adolescent weight change. Obesity Res. 2004;
12: 778–788.[Abstract/Free Full Text]
30. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn
syrup in beverages may play a role in the epidemic of obesity. Am J Clin
Nutr. 2004; 79: 537–543.[Abstract/Free Full Text]
31. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Fructose, weight
gain, and the insulin resistance syndrome. Am J Clin Nutr. 2002; 76:
911–922.[Abstract/Free Full Text]
32. Frost G, Leeds AA, Dore CJ, Madeiros S, Brading S, Dornhorst A.
Glycaemic index as a determinant of serum HDL-cholesterol concentration.
Lancet. 1999; 353: 1045–1048.[CrossRef][Medline] [Order article via
Infotrieve]
33. Van Wymelbeke V, Beridot-Therond ME, de LG, V, Fantino M.
Influence of repeated consumption of beverages containing sucrose or
intense sweeteners on food intake. Eur J Clin Nutr. 2004; 58:
154–161.[CrossRef][Medline] [Order article via Infotrieve]
34. Holt SH, Sandona N, Brand-Miller JC. The effects of sugar-free vs
sugar-rich beverages on feelings of fullness and subsequent food intake.
Int J Food Sci Nutr. 2000; 51: 59–71.[CrossRef][Medline] [Order article
via Infotrieve]
35. Davidson TL, Swithers SE. A Pavlovian approach to the problem of
obesity. Int J Obes Relat Metab Disord. 2004; 28:
933–935.[CrossRef][Medline] [Order article via Infotrieve]
36. Hofmann SM, Dong HJ, Li Z, Cai W, Altomonte J, Thung SN, Zeng F,
Fisher EA, Vlassara H. Improved insulin sensitivity is associated with
restricted intake of dietary glycoxidation products in the db/db mouse.
Diabetes. 2002; 51: 2082–2089.[Abstract/Free Full Text]
37. Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine
V, Peppa M, Rayfield EJ. Inflammatory mediators are induced by dietary
glycotoxins, a major risk factor for diabetic angiopathy (published
correction appears in Proc Natl Acad Sci U S A. 2003;100:763). Proc Natl
Acad Sci U S A. 2002; 99: 15596–15601.[Abstract/Free Full Text]
38. Pereira MA, Kartashov AI, Ebbeling CB, Van Horn L, Slattery ML,
Jacobs DR Jr, Ludwig DS. Fast-food habits, weight gain, and insulin
resistance (the CARDIA study): 15-year prospective analysis. Lancet.
2005; 365: 36–42.[CrossRef][Medline] [Order article via Infotrieve]
39. Rampersaud GC, Bailey LB, Kauwell GP. National survey beverage
consumption data for children and adolescents indicate the need to
encourage a shift toward more nutritive beverages. J Am Diet Assoc.
2003; 103: 97–100.[CrossRef][Medline] [Order article via Infotrieve]
40. Hu FB, Li TY, Colditz GA, Willett WC, Manson JE. Television
watching and other sedentary behaviors in relation to risk of obesity
and type 2 diabetes mellitus in women. JAMA. 2003; 289:
1785–1791.[Abstract/Free Full Text]
41. World Health Organization. Definition, Diagnosis and
Classification of Diabetes Mellitus and Its Complications: Report of a
WHO Consultation, Part 1: Diagnosis and Classification of Diabetes
Mellitus. Geneva, Switzerland: World Health Organization; 1999: 1–59.
42. Boronat M, Chirino R, Varillas VF, Saavedra P, Marrero D,
Fabregas M, Novoa J. Prevalence of the metabolic syndrome in the island
of Gran Canaria: comparison of 3 major diagnostic proposals. Diabet Med.
2005; 22: 1751–1756.[CrossRef][Medline] [Order article via Infotrieve]
p 488 CLINICAL PERSPECTIVE
Consumption of soft drinks among children, adolescents, and middle-aged
adults has risen in the United States and Europe during the past 3 decades.
Prior studies have shown a higher prevalence of obesity and diabetes
mellitus in children who consume more soft drinks, although these
associations are less clear for adults.
We evaluated the relations of metabolic syndrome and its components to
soft drink consumption in Framingham participants.
Cross-sectionally, individuals consuming at least 1 soft drink per day
had about 50 % higher prevalence of the metabolic syndrome than those
consuming under 1 drink per day.
