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OCR for page 72
s
Characteristics of the Environment,
Aging, and the Aged
The toxic environments of the aging and the aged are diverse.
A person's environment includes at least the following compo-
nents: water, food, air, x rays, ultraviolet radiation, visible light,
heat, life-style, pharmaceuticals, and health maintenance. Food
and water can be considered separately, inasmuch as a federally
established dichotomy assigns the analysis and regulation of water
to the Environmental Protection Agency and the analysis and reg-
ulation of food primarily to the Food and Drug Administration.
Scientific considerations have followed this dichotomy. Life-style
is included as a component of a person's environment because of
the profound impact of such phenomena as smoking, recreational
sun exposure, and recreational drug use on disease prevalence and
longevity.
Pharmaceuticals, even though they play an important role
in health maintenance, are considered separately. Health main-
tenance is a more generic and inclusive category, and changes
in health care (with changes in diet) have been documented as
the principal cause of extended life expectation in many countries
(U.S. NTEHS, 1977, 1984~.
Although a person might live in a general environment that
seems constant, even over a long period, exposure to potentially
toxic agents varies widely, that is, the toxic environment changes.
72
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ENVIRONMENT, A GINO, AND THE A GED
73
Chemicals in the air, in food, and in water vary widely, even in
isolated environments. Whether these changes are significant with
respect to aging or the aged is one of the main questions in this
study. In any event, it is both useful and correct to state that
there is no average toxic environment. Therefore, no average toxic
environment can be simulated ~ a laboratory, and there is no
way to perform laboratory experiments whose results can be ex-
trapolated in a general way to the composite human environment.
However, the fact that human populations live in different environ-
ments offers an opportunity for comparative studies in biochemical
toxicology.
All elements of the human environment contain toxic sum
stances. The important question is whether exposures to these
substances affect aging or produce toxic effects. This question can
be framed in the context of each constituent of the environment.
Water. The content of drinking water varies widely with
locale. Generally, few substances are deliberately added to drink-
ing water; those deliberately added include chlorine species and
fluorides. Some chemicals found in trace concentrations in water
supplies have been tested for some toxic effects and others have not.
For instance, pesticides and other commercial chemicals have been
detected ~ many water supplies, but at concentrations deemed by
regulatory agencies to constitute only reasonable hazards to pub
kc health. What is not clear is whether the toxicologic methods
applied by regulatory agencies can evaluate age-associated toxic
effects adequately.
. Foodi. The term food, as opposed to diet, applies to the
intake in foodstuffs of possibly toxic substances that can alter life
span, as distinct from quantitative intake of putatively nontoxic
normal foodstuffs. Food consists mainly of complex mixtures and
is not well defined from a toxicologic perspective. The ingestion of
food accounts for the bulk of the chemical substances that enter
the body, of which most, but not all, are probably innocuous. Food
acts both as an inducer of biologic processes relevant to aging and
as a carrier of potentially deleterious substances. These substances
can be divided grossly into four components: natural constituents,
contaminants from the environment of its growth, contaminants
from its processing, and contaminants from its preparation.
· Air an] its contaminants. Inhalation has the third great-
est responsibility (after ingestion of food and water) for bringing
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74
AGING IN TODAY'S ENVIRONMENT
chemical substances into contact with the body. Of the airborne
agents that produce specific toxic effects, the major one is cigarette
smoke. Inhalation can bring both gases and particles into contact
with the lining of the airways. These substances differ with re-
spect to absorption and clearance via the mucociliary escalator
and possible toxic effects. Breathing volume, clearance, and am
sorption vary with age. The makeup of air varies greatly among
geographic locations and among indoor, outdoor, and occupational
environments. The aged generally spend more time indoors and
less time in occupational environments than do others. But the
variation among indoor environments is so great that it precludes
generalization about exposure.
