Antioxidant Anthony

nutrients

Interest

speculation

that

diseases.

The

their

in free

disorder

reduction

active

intermediates.

of an nium,

enzymatic copper,

events

be involved

of dioxygen

to water

The

control

system zinc, and

proliferation

radical

may

ofthis

oxygen

with

ascorbic

carotene

also

acid,

can

intervene.

of a number of diseases linking low intake ofthe incidence. glimpses disease.

KEY

Improvements into what may

WORDS

may

tamin

and

occur.

on theory nutrients

Tar-

fi-

A and

in the

etiology

and on evidence with a high disease have resulted between diet

in and

1991;53:189S-935. nutrients,

cancer,

selenium,

human

vitamin

disease,

car-

E, vitamin

C, vi-

possibility

of a relationship

chronic

of nutritional history. Many

or acute

relationships and various

of particular constituents

ventive

causative

ofthe major last

has been

factors

Society

decade,

and

others

have

been

emerged further Sciences

national initiative, Institute,

able

and been

the

the

diseases

the

concepts .

,

methodologic with

Am J C/in Nuir

One

and far reaching reviews concerning that ofa task group established by the Nutrition

findings to

towards

(1) provide

build,

results

and

of this

Their objective (3), Co-Chairman

scientific

idemiological health. .

of disease.

the

from

the end basis

In a report two

variation runs

to 400

(4,

5) dealt

between

emphasis mentum

which

which

there

have

was

and

considerations particular

emphasis

1991 ;53:189S-93S.

were

published

in the words of Dr Artemis of the Symposium, “a review

principles

and experimental the concepts and

A Life Life

in Brighton in 1985, experts in Portugal

symposium

that

studies approaches

form

Printed

basis

the

on diet adequacy

in USA.

and

studies,”

seems

area of interest during the past

all of which

recommendations.

it is perhaps

specifically

of

contribution

surprising

with

the

nutrients

and

likely

to remedy

that

issue

of the

disease.

that has been decade. It brings

this

under-

gathering together

moboth

basic scientists, and medical practitioners in a forum in which they can exchange ideas

and epidemiologists from their respective

viewpoints

some

to attempt

clusions

as to the role

disease.

Many

(3) apply

that

to come

of the

lead

highlighted ofthe

oxidative

Among

the past 10 y, a rapidly studies that concern the

medical

in living

scientists

systems

ample

evi-

at an early stage the consumption

that there of foods,

particularly leafy green-yellow vegetables, and certain More recently attention has focused on the constituents

diseases. of these

vegetables

namely

great

to bridge

need

the

basic

some

scientist

diffident about more concerned diffIdent

about

admitting

and

ofthe

the and

suggested between

Simopoulos

conference.

processes

Among

con-

of human

by Dr

present

there has been, during in, and emphasis on, to disease.

tentative

in the prevention

principles

ofuncontrolled

may

to at least

ofantioxidants

to the deliberations

prevention

gap the

antioxidant that

nutrients.

is often

clinician;

seen

basic

There

to exist

scientists

expressing

opinions

accepting

honestly

about these

the

is a

between often

expressing views on topics that may with clinical aspects and clinicians

feel

seem to be may feel

basic

science.

limitations

trying to help one another to make achieved in promoting understanding.

By

in a spirit

progress,

much

of

can

be

chronic

© 1991 American

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/189S/4691418 by Washington University School of Medicine Library user on 06 June 2018

biochemical

problems

The defense of living enkaryotic by activated oxygen is a complex of interrelated protective agencies. have ally

come

to be regarded

at the heart

of this

selenium,

cells process Those

as antioxidant protective

copper,

zinc,

against damage caused that involves a battery micronutrients, which nutrients,

mechanism. and

lie function-

They

manganese,

include and

the

vitamins

P of

of ep-

of dietary

Basic

minerals

in the area of diet and to scientific inquiry,

of studies on

the

pages,

standards

of the

dietary

antioxidant

symposium

on an steadily

of scientific analysis

to nutritional

that

present

an

in formulating

papers

relationship The

and

of the

on

guidelines in at least 13 different countries. begun in 1984 within the International was developed at the XIII International