During a follow-up period of about 4 years, consumption of over 1 soft
drink per day was associated with a higher incidence of metabolic
syndrome and a higher incidence of each of its components, ie, obesity,
increased waist circumference, impaired fasting glucose, higher blood
pressure, hypertriglyceridemia, and low high-density lipoprotein
cholesterol.
Analyses that used food frequency questionnaire data suggested that
intake of over 1 drink per day of either regular or diet soft drinks was
associated with a over 50% higher incidence of metabolic syndrome
compared with intake of under 1 soft drink per week.
We conclude that consumption of more than 1 soft drink per day is
associated with a higher prevalence and incidence of multiple metabolic
risk factors in middle-aged adults.
Our observational data raise the possibility that public health measures
to limit consumption of soft drinks may be associated with a lowering of
the burden of cardiometabolic risk factors in adults.
Footnotes
The online-only Data Supplement, consisting of tables, is available with
this article at
http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.689935/DC1.
Guest Editor for this article was Gregory L. Burke, MD, MSc.
[ Dr. Gregory L. Burke is Professor and Chair of the Department of
Public Health Sciences at the Wake Forest University School of Medicine.
His research interests include epidemiology and cardiovascular disease,
atherosclerosis and subclinical CVD, measurement issues in epidemiology,
clinical trials of chronic disease prevention, women's health,
translation of scientific data for physicians and the general public,
and alternative strategies for chronic disease prevention. Dr. Burke
received his M.D. from the University of Iowa in 1981.
Departments of Public Health Sciences, Pathology, and Obstetrics and
Gynecology, Wake Forest University School of Medicine,
and Lyndhurst Gynecology Associates, Winston-Salem, NC 27157, USA.
gburke@..., ]
Find additional patient-related information at:
http://www.americanheart.org/presenter.jhtml?identifier=3050553
Related Article:
Issue Highlights
Circulation 2007 116: 457. [Full Text]
Related Internet Resources:
Podcast
Press Release
Video News Release
////////////////////////////////////////////////////////////
" When studying individual classes of caffeinated beverages, habitual
coffee consumption was not associated with increased risk of hypertension.
By contrast, consumption of cola beverages was associated with an
increased risk of hypertension, independent of whether it was sugared or
diet cola (P for trend <.001).
Conclusion
No linear association between caffeine consumption and incident
hypertension was found.
Even though habitual coffee consumption was not associated with an
increased risk of hypertension, consumption of sugared or diet cola was
associated with it.
Further research to elucidate the role of cola beverages in hypertension
is warranted. "
" The findings were consistent between the cohorts and were present
across types of soda beverages:
both sugared cola and diet cola beverages were associated with an
increased risk of hypertension (Table 5 and Table 6).
Hence, we speculate that it is not caffeine but perhaps some other
compound contained in soda-type soft drinks that may be responsible for
the increased risk in hypertension.
If these associations are causal, they may have considerable impact on
public health. "
" Finally, an examination of the possible associations between
caffeinated cola beverages and the risk of hypertension
showed that
sugared caffeinated cola (NHS I, P for trend = .03; NHS II, P for trend
<.001) (Table 5)
and diet caffeinated cola (NHS I, P for trend = .02; NHS II, P for
trend <.001) (Table 6)
were positively associated with hypertension in both cohorts. "
" Table 6. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Diet Cola Intake
Glasses or Cans of Diet Cola per Day
under 1 ------- 1 ----------- 2-3 ------- 4 and more --- P for Trend
Nurses’ Health Study I (1990-2002) 53,175 nurses, ages 44-69 in 1990
No. of cases of Incident Hypertension
17,268 ------- 1,154 ---------- 662 --------- 130
% 100 ---------- 6.7 ---------- 3.8 -------- 0.75
#% 32.5 -------- 2.2 ---------- 1.3 -------- 0.25 #% of 53,175
Person-years
479,890 ----- 30,579 --------17,316 ------- 3,173
% 100 -----------6.4 ---------- 3.6 -------- 0.66
Age-adjusted relative risk (95% CI)
1.00 -- 1.16(1.10-1.24)-- 1.23(1.13-1.33)-- 1.37(1.15-1.62)-- under .001
Multivariate relative risk (95% CI)*
1.00 -- 1.07(1.00-1.13) -- 1.06(0.98-1.15) -- 1.16(0.97-1.37)------ .02
Nurses’ Health Study II (1991-2003) 87,369 nurses, ages 27-44 in 1991
No. of cases of Incident Hypertension
10,192 -------- 1,452 -------- 1,358 --------- 449
% 100 ---------- 14.3 ----------- 13.3 --------- 4.4
#% 11.7 --------- 1.7 ------------ 1.6 --------- 0.51 #% of 87,369
Person-years
713,971 ----- 91,144 ------- 77,398 ------- 21,265
% 100 --------- 12.8 --------- 10.8 ---------- 3.0
Age-adjusted relative risk (95% CI)
1.00 -- 1.16(1.10-1.23) -- 1.33(1.26-1.41) -- 1.63(1.49-1.80) under .001
Multivariate relative risk (95% CI)*
1.00 -- 1.05(0.99-1.11) -- 1.09(1.03-1.15) -- 1.19(1.08-1.32) under .001
Abbreviation: CI, confidence interval.