~ Pharmaceutical exposure. Pharmaceutical agents, as op-
posed to environmental agents, are designed to elicit biologic ef-
fects. The toxicologic data on pharmaceuticals are extensive and
usually include substantial human response data. Consideration
of the pharmaceutical environment is ~rnportant to the problem
being evaluated in this report for two main reasons. First, the
aged are exposed to pharmaceuticals more than the young. Sec-
ond, some pharmaceutical agents place biologic stress on exposed
people. If an essential component of aging is a reduction in the
capacity to respond to stress, then consideration of aged people's
responses to pharmaceuticals could be important. There is no type
ical or average pharmaceutical environment for the aged, but some
groups with defined pharmaceutical exposure for extended periods
might be important in studying the response of aged populations
to toxic stress.
. L,ife-style. Life-style including smoking, sun-tanning, and
taking of recreational drugs is included as a separate category of
environmental exposure for two reasons. First, life-style is consid-
ered as creating optional environmental exposure. Second, expo-
sures in this category are known or suspected to increase disease
prevalence that might shorten life or mimic aging processes, or
both. Thus, this category of environmental exposure must be
considered avoidable toxic stress that is relevant for only some
populations.
. Bealth maintenance. This category is included only be-
cause improvement in health care changes life expectancy dramat-
ically in some human populations (Schneider and Reed, 1985~.
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ENVIRONMENT, AGING, AND THE AGED
75
Improvement in health care is usually accompanied by improve-
ment in nutrition; it has been difficult to separate these two factors
as contributors to life-span extension.
NUTRITION
Until fairly recently, there has been a tendency to consider
the issue of chemucal toxicity and the environment in terms of
the contamination of the "natural" environment with man-made
pollutants, such as DDT. Efforts like those of Higginson (1969) and
Doll and Peto (1981) have led to a growing recognition that the
environment includes such factors as diet and life style. Indeed,
one of the most important factors in chronic human toxicity is
natural components of the diet.
Whereas man-made pollutants (so-called contaminants) are
commonly measured in picograrns, dietary components that can
be toxic are more often measured in milligrams or even grams.
Common foods are replete with naturally occurring biologically
active compounds, for example, vasoactive amines in bananas,
cyanogens in corn, oxalates in spinach, goitrogens in cabbage, and
anti-inflammatory compounds in licorice (Sapeika, 1978~. This is
not surprising, in that the plants forrn~ng much of our diet have
evolved mechanisms to prevent overpredation by insects (natural
insecticides~and other animals(Ames,1983~.
As a whole, it appears (Ames, 1983) that the most important
chemical exposure of humans, both in quantity and in diversity,
results from diet. Thus, diet is considered to be one of the most
important aspects of the environment that should be taken into
account in the studies of chemical toxicity and aging. Diet is a
broad term that usually includes natural contaminants, such as
mold-produced aflatoxin; the residues of food preparation prac-
tices, such as mutagens produced by charring of foods (National
Research Council, 1982~; and food additives. However, in focusing
this discussion on nutrition, we will emphasize the portion of diet
that maintains an organism's health or growth.
An interesting topic that is excluded from the present discus-
sion is the recently suggested importance of some environmental
agents in the induction of parkinsonism, a disease considered char-
acteristic of age. The suggestion was based on the development of
a mode! for parkinsonism related to the production of a metabolite
of an agent that causes parkinsonism in humans and animals, and
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76
AGING IN TODAY'S ENVIRONMENT
on the presence of antibodies to this metabolite in people who have
parkinsonism but no history of exposure to the chern~cal (Lewin,
1986~.
It is well known that the lack of a nutrient often leads to a
deficiency syndrome and that an excess of the same component
can sometimes lead to overt toxicity. The current discussion con-
centrates on manipulations within what is generally considered to
be a fairly normal range.
Effects of Nutrition on CCbx~city
Various nutritive components have major effects on the ex-
pression of toxicity. For instance, by increasing the amount of
casein given to rats for a month, one can increase the LD50
(the dose required to kill 50~o) of some herbicides by a factor
of at least 6 (Shakman, 1974~. Protein quality and methionine
content Knight also affect the detoxification of some pesticides
(Boyd, 1972~. Compared with purified diets, cereal-based chow
suppressed dipheny~hydantoin-induced cleft palate in mice (Mc-
CIain and Rohrs, 1985~.