1986;

in 1987 (2). Simopoulos

particular diseases, seen both as pre-

etiogenesis

Sciences Congress of Nutritional Sciences and resulted in a meeting of international in October

between

preoccupation

through a long period of have attempted to evaluate

in the

for Clinical whose

subjects

a major

dietary factors of food have

most comprehensive dietary factors was

American

in human

disease

and medical scientists national organizations

and

genetic

to be considered

only

delineation

dence from dietary surveys was an inverse correlation

Introduction

and

the methods,

basic scientists growing interest

A, carotenoids

The

measurements,

need

phoswill E, per-

vitamin

of this

in epidemiology prove to be links

Antioxidant

disease,

this,

implication

AmJClinNuir

diovascular

diet

an overview1’2

epidemiological of human

several

on the integrity

metabolites

depends antioxidant

of

adequate intake of seleif their level of intake is

prevent

The

intake

stimulated

involves

depends

that requires manganese;

of active

has

in a number

gets for attack are DNA, proteins, and polyunsaturated pholipids. Peroxidation of polyunsaturated phospholipids result in disruption of membrane architecture. vitamin haps

prevention:

TDiplock

ABSTRACT

low,

and disease

From the Division of Biochemistry, United Medical and Dental Schools, University of London, Guy’s Hospital, London. 2 Address reprint requests to AT Diplock, Division of Biochemistry, United Medical and Dental Schools, pital, London SEJ 9RT, UK. Society

for Clinical

Nutrition

University

of London,

Guy’s

Hos-

1 89S

DIPLOCK

I 90S

E, C, and the

probably

nature

now

give

ofthe The

has been

complete

initially

unravelling task

which

we can

explains

most

oxygen radical,

is defined

to water

the

involves

superoxide

electron,

either

as an atom

from

an electron

transfer

that

is located (eg, cytochrome transfer chain or cytochrome

microsomal

system),

or at random

from

an organic

vicinity.

The

product

anion which, peroxide.

with

two

protons

from

solution

has

in which

02+

oxygen moval are

formed.

or inorganic is the

will form

O

-

This

is because

divalent

on the

ficiency

radical

acid

moeities

dence

that

effect

of

such

as iron,

interaction free radical,

or

of these two the hydroxyl

H0.

the

Fe3

-

02

+ Fe2

-

OH

+

H202

+ HO

ogenesis No clear

answer

primary

from

almost

initiate

radical is very highly reactive and potentially sein living systems because it can pluck an electron any

further

the heart

organic

radical

ofthe

this

is not

potentially

always

A further reactive in the present context as an excited

the

severe

state

case

that

this

by

metabolite,

which

may the

be of significance microbiocidal

important erated

by the

and This

state

to the The above H202.

regarded

energy

radical,

a peripheral

biochemical

damage.

Such

biological control

system

removal anion

compartment

depends

by H0

large.

in the

process

radical

attack

peroxyl The

acids

has

DNA

been

with

which

ex-

molecular

in turn

gives

of the hydroperoxide

of hydrogen,

either

E or,

absence

from other polyunsaturated giving rise to further radical

to

carbon-centered

interacts

formation

may above,

lead

initial

radical,

nucleus

disappointingly

fatty (9). The

in vivo. however,

outlined

would

eti-

question,

it is likely,

reviewed

as vitamin

key

to this question; arise

to

in the

of cancer

is, however,

hydroperoxide.

such

The

in situ

a lipid

damage

etiogenesis

polyunsaturated

and

sysoxidase,

damage

process

on the abstraction

tioxidant

in the

from

a lipid

an-

of vitamin

E,

fatty acid molecules in the vicinity, species and the initiation of a chain

reaction. LH

either

that and eg, as

it may

also

damage

may

activity

of vitamin

change

02 ground

in which

of generation

depends on the The superoxide

the mitochondrial

chemical

to the

on

+ HO’ L’ +02

elec-

processes, (8);

oxygen-scavenging

without

is returned

rise to a lipid

capture.

of polymorphs

tissue

to produce

as

be

state

so that without

the

A

-

L’ + H2O

-+

LOO’

LOO’

+ E-H

-*

LOOH

+ E’

LO0’

+ LH

-+

LOOH

+ L

excited

similar

to that

control

the

intervention

vitamin from acid

E’; vitamin

by Tappel damage

ascorbic

initiated

described and in

(SOD),

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/189S/4691418 by Washington University School of Medicine Library user on 06 June 2018

that

-OOH seeks

cause

acid

pholipid.