*Adjusted for age, body mass index, intake of alcohol, family history of
hypertension, oral contraceptive use (in Nurses’Health Study II only),
physical activity, and smoking status, as well as the other classes of
beverage. "
http://jama.ama-assn.org/cgi/reprint/294/18/2330?ijkey=ff7fa86b688f2c2e23d9b6185\
19b890439fefb9e
full text pdf
http://jama.ama-assn.org/cgi/content/abstract/294/18/2330?ijkey=ff7fa86b688f2c2e\
23d9b618519b890439fefb9e&keytype2=tf_ipsecsha
full text html
JAMA Vol. 294 No. 18, November 9, 2005
Online Features
Original Contribution
Habitual Caffeine Intake and the Risk of Hypertension in Women
Wolfgang C. Winkelmayer, MD, ScD;
wwinkelmayer@...,
Meir J. Stampfer, MD, DrPH;
stampfer@...,
Walter C. Willett, MD, DrPH;
walter.willett@...,
Gary C. Curhan, MD, ScD
gary.curhan@...,
JAMA. 2005; 294: 2330-2335.
Context
Caffeine acutely increases blood pressure, but the association between
habitual consumption of caffeinated beverages and incident hypertension
is uncertain.
Objective
To examine the association between caffeine intake and incident
hypertension in women.
Design, Setting, and Participants
Prospective cohort study conducted in the Nurses’ Health Studies
(NHSs) I and II of 155,594 US women free from physician-diagnosed
hypertension followed up over 12 years
(1990-1991 to 2002-2003 questionnaires).
Caffeine intake and possible confounders were ascertained from regularly
administered questionnaires.
We also tested the associations with types of caffeinated beverages.
Main Outcome Measure
Incident physician-diagnosed hypertension.
Results
During follow-up, 19.541 incident cases of physician-diagnosed
hypertension were reported in NHS I and 13,536 in NHS II.
In both cohorts, no linear association between caffeine consumption and
risk of incident hypertension was observed after multivariate adjustment
(NHS I, P for trend = .29; NHS II, P for trend = .53).
Using categorical analysis, an inverse U-shaped association between
caffeine consumption and incident hypertension was found.
Compared with participants in the lowest quintile of caffeine
consumption, those in the third quintile had a 13 % and 12 % increased
risk of hypertension, respectively (95 % confidence interval in NHS I, 8
% - 18 %; in NHS II, 6 % - 18 %).
When studying individual classes of caffeinated beverages, habitual
coffee consumption was not associated with increased risk of hypertension.
By contrast, consumption of cola beverages was associated with an
increased risk of hypertension, independent of whether it was sugared or
diet cola (P for trend <.001).
Conclusion
No linear association between caffeine consumption and incident
hypertension was found.
Even though habitual coffee consumption was not associated with an
increased risk of hypertension, consumption of sugared or diet cola was
associated with it.
Further research to elucidate the role of cola beverages in hypertension
is warranted.
Author Affiliations:
Division of Pharmacoepidemiology and Pharmacoeconomics (Dr Winkelmayer),
Renal Division (Drs Winkelmayer and Curhan),
and Channing Laboratory (Drs Stampfer, Willett, and Curhan),
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical
School,
and Departments of Epidemiology (Drs Stampfer, Willett, and Curhan) and
Nutrition (Drs Stampfer and Willett), Harvard School of Public Health,
Boston, Mass.
RELATED LETTERS
Caffeine and Incident Hypertension in Women
Joe A. Vinson
JAMA. 2006;295:2135.