Because chronic disease often has a long latency, it can be
especially susceptible to the influence of nutrition. Nutrition is
important in the pathogenesis of coronary heart disease, gallstones,
appendicitis, varicose veins, obesity, hiatus hernia, and cancer
(Burkitt, 1982~. Some of these relationships have become evident
through the effect of a change to Western diet in groups whose
traditional diets were different; for example, Eskimos who switched
to Western diets suffered an increased rate of acute appendicitis
(SincIair, 1982~. Other effects have been revealed by epidemiologic
studies, such as the Framingham study, which related cholesterol
to risk of coronary heart disease (Kanne! et al., 1971~.
Experunental studies demonstrating the role of diet in chronic
disease have been plentiful since the beginning of modern experi-
mental nutrition; for example, some diets influence the progression
of atherosclerotic lesions in rabbits (Anitschkow, 1913) and diet
modifies induced tumorigenesis in mice (Watson and Melianby,
1930).
In view of the long history of such studies, the lack of under-
standing of the mechanisms by which nutrition influences chronic
disease and toxicity is surprising. One reason is the complexity of
the diet. As noted above, many substances are consumed in food.
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ENVIRONMENT, A GINO, AND THE A GED
77
Changes in dietary composition can alter xenobiotic metabolism
(Rogers and Newberne, 1971), change intestinal microflora quan-
titatively and qualitatively (Stasse-Wolthuis, 1981) thereby mod-
ifying transport and production of bacterial metabolites, affect
bile acids (Ready et al., 1980), and change glutathione synthetase
(Beutler, 1972~. With the number of substances in food, many of
which are needed for maintenance of function, almost any step in
the interaction of agent and organism is likely to be influenced by
altering nutrition, which would thus lead to an effect on toxicity.
The effects of individual macronutrients, such as dietary pro-
tein and fat, on toxicity, longevity, and associated aging events
have been explored by altering the dietary content of the macronu-
trients being assessed. A major problem with this type of analysis
is that such changes in dietary composition might influence the
amount of food eaten. Unfortunately, the food intake is often not
accurately determined or not taken into account In the interpreta-
tion of findings. Because the amount and type of food eaten might
profoundly influence both aging processes and toxicity of environ-
mental agents, failure to address this issue reduces the value of a
study.
The micronutrients, that is, minerals and vitamins, are diffi-
cult to study in the context of toxicity and aging partly because
there are so many substances in each class of nutrients. In addi-
tion, toxicity data are generally lacking on these compounds and
elements. There is also little information on the role of these sum
stances in aging, although considerable study has been aimed at
ascertaining the relationship of specific components to age-related
pathologic processes (e.g., calcium and vitamin D in relation to
osteoporosis and calcium and sodium in relation to hypertension).
Because a given nutrient is probably involved at several stages
in the maintenance of body function, it might have different im-
pacts on toxicity. This is especially true for the more complex toxic
effects such as cancer. Although several factors in the diet might
be involved in the toxicity, evidence that one agent can inhibit
or promote the carcinogenic effects of another, depending on the
sequence of exposures (e.g., Kitagawa et al., 1984), indicates that
the effect of altering nutrient intake on complex toxic end points
is difficult to determine.
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78
AGING IN TODAY'S ENVIRONMENT
Nutrition and Cancer
Cancer is actually over 200 different diseases. It occurs in al-
most all tissues that have the capacity to replicate. A recent review
summarized much of the present consensus about the mechanisms
of cancer (U.S. Interagency Staff Group on Carcinogens, 1986~.
Simplistically, cancer can be considered as a multistage process
that usually involves agent uptake; agent metabolism (for car-
cinogen activation); cellular processes, such as DNA repair and
proliferation; and organismic responses, such as attack by the
immune system. Each of these major factors can be affected by
changes in nutrition. A recent review (NRC, 1982) analyzed many
of these issues. The following discussion gives some examples of
the insights that have been gained on the relationship between
nutrition and cancer.
