Table Of ContentCaffeine
Perspectives from Recent Research
Edited by P. B. Dews
With 32 Figures and 36 Tables
Springer-Verlag
Berlin Heidelberg New York Tokyo 1984
Sponsored by the
International Life Sciences Institute
Officers of the ILSI
Alex Malaspina, Atlanta - President
P. B. Dews, Newtonville - Vice President
Ulrich Mohr, Hannover - Vice President
Roger D. Middlekauff, Washington - Secretary/Treasurer
Dr. Peter B. Dews
181 Upland Road, Newtonville, MA 02160, USA
ILSI International Life Sciences Institute,
w.,
1126 Sixteenth Street, N. Washington, DC 20036, USA
ISBN-13: 978-3-642-69825-5 e-ISBN-13: 978-3-642-69823-1
DOl: 10.1007/978-3-642-69823-1
Library of Congress Cataloging in Publication Data. Caffeine: perspectives form recent
research. "Sponsored by the International Life Sciences Institute" -Includes bibliographical
references and index. t.Caffeine-Physiological effect. 2. Caffeine-Metabolism.
3. Caffeine-Toxicology. I. Dews, Peter B., 1922 -. II. International Life Sciences Institute.
[DNLM: t. Caffeine-pharmacodynamics. 2. Caffeine-metabolism. QV 107
C129] QP80t.C24C341984 615'.785 84-5602
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Foreword
Before the late 1970s, interest in caffeine among both the general
public and the scientific community was at a relatively low level for
many years, even though it was recognized that caffeine was an al
most universal component of the diet. The National Coffee Associa
tion was supporting a continuing program of research, some re
search was being conducted by a few of the largest companies
selling coffee, and an occasional university researcher became inter
ested in caffeine and conducted experiments, often on effects of caf
feine in very high concentration in vitro on skeletal muscle fibres or
on dividing cells. Since 1978, however, there has been a mighty up
surge in both public and scientific interest in caffeine. It is interest
ing to note that this was prompted not by discovery of hitherto un
known effects or hazards of caffeine, but by the actions of a
regulatory agency, the Food & Drug Administration (FDA) of the
U. S. Public Health Service.
The U.S. Congress passed new laws on foods and drugs in 1958.
One of the provisions was for testing of food additives to assess risk
to health. As it was clearly impracticable to require immediate test
ing of all additives already in use, a list was drawn up of some hun
dreds of additives that were generally recognized as safe (GRAS).
When the law had been operating for some years, a presidential di
rective required the FDA to reexamine the evidence on risk of the
substances on the GRAS list. The FDA commissioned a special
committee on GRAS substances (SCOGS) to examine the evidence.
Caffeine was on the GRAS list. In 1978, the SCOGS issued a draft
of its commentary on caffeine, which immediately occasioned both
public and industry interest. The soft drinks industry, because of
their practice of adding caffeine to colas and other soft drinks, be
came particularly involved. Its main response, surely appropriate,
took the form of initiation of support for scientific research on caf
feine. The research program continues under the auspices of the In
ternational Life Sciences Institute (ILSI), a foundation developed
primarily to permit companies to pool resources to support research
programs of common interest. On caffeine, the ILSI has also sup
ported a series of international workshops for exchange of informa
tion on caffeine between researchers, both supported and not sup-
v
ported by ILSI, and an interested technical audience, including in
dividuals from regulatory agencies.
In 1981, ~he FDA published a proposed regulation on caffeine in
the Federal Register and invited comments. Among the groups that
commented was the ILSI, which collected a group of experts to re
view and address the various points raised by the FDA. The result
ing report represented a rather comprehensive update of scientific
information on caffeine by many of the leading experts in the fields
covered. ILSI had been discussing the desirability of sponsoring a
monograph on caffeine, and the work done for the report provided
a good starting point. This volume is the result. While it shows clear
signs of its origin, coverage has been expanded considerably beyond
the original report by the addition of a number of authors to cover
areas not addressed by the FDA. The book is by no means a primer,
but it is intendend to be intelligible to the wide audience of people
with technical interest in caffeine. It was suggested to authors that
they start their update from the publication in 1976 of the compre
hensive monograph by Eichler and collaborators (KajJee und Col
fein. Springer-Verlag, Berlin Heidelberg New York).