Caffeine and Incident Hypertension in Women
Johanna M. Geleijnse
JAMA. 2006;295:2135-2136.
Caffeine and Incident Hypertension in Women
Paolo Palatini
JAMA. 2006;295:2136.
Caffeine and Incident Hypertension in Women
Dae Hyun Kim
JAMA. 2006;295:2136-2137.
Caffeine and Incident Hypertension in Women—Reply
Wolfgang C. Winkelmayer and Gary C. Curhan
JAMA. 2006;295:2137.
RELATED ARTICLE
This Week in JAMA
JAMA. 2005;294:2273.
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Reply to S Voutilainen et al
Uiterwaal et al.
Am. J. Clin. Nutr. 2007;86:1249-1249.
The neuroprotective effects of caffeine: A prospective population study
(the Three City Study)
Ritchie et al.
Neurology 2007;69:536-545.
Coffee consumption and the incidence of antihypertensive drug treatment
in Finnish men and women
Hu et al.
Am. J. Clin. Nutr. 2007;86:457-464.
Soft Drink Consumption and Risk of Developing Cardiometabolic Risk
Factors and the Metabolic Syndrome in Middle-Aged Adults in the Community
Dhingra et al.
Circulation 2007;116:480-488.
Effects of Soft Drink Consumption on Nutrition and Health: A Systematic
Review and Meta-Analysis
Vartanian et al.
Am. J. Public Health 2007;97:667-675.
Coffee intake and incidence of hypertension
Uiterwaal et al.
Am. J. Clin. Nutr. 2007;85:718-723.
What's new in hypertension?
Mann
Nephrol Dial Transplant 2007;22:47-52.
Caffeine and incident hypertension in women.
Vinson
JAMA 2006;295:2135-2135.
Caffeine and incident hypertension in women.
Palatini
JAMA 2006;295:2136-2136.
Caffeine and incident hypertension in women.
Geleijnse
JAMA 2006;295:2135-2136.
Caffeine and incident hypertension in women.
Kim
JAMA 2006;295:2136-2137.
Cola, but Not Coffee, Appears to Raise Hypertension Risk
JWatch Women's Health 2006;2006:1-1.
Make That a Double Espresso!
Journal Watch Cardiology 2005;2005:4-4.
What's new in the other general journals
Tonks
BMJ 2005;331:1165-1166.
INTRODUCTION
Approximately 50 million people in the United States have hypertension,
and the prevalence is increasing. 1
Hypertension is a major risk factor for coronary heart disease, stroke,
and congestive heart failure. 2-3
Therefore, even small reductions in the prevalence of hypertension could
have a potentially large public health and financial impact.
Much clinical lore about the possible association between caffeine
intake and the risk of hypertension is available.
Short-term studies have demonstrated that caffeine intake acutely
increases blood pressure, but over time, attenuation of this effect does
occur. 4
Experimental studies have shown that caffeine can raise plasma levels of
several stress hormones, such as epinephrine, norepinephrine, 5-6 and
cortisol, all of which can lead to an increase in blood pressure. 6-7
However, these experiments have been limited to relatively short
periods of observation, typically less than 1 week; information on a
more sustained neuroendocrine response to regular exposure to caffeine
is not available.
A long-term effect of caffeine intake on the risk of developing
hypertension would be of substantial public health importance given the
widespread consumption of beverages containing caffeine, but currently,
studies of this association are scarce.
A recent longitudinal study in 1,017 men found a positive association
between coffee consumption and blood pressure and incident hypertension
in unadjusted analyses. 8
Although the association with blood pressure level was significant in
multivariate analyses, a nonsignificant 40 % increase in the risk of
incident diagnosis of hypertension (95 % confidence interval [CI], –6 %
to 109 %) for 3 to 4 cups per day and a 43 % increase (95% CI, –6 % to
118 %) for 5 or more cups per day vs no coffee consumption was found.
No published studies to date of the association between caffeine intake
and the risk of hypertension in women are available.
To prospectively elucidate whether caffeine intake or consumption of
certain caffeine-containing beverages is associated with the risk of
incident hypertension in women, we examined these questions in 2 large
cohort studies of women, the Nurses’ Health Studies (NHSs) I and II.
METHODS
Study Populations
The NHS I cohort was assembled in 1976 when 121,700 female registered
nurses, aged 30 to 55 years, completed and returned a mailed
questionnaire. 9
Follow-up questionnaires have been mailed every 2 years to update
information on health-related behaviors and medical events.