One of the most well-tested effects in modulation of carcino-
genicity by nutrition is the inhibition of spontaneous and induced
carcinogenesis by restriction of total caloric intake. In practice,
this is usually accomplished by allowing ingestion of less food than
is eaten by a control population. Many studies have demonstrated
the effect of caloric restriction, including that of Tannenbaum
(1945), who characterized the effect on benzota~pyrene-induced
mammary tumors in mice, and Kritchevsky et al. (1984), who
found a similar effect in 7,12-dimethy~benz~ajanthracene-induced
mammary tumors in rats. Life-span studies have shown a decrease
in the incidence of spontaneous tumors of many types. Human ev-
idence is less clear because it is hard to separate the effects of
changes in diet composition and total caloric content, socioeco-
nomic status, and so on; but there is some evidence that the
incidence of colorectal cancer is affected by caloric intake (e.g.,
Hill et al., 1979~.
Lower dietary protein content is generally associated with
lower incidences of tumors (NRC, 1982), such as 3-methy~cholan-
threne-induced mammary adenocarcinoma in rats fed high-protein
diets (Stray et al., 1964) and aflatoxin-induced liver tumors in rats
(Newberne and Rogers, in press). In contrast, Clinton et al. (1979)
found that a decrease in dietary protein increased the incidence
of mammary tumors induced by 7,12-dimethy~benz~aJanthracene
and that the protein effect depended on the sequence of nutritional
changes and agent administration.
Increased dietary fat has been implicated in an increasing
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ENVIRONMENT, AGING, AND THE AGED
79
incidence of cancer at several sites (NRC, 1982~. For example, in-
creasing dietary fat from To to 20~o usually increases the incidence
of mammary tumors both spontaneous tumors and, depending
on the carcinogen used, induced tumors. Interpretation of the ef-
fect has been complicated by the observations that restricting total
calories eliminates much of the high-fat effect (Kritchevsky et al.,
1984), that energy intake, and body size play a role (Boissonneault
et al., 1986), and that essential fatty acids are also important.
Dietary fiber has been implicated in modulating toxicity. How-
ever, there are many different dietary fibers, and they might act
by various mechanisms, such as by altering the metabolism of di-
etary agents (DeBethizy et al., 1983) or altering the turnover of
gastrointestinal epithelium (Cassidy et al., 1981~.
Most of the recent work on cancer and vitamins has focused
on ~ritarnins A, C, and E. As a rule, vitamin A deficiency increases
susceptibility to tumors, and an increase in its intake is protective.
However, vitamin A also induces tumors in hamsters (Smith et al.,
1985), and retiny] acetate, a related compound, increases hormone-
induced mammary carcinogenesis in mice (Welsch et al., 1981~.
Vitamin C has little effect on carcinogenesis except through its
inhibition of the intestinal reaction of nitrites with Gaines to form
nitrosamines (Mirvish, 1981~.
There are a number of mechanisms by which vitamin E could
inhibit cancer formation, particularly by its antioxidizing activity.
Most animal studies have tended to confirm this effect, but others
have found no such effect, and a few have found that vitamin
E enhances carcinogenesis under some conditions (Newberne and
Suphakarn, 1983; Toth and Patil, 1983; Wattenberg, 1972~.
There has been little systematic evaluation of the effect of
minerals on carcinogenesis. Selenium can be carcinogenic (USNCI,
1980~; but it also appears to protect against the formation of some
induced tumors (Medina et al., 1983; Newberne et al., 1986~.
Thus, the role of nutrition in carcinogenesis is far from fully
understood. However, two observations are worth noting in re-
gard to the effects of nutrition on aging. One is that the effects
of changes in nutrition or carcinogenesis are not simple or even
monotonic (i.e., an increasing effect with increasing nutrient con-
tent). That is not surprising, inasmuch as the diet is a complex
mixture and carcinogenesis is complex. Defining the components
of and biologic response to a standard semisynthetic diet, such as
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80
AGING IN TODAY'S ENVIRONMENT
NIH-31, might eliminate some of the problems encountered with
the cornrnonly used commercial diets.