The

fatty

peroxidized

of the

free

to

in the which

in the etilipid hydroin the

hydrophobic

memregion

architecture nonpolar

of endogenous acid

and

importance fate of the

in the

in the

nutritional

by free radicals

membrane

out

Thus

is essential

its formation

deep

of the to move

activation

the peroxidized

important; group

in disruption

function may

is also

the

result

polar This

LOOH with

E results

by a system that by a mechanism

37 y ago (10).

E and

reaction

E is thought

vitamin E’ radical glutathione, possibly

vitamin

ofmembrane

Chain

-

of vitamin

E radical

the and

proposed

of both

peroxide will

dismutase

that

of the

be regenerated involves ascorbic

brane

detriment

of the initial metabolites 0 radical is efficiently removed,

be noted

formation

may be expected to be of considerable ogenesis of a number of diseases. The

it occurs.

of HO’ by the mechanism

by superoxide

It will

adequacy

be mod-

other retinoids, and by fl-carotene and other carotenoids. quenching ability depends on the ability of these compounds

to absorb ‘02

be

formed

or

a free

in certain

singlet

must

is excited to an orbital above The resultant ‘02 is reactive

activity

in causing

may be an adhave a short

radical

‘0

is not

structure occupies.

lie at

will lead

such

that

evi-

systems.

by energy 02

In this

may that

HO

researched

fatty

is ample

radical-generating

of HO

for this

enzymes

in extensive

very

metabolites

production

Evidence

include There

to HO’ by the iron-catalyzed

oxygen

ofoxygen that is of significance oxygen, ‘02, which can be formed

of oxygen

tron in the oxygen which it normally

H0

to living

metabolite is singlet

will

its random reactivity will contained and eliminated;

and

threat

which

that

changes

high reactivity of HO the radical will certainly

in many instances that is quickly

a most

vicinity,

processes

ofbiochemical

the that

half-life in vivo and cause only damage

in its

or nonradical

etiogenesis

to disease. However, vantage in the sense

but

molecule

for

can be given oxygen

be converted

tensively The hydroxyl verely damaging

result

in the

hydroxyl

or xanthine

will

de-

defense

polyunsaturated

of a free

is therefore

ofthe

macromolecules

may the

lymphocytes

is its significance

antioxiAny

of the

on organic

potential

the

be initiated.

reactivity These

presence

The

of cancer

however,

will

on enzymes

selenium.

phospholipids.

to DNA

structure.

scanty. Attack

+ Fe3

the

proximity

the level

in particular

of membrane

is a

so-called

lower

attack

in-

which

ofthese

and

extreme

as phagocytosing

damage.

+ Fe2

and

and

in both of the initiation

zinc,

processes the

and

depends

of the

thus

of its generation.

in vitro

DNA

that

may

in random

proteins

such

and 02

vicinity

hydrogen

availability

that

result

other

the activity

disease

noted

may

in the

in turn, copper,

nutrients

so that been

the control damage

nutritional

in these

It has

Thus

manganese,

enzyme, is copper

peroxidase,

intracellular

enzymes;

minerals,

and

the need for reas soon as they

cations

may cause catalyzed formation of a further

depends

that

is metabolized

by glutathione enzyme.

ofthese

SOD

peroxide

radical-mediated

presence dant

by an

Hydrogen

selenium-containing

in close

detrimental

is a manganese-containing

compartment

compartments

peroxyl

H202

-

the potential

location

dependent.

tern,

in living systems to appreciate O and H2O2 from the system

possibly copper, metabolites with radical

O

-

to understanding

radicals of both

cytosolic

mechanism

a3 in the miP450 in the

2H

It is crucial

in this

in the

of free

imbalance free radical. will gain a

chain

reductase electron

in its immediate

radical

or molecule

the oxygen tochondrial species

which zinc

the pro-

anion

one or more unpaired electron(s): it is this electron that gives rise in most cases to high reactivity ofthe As the reduction of oxygen proceeds the O radical further

of

but

tracellular

of a free

radical

The

a major

account

known facts (6, 7). reduction of molecular

A free

.