The NHS II began in 1989, when 116,671 female registered nurses, aged 25
to 42 years, completed and returned a mailed questionnaire.
Questionnaires have been mailed every 2 years to update exposure
information and diagnosis of new diseases.
The follow-up for both cohorts exceeds 90 %.
In this analysis, all participants who had not been diagnosed with
hypertension before the return of the 1990 NHS I or 1991 NHS II
questionnaires were included.
This study was approved by the institutional review board at Brigham and
Women’s Hospital, Boston, Mass.
Receipt of each questionnaire implies participant’s consent.
Dietary Assessment
Food frequency questionnaires were used to measure dietary intake and
were completed in 1990, 1994, and 1998 for NHS I and 1991, 1995, and
1999 for NHS II.
Participants were asked about their usual intake of foods and beverages
during the past year.
The response options for specified serving sizes were the following:
never or less than once per month;
1 to 3 times per month;
1 per week;
2 to 4 per week;
5 to 6 per week;
1 per day;
2 to 3 per day;
4 to 5 per day;
and 6 or more per day.
The relevant beverages included on the questionnaire were the following:
low-calorie cola (eg, Diet Coke or Diet Pepsi with caffeine),
regular cola (eg, Coke, Pepsi,
or other cola beverages with sugar),
tea with caffeine, tea without caffeine,
coffee with caffeine, and decaffeinated coffee.
Total caffeine intake was calculated primarily using US Department of
Agriculture food composition sources.
In these calculations, it was assumed that the content of caffeine was
137 mg per cup of coffee, 47 mg per cup of tea, 46 mg per can or bottle
of cola beverage, and 7 mg per serving of chocolate candy. 10
This method of measuring coffee intake was shown to be valid in both the
NHS I cohort and a similar cohort study of male health professionals. 11-13
Assessment of Other Variables
Data on height and family history of hypertension were collected at
baseline in both cohorts.
Information on weight was updated every 4 years.
Using each participant’s updated weight, body mass index was calculated
by dividing the weight in kilograms by height in meters squared.
Also, an updated variable for weight difference between baseline and the
time of respective follow-up questionnaire was generated.
Information on oral contraceptive use in the NHS II cohort also was
updated every 4 years.
The same semiquantitative food frequency questionnaires were used to
determine intake of alcohol, sodium, potassium, magnesium, calcium, and
phosphorus. 14
Physical activity was assessed in NHS I (1988, 1992, and 1996) and NHS
II (1989, 1993, and 1997) cohorts; energy expenditure was expressed in
metabolic equivalent tasks. 15
In addition, the frequency of analgesic drug use (aspirin, nonsteroidal
anti-inflammatory drugs, and acetaminophen) was ascertained. 16-17
Outcome Definition
The baseline and biennial follow-up questionnaires inquired about
physician-diagnosed hypertension and the year of diagnosis.
Self-reported diagnosis of hypertension was found to be reliable in the
NHS I cohort. 18
In a subset of women who reported hypertension, review of medical
records confirmed a documented systolic and diastolic blood pressure,
respectively, higher than 140 mm Hg and 90 mm Hg in 100 % and higher
than 160 mm Hg and 95 mm Hg in 77 % of participants.
Additionally, self-reported hypertension was predictive of subsequent
cardiovascular events. 18
A study participant was considered to have a history of hypertension if
she reported a diagnosis of high blood pressure on any questionnaire up
to and including the 1990 questionnaire in NHS I and the 1991
questionnaire in NHS II, and therefore was excluded from the study.
Among the remaining women in each cohort, incident cases were included
as those who first reported hypertension on any of the subsequent
biennial questionnaires and whose date of diagnosis was after the return
of the 1990 NHS I or the 1991 NHS II questionnaire.
This method recently has been used in a study of folate intake and the
risk of hypertension in women. 19
Statistical Methods
The time of observation was between return of the 1990 NHS I and 1991
NHS II and the 2002 NHS I and 2003 NHS II questionnaires.
Participants who did not return the baseline questionnaires for this
study were allowed to contribute person-time for later time intervals,
provided that they had not been diagnosed with hypertension prior to
return of the respective questionnaire.
Participants were censored after being diagnosed with hypertension or at
the time of death.
Each cohort was analyzed separately.
Age-adjusted Cox proportional hazards regression models were used to
estimate relative risks and 95% CIs.