VI
Preface
Caffeine is a regular component of the diet for most people. What
happens to it when it has been ingested, and what are its conse
quences? In addressing these questions, the contributors to this
monograph illustrate some of the strengths and weaknesses of con
temporary dietary pharmacology, which studies the physiological,
biochemical and behavioral consequences of dietary intake of sub
stances. Never before has there been so much interest in dietary
pharmacology. Millions of joggers and other athletes, as well as
health zealots, spend much time and effort on selection of their diet,
clearly on the premise that proper choice of diet can benefit them in
an emphatic manner. In many top-ranking athletes the preoccupa
tion approaches a fetish, strongly encouraged by coaches. Other
classes of consumers are equally preoccupied with the possibility of
being harmed by components of the diet, whether added deliberate
ly or present as trace contaminants. "Organic" food stores prosper,
and there are periodic "scares" about particular foods or classes of
foods.
To an objective appraiser, it is likely that the great majority of ef
fects in dietary pharmacology are subtle, making for problems in
their detection and measurement. Subtle means hard to measure,
but not necessarily trivial; people eat every day, and the effects of
substances taken daily may, in the long run, have substantial effects.
If a regimen including caffeine helps worker A do better than work
er B by a 2.5% annual increment, then after 30 years A will be doing
more than twice as well as B. Small margins in competitiveness can
be cumulatively decisive.
We are accustomed to the analytical techniques of the chemist be
coming progressively more sensitive, so that we can measure smaller
and smaller amounts of components of the diet and of the body,
from milligrams to micrograms to nanograms and even picograms.
Pharmacologists and students of nutrition have taken avidly to
modem analytical techniques and to other boons from the physical
sciences in their studies of receptors and of the intimate molecular
mechanisms of drugs and foods. In contrast, there has been no sub
stantial increase in the sensitivity of methods of detecting physiolog
ical and behavioral effects, either beneficial or deleterious, in the
VII
past 20 years or so. Higher sensitivities in measuring subtle effects
are needed, both for purely scientific purposes and to answer ques
tions now b.eing asked urgently by the public. Among the classical
nutritional requirements for the maintenance of health are the inclu
sion of particular substances in the diet and a balanced intake of
carbohydrates and fats. Beyond this, the influences of quantity,
composition, and schedule of intake of foods on physiological and
behavioral performance are largely unkown. Folklore abounds with
stories ranging from the salutary effects of oysters to the "brain
food" functions of fish. The superstition of many athletes has al
ready been mentioned. In spite of the enduring public interest in
diet, there has been little systematic scientific study until recent
years, and many subtle effects may be unrecognized. These are not
matters oflife and death; but then, neither is music. It is to be hoped
that the increase of interest in the subtle effects of caffeine, benefi
cial or deleterious, will be one more factor leading to increased work
in dietary pharmacology.
On the basis of present information, some predictions about char
acteristics of dietary pharmacology may be ventured. First, to dem
onstrate an effect of a dietary component convincingly, it will be
necessary to show a quantitative relation between intake and effect,
corresponding to a dose-effect curve in classical pharmacology. But
dose-effect curves in dietary pharmacology will often reach an
asymptote at levels which are low relative to toxic levels, and so it
will be easy to miss dependence of the effect on the size of the dose.
Examples of asymptotes can be found in the fields of both nutrition
and pharmacology. Take a subject deficient only in Vitamin A. Ther
apeutic effect is related to dose of vitamin A over a limited range.
Once an optimum utilizable dose has been reached, additional,
amounts have no clear incremental effect until, with doses which are
orders of magnitude larger than the maximum therapeutic levels,
toxic effects become manifest. Mechanistically, such effects may
have little in common with the therapeutic effects. Among drugs,
acetylsalicylic acid, in its therapeutic range, operates quantitatively
in inhibiting synthetic pathways in the prostaglandin-prostacyclin
systems. Once effectively complete inhibition has been achieved in
any particular pathway, increasing doses have no substantial addi
tional effect on that system until, again, toxic levels are reached. The
mechanism of the toxic effects of acetylsalicylic acid, for example,
on respiration is different from that of the effects of small doses on
headache. It may be noted in passing that the irrelevance of actions
at high dose levels poses decisive problems for conventional strate
gies of risk assessment. It should also be noted that the occurrence
of asymptotes does not remove the necessity of demonstrating dose
dependence; it just makes it harder to achieve.
A second feature of dietary pharmacology may be illustrated with
the same two examples. Reasonable amounts of Vitamin A have no
VIII
discernible effects in a nondeficient subject, and reasonable
amounts of acetylsalicyclic acid have no discernible behavioral ef
fects in subjects free from pain and fever. In both instances, many
characteristic effects of the agent could not be detected and mea
sured in samples of subjects - humans or experimental animals -
chosen randomly from well cared for, normal populations.
Third, developments in dietary pharmacology are sure to blur fur
ther the dividing line between "foods" and "drugs". No one is about
to reclassify penicillin or digoxin as a food, but what of, for exam
ple, minerals, amines, and amino acids, ubiquitous components of
the diet that have undoubted conventional pharmacological effects?