as fl-carotene.

interaction

a reasonably

duction O

A, as well

oftheir

as the

environment.

phospholipase

A2 so

is cleft

from

the membrane

phos-

fatty

acid

will

then

be reduced

to a hydroxy

acid

by the

catalytic

ANTIOXIDANTS

AND

of glutathione

and

intervention

2LOOH Thus

a low

apparent

intake

the

subjects

originated;

which

peroxidase. + 2GSH

nutritional

significance

adequacy

in the

hydroperoxide

overall

may

degradation

2LOH

+ H2O

of selenium

is also

peroxidase

protective

otherwise

to radical

mechanism,

undergo

2) case-control

+ GSSG here

low

blood

the lipid

iron-catalyzed

quence

species.

LOOH

Antioxidant

nutrients

Antioxidant The

and

minerals

reviewed

has been

for the involvement

oflow

levels

( 1 1 ). Little

ofdietary

factor in this factor that

intake

exists

of manganese,

tions are those mixed function

cancer.

of the

indeed

would

ofevidence

protective

effect

of intake

approach

the level

be observed.

that

is now

of much controversy at present and been put forward. Among the suggesin the liver for the me-

of chemical carcinogens; the contention that the effect of selenium is mediated through glutathione though

to rapidly

Deficiency

maximal

tissue

proliferating ofselenium

diseases,

ofChina

both

where

in very

low

levels

tumour

proper-

of glutathione

per-

ofwhich

and

are only

levels.

occurs

somewhat

public

of China

blood) in the

must range

strong

epidemiological

low

blood

creased falls

levels risk

into

at a time

Despite

three

a correlation

when

supplements

is an

Both

disbut

in the

world

found

these

that (or low

of cancer

blood

diseases

mg/mL

between

intake) In brief

of Re-

to values body of

correlations

dietary (11).

(8-20

these refer is a growing

shows

levels

in the People’s

and this

an in-

evidence

categories: evidence, between

which high

frequently, cancer

but incidence

or death

rate

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/189S/4691418 by Washington University School of Medicine Library user on 06 June 2018

population

that

or a precancerous

the

that

and

between

that

E

The

literature with

studies

been

have

quite

on

limited

firm

data

ofischemic

numbers

it was

not

a role

for

disease.

for years

many

the

In the

ment of the vitamin the sample is taken.

serum,

E status disease

It seems,

case

for analysis

of vitamin

into plan,

of the

as soon storage

factors

that

the

E. Many early studies Other defects of earlier of only

a small

method

cancer

in man,

a study

men

( 15).

the serum

of27

1 men,

for the

serum

notified

necessary

controls. 1 y from

The mean level the date ofblood

ever, significantly was interpreted

dence

has emerged

level

related

or con-

the

the controls that the

was a consequence studies, however, between

(P low

measured

and

533 controls

mean

serum

in

vitamin

that of the matched diagnosed within cancer was, how=

0.003).

serum

This vitamin

rather than a cause some more convincing low

of

a cohort

was

cancer

from

in

for the the raw

incidence using

in the cancer subjects collection as having

for a link

cases

to future

concentration as having

different

lower than as suggesting

suffer studies

of tocopherol

in London

parameters;

E level was not significantly

cardiovasof the in-

Gey (14) has argued values rather than

was conducted The

of either the

connection standardized

level in the sample. whether vitamin E was

of 22 000 matched

measure-

as possible after of the plasma or

unfortunately inconsistent

number

of expressing

the sample. In this last need to use cholesterol tocopherol To test

of that

analyses only of samples subsequently (and often afterwards) identified as being of interest, because

analysis and

re-

taking

the subject concerned was shown to have developed cular disease or cancer, cannot be accepted because

trols,

in are

been

the

E, it is vital

has there

account which

have

requires

should be made Low temperature

cancer that

that

studies

samples

of human

and

however,

inconsistencies

of prospective

Similarly,

other antioxidant and ischemia.

that need to be taken of the experimental

of blood

are of interest.

in the

available,

of vitamin

inconsistent.