The second observation (discussed more extensively in the fol-
lowing sections) is that, of the various nutritional modifications
. . . . . .
~ ,
caloric restriction is likely, at least initially, to be the most gen-
erally important for chronic end points. Although caloric restric-
tion is a broad brush that involves many integrative, physiologic,
metabolic, and cellular processes, it appears to have the most
reproducible effects on chronic end points. Therefore, it is reason-
able to assume that it is highly likely to provide a route to the
understanding of mechanisms of aging.
Nutrition and Agmg
Although the discussion of environmental influences on toxic-
ity and aging has not traditionally considered nutrition explicitly,
eating and drinking are the greatest sources of chemical exposure
of humans. Diet has an effect on toxic response, both acute and
chronic. Nutrition is also known to be a factor in the develop-
ment of chronic disease in humans and animals. However, the
complexity of diet involves many steps in the interaction of agent
and organism. The more complicated the interaction, the more
complicated the influence of diet. Indications that this is true are
the multiphasic responses of agents that interact with carcinogens
and that can function as promoters or inhibitors, depending on
the timing of exposure. Such complex behavior is manifest when
cancer is used to mode! the interaction of toxicity and nutrition in
regard to aging processes.
. .. ~ .. . . .
Background and Criteria for Evaluating Aging
The data from the cancer model on the effect of nutritional
modulation in general en cl caloric restriction in particular consti-
tute only one of many indications of an important role of nutrition
in toxicity. In addition, nutrition is often claimed to be important
in influencing the aging processes of humans and other animals
(Porte, 1980~. Some published data do indicate that nutrition
modulates many adverse effects of aging (Masoro, 1985~. Further-
more, some nutritional regimens and dietary components appear
to promote aging processes, or at least the occurrence of age-
associated deterioration (Guigoz and Munro, 1985~. A substantial
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ENVIRONMENT, AGING, AND THE AGED
81
data base exists on nutrition and aging, as well as on the role of
nutrition in cancer, but strategies to determine the mechanism by
which nutrition modifies these processes are needed.
However, before considering the effect of nutritional modifica-
tion of aging, we should clarify some of the concepts that underlie
research in this field. In tumorigenesis, "bumps and lumpish can
be counted fairly directly, but the situation for aging is more
complex. Changes in longevity have been widely used as criteria
for determining the impact of dietary modification on senescence.
However, there are problems with that approach. For instance,
during the last 140 years, life expectancy at birth in the United
States has markedly increased (Hazzard, 1983~. The increase is
probably not a result of factors influencing basic aging processes,
but rather results primarily from protecting the population from
premature death due to specific infectious diseases and injuries.
A change in the life span of a species is a better criterion
than life expectancy. A nutritional manipulation that increases
life span probably does so by lowering the rate of aging. However,
a nutritional manipulation that decreases life span might do so by
speeding the aging process or through a number of other possible
mechanisms, such as modifying responses to toxic reactions or
speeding disease processes.
A major problem in the use of longevity as a criterion to
identify factors influencing the rate of aging is the length of time
needed to make this assessment. Indeed, for practical purposes this
criterion can be used only with short-lived animal models such as
rodents. Therefore, there has been much effort toward developing
reliable biomarkers of aging (Reff and Schneider, 19823.
It has been difficult to be certain that a particular functional
or morphologic measurement is a reliable biomarker of aging, be-
cause it is not possible to define aging in the fundamental biologic
terms that could serve as a primary standard. Changes in many
functional activities and the occurrence of many disease processes
are associated with aging, and it is important to learn about nu-
tritional manipulations that influence these age-associated events.
However, the influence on such age-associated events should not be
taken as evidence that a nutritional manipulation has modulated
the aging processes.