In addition, multivariate models were constructed that adjusted for
other known risk factors of the study outcome:
age (continuous), body mass index (continuous), alcohol use (6
categories), physical activity (quintiles of metabolic equivalent
tasks), smoking status (current, past, or never), family history of
hypertension (yes/no), and current oral contraceptive use (yes/no; only
in NHS II).
In additional analyses, we ensured that sodium, magnesium, calcium,
potassium, and phosphorus intake (quintiles) did not confound the
estimates from these multivariate models.
All variables were updated to reflect the most recent value provided by
the participants on the biennial questionnaires.
Participants with missing data were assigned to a missing category for
that specific time period.
We determined P values for trend for each of the exposures of interest
by using the median for each category.
Level of significance for P values for trend was <.05.
Also the interaction between caffeine intake and the other variables was
tested.
We used SAS version 8.2 for UNIX statistical software package
(SAS Institute Inc, Cary, NC).
RESULTS
In NHS I, 53,175 women had not been diagnosed with hypertension at
baseline in 1990.
Another 7,916 participants who did not respond to the 1990 questionnaire
but who did respond to a later questionnaire disclosing that they
previously had not been diagnosed with hypertension allowed them to
contribute person-time from that point in time.
Over the 12 years (539,388 person-years of follow-up), 19,541 incident
cases of physician-diagnosed hypertension were reported.
In NHS II, 94,503 participants who were free of hypertension (87,369 in
1991 and an additional 7,134 at a later point in time) were included in
the analyses of younger women.
During 909,199 person-years of observation, 13,536 participants
responded that they were diagnosed with hypertension by a physician.
Participant characteristics by quintile of caffeine intake are presented
in Table 1.
In both cohorts, mean caffeine consumption ranged from less than 20 mg/d
in the lowest quintile to approximately 600 mg/d in the highest quintile.
Caffeine intake was correlated positively with alcohol consumption and
smoking status
r = 0.12, P < .001 for NHS I; r = 0.23, P < .001 for NHS II),
whereas all other relevant characteristics did not differ
materially across quintiles of caffeine consumption.
Table 1. Baseline Characteristics of Cohort by Quintile of Caffeine
Intake in Nurses’ Health Study I (N = 53,175)
and Nurses’ Health Study II (N = 87,369)*
Age-adjusted analyses demonstrated an inverse U-shaped relation between
caffeine intake and the incidence of hypertension in both cohorts.
Compared with participants in the lowest quintile of caffeine
consumption, the risk of incident hypertension was increased by 14 % (95
% CI, 9 % -19 % for NHS I) and 15 % (95 % CI, 9 % - 21 % for NHS II) for
those in the third quintile, whereas those in the highest quintile were
not at an increased risk of hypertension (Table 2).
Multivariate adjustment did not materially change these findings (Table 2).
Table 2. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Quintile of Caffeine Intake
To further examine this inverse U-shaped association, the frequency of
use of different caffeine-containing beverages in relation to the risk
of incident hypertension was evaluated.
In multivariate models including beverage type, rather than actual
caffeine intake, no association between frequency of intake of
caffeinated coffee and incident hypertension was observed in either cohort.
Compared with NHS I participants drinking less than 1 cup per day of
caffeinated coffee, the relative risks were
1.06 (95% CI, 1.01-1.10) for those consuming 1 cup per day,
1.00 (95% CI, 0.97-1.04) for those drinking 2 to 3 cups per day,
0.93 (95% CI, 0.88-0.99) for those drinking 4 to 5 cups per day,
and 0.88 (95% CI, 0.80-0.98) for those drinking 6 or more cups per day
(Table 3).
The trend for the NHS I cohort was marginally significant for
an inverse association between coffee intake and the risk of
hypertension (Table 3; P for trend = .02).
The findings in the NHS II cohort were practically identical (P for
trend = .03).
The results for intake of decaffeinated coffee also were similar to the
data for caffeinated coffee intake (data not shown);
the trend suggested an inverse association of risk of hypertension in
the NHS I cohort (P for trend = .08)
but not in the NHS II cohort (P for trend = .67).
Table 3. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Coffee Intake
An association between caffeinated tea intake and incident hypertension
in the NHS I cohort (Table 4; P for trend = .79) was not found.
However, in the cohort of younger women in NHS
(Message over 64k, truncated.)
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.
Offline 
Send Email