in eliminating use

pur-

factor

regarding heart

ofcardiovascular

a number of factors design and execution The

and studies

conducted

is a risk

conclusion

correlation

severely

of

selenium

developing

been

intake

ofthe

to any

incidence

several

ischemia and atherosclerosis, there are the WHO Task Group (13) were forced

in the prevention

Vitamin

level;

years later, but these data are available.

selenium

because

to come

years

a number

low blood

have

his-

many

is, for

there is no substantive evidence linking the minerals with the etiogenesis of atherosclerosis

large

state;

medical for

selenium

there

may

many

etiology of myocardial many inconsistencies

ported.

in subjects

the subsequent

measuring

disease

low

important

between

of cancer

is monitored

correlation

that

are the

from

a correlation

cancer

shown

the

fact

the cancer cases disease. In other

not consistently,

overt

of cancer some only preliminary

to show

include

disease

selenium

as insufficient; blood. There

of selenium kinds

Beck

the

porting

and now

an excellent

stability of vitamin from this defect.

is a cardiomyopathy people.

those

with

evidence

of some

1) ecological shows

associated

Republic are reflected

in young

with

of

prevent the conclusion that they diseases; rather, they are multideficiency is a major factor in

than

still be regarded 20-50 mg/mL

element

Kachin

mainly

1 3). Elsewhere higher

in the People’s

Disease

by therapy

( 12,

etiology

the development

ofthe

and

several features of the diseases are simple selenium deficiency factorial in origin and selenium selenium

seen

Keshan women,

that

eases are preventable

with

low soil levels

young

osteoarthropathy

cells.

is associated

acutely

blood

of children

their

level

been

oxidase are achieved at levels of selenium considerably lower than those needed to prevent cancer; and the proposal that the high levels of selenium are necessary because the element is

two

sites,

subjects

amounts

shows

incidence

of subjects

blood

cancer

The

available,

of pharmacological

that propose a direct role ofselenium oxidase system that is responsible

even

cohort have

to conclude

of 5 ppm

level

may

toxicity

body

Much

order

the physiological

and

at which

for the large of this

than

1 ppm)

of selenium

against

is generally

higher

of selenium, is the subject no clear explanation has

toxic

studies

of hu-

evidence

regard. However, selenium may prove to be of major

agent

which

0.01-0.

explanation

oxidase,

sampling

such

selenium

is much

in support

after

exists that selenium at high levels of intake can prein animals. It must be stressed that the protective

(in the range of intake

of a large

possible

of selenium,

in the diet,

in the etiogenesis

recently

as a prophylactic

dence now vent cancer

tory

evi-

significance

as having

in the

is, however, flawed since it can never be clear low blood selenium level was a cause or a conse-

a higher incidence are ongoing and

copper, or zinc as a risk is emerging as a dietary

amount

+ 0H

disease

of the antioxidant

cancer

tabolism tective

LO’ + Fe3

-

minerals

role

man

+ Fe2

high

ofthe disease; and prospective studies, in which

3)

LOOH+Fe3-’LO0’+Fe2’+H

which

and

diagnosed

such evidence whether the

of selenium

evidence,

selenium

actually

of major

since

further

l9lS

DISEASE

serum

vitamin

result E in of the eviE and

1 92S

DIPLOCK

high

cancer

incidence,

particular

cancer

19). In particular the

most

also revealed

and

a further

factor

on

of vitamin

E may antioxidant

of others

falls,

may

be inadequate.

now

effects

appear

the other

Ascorbic

acid

Much vitamin

of the evidence C as a protective

or cancer

comes

gests

that

the

that

have

have shown concentration)

I, ilanin

that

when

the

level

green

(27).

Thus,

term

increases

vegetables

or fruit

can

intervene

in model

sys-

epidemiological

a low dietary level (or ischemic heart disease

of vitamin A is closely controlled that involves the retinol-binding

increases

in dietary

in the level

the surplus is merely perhaps be expected have any preventive involve free radical substantial

singlet role

vitamin

A do not

ofcirculating

and

tissue

oxygen

ofvitamin

scavenging A and

other

in longbecause

ability

of vitamin in cancer

been reviewed recently (28). interest in whether carotenoids

in slightly

higher

have

a dis-

A role. absorbed

oxygenase to ret(29). Lycopene is

concentration

fl-carotene and more effectively

is capable also ofquenching singlet (30). It is therefore of considerable

note

prospective

epidemiological

A. The preven-

pro-vitamin fl-carotene

in man is converted by the intestinal carotene inol; some is certainly absorbed unchanged