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82
Food Restriction
AGING IN TODAY'S ENVIRON~NT
The only nutritional manipulation that has been shown to
increase life span in mammals is food restriction, and it has been
truly demonstrated only in laboratory rodents. The phenomenon
was first demonstrated by McCay and Crowell (1934) and has
been confirmed by many others (Barrows and Kokkonen, 1977~.
Although the dietary protocols have varied widely, all successful
approaches have reduced caloric intake by 20-60% (weindruch'
1985~. In the initial studies, food restriction was started at wean-
ing; it was later found that life span also increased when food
restriction began during adult life (Beauchene et al., 1986; Cheney
et al., 1983; Goodrick et al., 1983; Stuchlikov et al., 1975; Wein-
druch and Walford, 1982; Yu et al., 1985~. Indeed, Yu et al. (1985)
found that food restriction begun at the age of 6 months (early in
adult life) was as effective in extending the life span of rats as that
begun at the age of 6 weeks (2 weeks after weaning).
This effect of food restriction has not been shown in other
mammals, but careful research has not been done on long-lived
marnInals. Findings similar to those in rodents have been obtained
in nonmammals: protozoa (Rudzinska, 1952), rotifers (FanestiT
and Barrows, 1965), Dapinia (Ingle et al., 1937), Drosophila (Loeb
and Northrop, 1917), and fish (Comfort, 1963~.
Food restriction not only influences longevity, but delays or
prevents many age-related functional changes (Table 5-1~. It also
slows or prevents a spectrum of age-associated diseases (Table
5-2~.
McCay et al. (1935) suggested that food restriction delayed the
aging processes by slowing growth and development. The findings
of Barrows and Roeder (1965) supported that view. Indeed, for
many years, the view prevailed that retarding maturation and
slowing and prolonging growth were at the basis of the effects of
food restriction on longevity. However, since 1965, many studies
have challenged the concept (Cheney et al.5 1983; Goodrick et al.,
1983; Stuchlikov et al., 1975; Weindruch and Walford, 1982~.
Moreover, Yu et al. (1985) found that food restriction in rats
only from the age of 6 weeks to the age of 6 months (the period of
rapid growth) was less effective in extending life span and retarding
age-associated processes than food restriction begun at either the
age of 6 weeks or the age of 6 months. Those findings have
redirected views on the action of food restriction away from growth
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98
AGING IN TODAY'S ENVIRONMENT
in nursing homes, each resident was matched with an ambulatory
person enrolled in Medicaid (Ray et al., 1980~. Among nursing-
home patients, central nervous system (CNS) drugs were the most
often prescribed medications, being given to 74% of patients; only
36~o of the ambulatory comparison group received CNS drugs.
Nursing-home patients often received prescriptions from mul-
tiple categories of CNS drugs: 34~o from two or more categories,
To from three or more, and 1.6%0 from four. The most com-
mon combinations were those of an antipsychotic and a sedative-
hypnotic, most often thioridazine and flurazepam. The next most
common combinations were those of a minor tranquilizer and a
sedative-hypnotic, usually diazepam and chIoral hydrate.
The three most commonly prescribed antipsychotic drugs were
thioridazine, chlorpromazine, and haloperidol. The authors sug-
gested that those drugs might be used to mold patients into the
institutional routine.
Medication Compliance in the Elderly
Many patients have difficulty in taking medications as pre-
scribed by their physicians. Blackwell (1972) reviewed over 50
studies and found that 25-50~o of all outpatients completely failed
to take their medication.
On the basis of careful review of drug histories in 178 chroni-
cally ill ambulatory patients aged 60 or over in the General Med-
ical Clinic at New York Hospital, Schwartz et al. (1962) found
that 59~o made one or more medication errors and 26~o made
potentially serious errors. Error-prone patients were more likely
to make multiple than single mistakes. The average number of
errors-was 2.6 per error-making patient. Omission of medication
was the most frequent error, followed by lack of knowledge about
medications, use of medications not prescribed by a physician, and
errors in dosage, sequence, or timing. Almost identical data were
obtained using similar techniques in a Seattle-area clinic (Neely
and Patrick, 1968~.