Dietary pharmacology is well exemplified by caffeine. Caffeine
can have subtle behavioral effects quantitatively related to dose at
levels far below toxic levels. Increasing amounts do not then cause
increases in most of the characteristic behavioral effects. Eventually,
at toxic levels, the mechanisms have a dubious relationship to those
of the characteristic effects at low doses. A variety of behavioral ef
fects of caffeine that are relatively easily detected in fatigued, bored,
or sleepy subjects may be essentially undetectable in alert, fresh sub
jects. Caffeine is a component of natural foods and is essentially
completely metabolized in a way that is not characteristically quali
tatively different from the general manner in which, for example,
other purines in the diet are handled.
In this volume we start from the firm ground of metabolism and
kinetics. We then consider consumption levels, always a crucial
component in determining societal consequences of dietary prac
tices. Physiological and behavioral effects are then assessed and in
formation on molecular mechanism of action is examined. The next
group of chapters reviews risk-assessment studies, which are useful
without pretending to any "proof of safety." The volume concludes,
deliberately, with a contribution to pure science, a designation
which does not preclude possible practical importance.
IX
Contents
Section I Metabolism and Kinetics
I ProductsofMetabolismofCaffeine(M.l.Amaud). 3
1 Discovery and Chemical Structure of Methylxanthines . 3
2 Formation of Uric Acid Metabolites . . . . . . 5
3 Introduction of Chromatographic Techniques . 7
4 The Metabolic Studies by H. H. Cornish . . . . 10
5 Use of Labeled Methylxanthines . . . . . . . . 11
6 Metabolism of Theophylline in the Premature Infant 16
7 Metabolism of Labeled Theobromine and Identification of
Uracil Derivatives . . . . . . . . . . . . . . . . . 19
8 Use of Methyl-Labeled Caffeine in Breath Tests . . . . . 21
9 Perinatal Caffeine and Theophylline Metabolism . . . . 23
10 Quantitative Metabolic Pathways of Dimethylxanthines 26
11 Identification of an Acetylated Uracil Metabolite in Man. 30
References . . . . . . . . . . . . . . . . . . . . . . . . .. 32
II Measurement ofC affeine and Its Metabolites in Biological
Fluids (H. D. Christensen and A. H. Neims) . 39
1 Ultraviolet Spectrophotometry 39
2 Liquid Chromatography. . . 40
3 Thin-Layer Chromatography . 42
4 Immunoassays . . . . . . . . . 43
5 Gas Chromatography - Mass Spectrometry 44
6 Carbon Dioxide Breath Test. 44
7 Conclusions 45
References . . . . . . . . . . 45
III Interspecies Comparison of Caffeine Disposition
(M. Bonati and S. Garattini) 48
1 Absorption........ 48
2 Plasma Protein Binding . 48
3 Distribution 48
4 Clearance ....... . 49
XI
4.1 Renal Clearance . . . 49
4.2 Metabolic Clearance 49
4.3 Urinary Metabolism. 51
5 Kinetics of Primary Metabolites of Caffeine. 52
6 Nonlinear Kinetics ..... . 52
7 Chronic Treatment in the Rat . 53
References . . . . . . . . . . . 54
Section II Intake
IV Human Consumption of Caffeine (1.1. Barone and
H. Roberts) ..... 59
1 Introduction.... 59
2 Sources and Levels 60
2.1 Coffee ...... . 60
2.2 Tea ........ . 62
2.3 Cocoa and Chocolate Products . 62
2.4 Soft Drinks. . . . . . . . . . . . 62
2.5 Drug Products . . . . . . . . . . 63
2.6 Standard Caffeine Content Values 63
3 Consumption Data Sources .. . 63
4 Consumption Estimates .... . 65
4.1 Market Research Corporation of America Survey 65
4.2 Market Facts Survey .......... . 66
4.3 Nationwide Food Consumption Survey. 67
4.4 1982 Coffee Drinking Study .... 69
4.5 Standard Consumption Estimates . . 70
4.6 Consumption by Pregnant Women. . 71
5 Time Distribution of Caffeine Intake 72
6 Summary .. 72
References .............. . 73
Section III Physiological and Behavioral Effects
V The Cardiovascular Effects of Caffeine
(D. Robertson and P. W. Curatolo) . 77
1 Introduction....... 77
2 Myocardial Contractility 78
3 Heart Rate . . . . . . . 78
4 Blood Pressure. . . . . 78
5 Clinical Pharmacology 79
References . . . . . . . 83
XII