strong

result retinol

retinoids

ease-preventing role independent of their There is no doubt that not all the dietary

in plasma

by a hoprotein

stored in the liver. It would not therefore that increase in dietary vitamin A would effect in the incidence ofdiseases that may mechanisms in their etiology, despite the

tion has, however, There is increasing

that

sug-

carotenoids

The serum level meostatic mechanism

present

role for disease that

formation

between C and

E

in populations

acid

prospective

a correlation of vitamin

of vitamin

ofevidence

ascorbic

of all

the level

in a possible cardiovascular

ofcarcinogen several

level

level

when

than

that

of

oxygen rather interest to

evidence

is emerging

that implies a close correlation between a high level of serum (3carotene and a lowered incidence of cancer. Thus in the study of Wald et al (31) the concentration of fl-carotene was measured in the stored serum samples of 271 men diagnosed as having cancer and in 533 unaffected controls matched for age, smoking history,

and

fl-carotene

duration levels

0.007) than the respectively). Men =

only

of storage of cancer

of the serum

subjects

corresponding in the top two

levels

had

men

in the

bottom

60%

quintile;

of the

small

sample

size

to identify

was controls quintiles

risk it was the

samples.

The

significantly

mean

lower

(P

(198 and 221 tg/L, of serum fl-carotene

of developing

cancer

as the

not

possible

because

of the

particular

sites

of cancer

where

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although

the

substantive

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quently

died

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evidence

is now

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initiated

were

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levels

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matched

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at hand

strongest

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healthy

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no correlations,

and

cancer

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the conclusion

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1975

who

subsematched

date of randomand fl-carotene

cancer

of cigarettes smoked, alcohol Serum levels of retinol and

evidence

men

persisted

for the number other parameters. further

and

of (3-carotene

individually

group, carotenoids

relationship

the Multiple

1973

levels

in 3 1 1 controls

this

from

between

of serum

for age, smoking status, randomization ization, and clinical center. Both total

26). A and

possible

of leafy

namely,

applied,

cancer.

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has

nutrient, rather than

a certain

is lower

isch-

study

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body

E

of both This

association Further

vitamin

the data,

of that

diseases

too

Furthermore,

(5)orcancer(5,

effect

intake

suppressor

(25).

is sufficient,

ofthese

is evidence

as a powerful studies blood

to be adequate

the substantial

incidence

There

one.

the

for lung

Europe,

low

sites.

for and interest agent against

an abundant

(2 1-24). tems

from

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in assessing

(16-

(5, 20), which across

than one antioxidant also be considered,

of only

protective

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groups

at certain

nutrients

the

from

to

possible

in the etiogenesis

cancer

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the

restricted

were

evidence

that a low level ofintake ofmore which may act in concert, must concentrating

usually

of population

risk

disease

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coordinated

convincing

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this

no generalizations

survey

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and

the study

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emic

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and some E showed

the results

offi-carotene

than adjusting

provided

against

lung

B

References 1 . American Society for Clinical Nutrition, Inc. The evidence relating six dietary factors to the nation’s health. Am J Clin Nutr 1979;32(suppl):262 1-2748. 2. Simopoulos AP, ed. Diet and health: scientific concepts and primciples. Am J Clin Nutr l987;45:lOl5-4l4. 3. Simopoulos AP. Preface. Am J Clim Nutr 1987;45:l027-8. 4. Kromhout D. Essential micronutrients in relation to carcinogenesis. Am J Clin Nutr l987;45:l361-7. 5. Gey KF, Brubacher GB, Stahelin HB. Plasma levels of antioxidant vitamins in relation to ischemic heart disease and cancer. Am J Clin Nutr l987;45: 1368-77. 6. Diplock AT. Free radicals in medicine and the biological role oflenium. In: Taylor TG, Jenkins NK, eds. Proceedings ofthe XIII International Congress Nutrition, London: John Wiley 1986:585-9. 7. Diplock AT. Micronutrients and trace elements in cancer prevention. In: Reed P1, Hill MJ, eds. Gastric carcinogenesis. Amsterdam: Excerpta Medica, 1988:99-104. 8. Klebanoff SJ, Rosen H. The role of myeloperoxidase in the microbicidal activity of polymorphonuclear leucocytes. In: Oxygen free radicals and tissue damage, Ciba Foundation Symposium No. 65, Amsterdam: Excepta Medica, 1979:263-81. 9. Gutteridge JMC. Lipid peroxidation: some problems and concepts. In: Halliwell B, ed. Oxygen radicals and tissue injury. Bethesda, MD: Upjohn and Fed Amer Socs Exp Biol, 1988:9-19. 10. Tappel AL. Vitamin E as the biological lipid antioxidant. Vitam Horm l962;20:493-5 10. 1 1 . Diplock AT. Mineral insufficiency and cancer. Med Oncol Tumor Pharmacother l990;7: 193-8. 12. Diplock AT. Trace elements in human health with special reference to selenium. Am J Clin Nutr l988;45:l3l3-22. 13. WHO: Environmental Health Criteria, 58-Selenium. Geneva: World Health Organization, 1987. 14. Gey KF. On the antioxidant hypothesis with regard to arteriosclerosis. Bibl Nutr Dicta l986;37:53-9l. 15. Wald J, Thompson SG, Densem JW, Boreham J, Bailey A. Serum vitamin E and subsequent cancer risk. Br J Cancer 1987;56:69-72. 16. Willett WC, Polk B, Underwood BA. Relation of serum vitamins A and E and carotenoids to the risk of cancer. N Engl J Med l985;3 10:430-4. 17. Willett WC. Selenium, vitamin E, fiber, and the incidence of human cancer: an epidemiologic perspective. Adv Exp Med Biol 1986;206: 27-34. 18. Knekt P. Aromaa A, Maatela J, et al. Serum vitamin E and risk of cancer among Finnish men during a 10 year follow up. Am J Epidemiol l988;127:28-4l. 19. Knekt P. Serum vitamin F level and risk of female cancers. Int J Epidemiol 1988;! 7:281-6.

ANTIOXIDANTS 20. 21.

22. 23. 24.

25.

26.

Stahelin HB, Rosel F, Buess F, Brubacher GB. Dietary risk factors for cancer in the Basel Study. BibI Nutr Dicta l986;37: 144-53. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. JNCI 198 l;66: 1191-1208. Acheson RM, Williams DDR. Does consumption of fruit and vegetables protect against stroke? Lamcet 1983;l:l 19 1-3. Knox EG. Ischaemic heart disease mortality and intake of calcium. Lancet l973;l: 1465-8. Palgi AA. Association between dietary changes and mortality rates: Israel 1949-1970; a trend free regression model. Am J (Jim Nutr 198 I;34: 1569-83. Terraa J, Matsushita S. Quinone formation from benzo(a)pyrene by free radicals: effects of antioxidants. Free Radic Biol Med 1988;4: 205-8. Nomura AMY, Stemmerman GN, Heilbrun LK, Salkeld RM, Villeumier JP. Serum vitamin levels and the risk of cancer of specific

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/189S/4691418 by Washington University School of Medicine Library user on 06 June 2018

AND

27. 28. 29. 30.

31.

32.

DISEASE

l93S

sites of men of Japanese ancestry in Hawaii. Cancer Res 1985:45: 2369-72. Olson JA. Vitamin A. In: MachIm U, ed. Handbook of vitamins. New York: Marcel Dekker, 1984:1-43. Wald NJ. Retinol, beta carotene and cancer. Cancer Sun’ 1987:6: 635-51. Thompson JN, Duval S. Verdier P. Studies on plasma carotenoids in man and animals. J Micronutr Anal l985;l:8l-9l. Di Mascio P. Kaiser 5, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989;274: 1-7. Wald NJ, Thompson SG, Densem JW, Boreham J, Bailey A. Serum beta carotene and subsequent risk of cancer: results from the BUPA study. Br J Cancer 1988;57:428-33. Connett JE, Kuller LH, Kjelsberg MO, et al. Relationship between carotenoids and cancer the Multiple Risk Intervention Trial Study. Cancer l989;64: 126-34.