In a study of geriatric patients 10 days after hospitalization,
Parkin et al. (1976) found that 66 of 130 patients deviated from
the drug regimens prescribed at discharge. Noncomprehension or
lack of a clear understanding of a regimen (in 46 patients) was
actually a greater problem than noncompliance or failure to follow
instruction (in 20 patients).
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ENVIRONMENT, AGING, AND 1lHE AGED
99
Although medication errors seem to be prevalent among el-
derly patients, studies that used objective measures of compliance
have indicated that the elderly are not necessarily more prone
to noncompliance than younger patients. That has been demon-
strated in patients taking digoxin (Weintraub et al., 1973~.
A recent example is the feasibility study for the multicenter
clinical trials in the United States called the Systolic Hypertension
in the Elderly Program (SHEP), which was conducted between
1980 and 1984. A final cohort of 551 persons over 65 years old
with isolated systolic hypertension was enrolled. Compliance with
therapy was evaluated by self-reporting, pill counts, and urinary
assay for the presence of study drugs. More than 80~o of partici-
pants in both treatment and placebo groups complied with their
SHEP prescriptions (Smith et al., 1985~.
Researchers must also allow for intelligent noncompliance by
patients who appropriately alter their drug regimen to minimize
side effects or to eliminate unnecessary treatment (Weintraub,
1984~. Additional research is needed to clarify the clinical impor-
tance of such noncompliance in older patients.
Adverse Drllg Reactions
Adverse drug reactions might be the inevitable price of im-
proved drug therapy for disease (Barr, 1955; Jick, 1974~. The
possibility that these reactions are costly in terms of human illness
and economics (Campbell et al., 1977; Melmon, 1971) is a mat-
ter of controversy. It has been stated that adverse drug reactions
constitute a formidable health problem with staggering economic
consequences that one-seventh of all hospital days are devoted to
the care of drug toxicity, at an estimated yearly cost of $3 billion
(Melmon, 1971~.
In support of that contention, previously cited studies from
several countries indicate that 3-5~o of all hospital admissions
are primarily for a drug reaction; that 1~30% of all hospitalized
patients have an adverse drug reaction, doubling the duration
of hospitalization; and that 30~o of these patients have a second
reaction during their hospital stay. The lay press has asserted
that 30,000 Americans die as a direct result of the use of drugs
prescribed by doctors (Rensberger, 19763.
In contrast, it has been suggested that drugs are remarkably
nontoxic, considering their extensive use (Jick, 1974~. According
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100
AGING IN TODAY'S ENVIRON
to data from the Boston Collaborative Drug Surveillance Program,
death from drugs occurs in less than 0.3~o of hospitalized medical
patients in the United States, and for each course of drug ther-
apy the frequency of adverse drug reactions IS only Who, or one
in 20 treatments. Furthermore, although associated with discom-
fort, most drug reactions such as nausea, drowsiness, diarrhea,
vomiting, and rash are transient and of minor consequence to
the patient. Others have rejected both positions, arguing that
estunates of the magnitude of the problem of adverse drug reac-
tions are characterized by incomplete, arbitrary, and uncontrolled
data and by unreliable and inaccurate cost estimates (Karch and
Lasagna, 1975).
In the context of unresolved controversy, the issue of adverse
reactions to drugs in the elderly must be considered. The extent
to which age itself is a risk factor for untoward therapeutic events
is uncertain and has been the subject of several critical reviews
(Gardner and Club, 1970; Klein et al., 1981; Nolan and O'Malley,
1987b; Vestal et at., 1985).
Not all the studies agree, but many have demonstrated a
higher incidence of adverse drug reactions in hospitalized geriatric
patients. In studies in which an age-related increase was observed,
it ranged from 1.6-fold to 5-fold. Patients over 70 appear to be
particularly vulnerable, with an incidence of about Who, compared
with 3-10~o in patients under 30 (Hurwitz, 1969; Seid! et al., 19663.
Studies performed in the United States (SeidI et al., 1966), North-
ern Ireland (Hurwitz, 1969), New Zealand (Smidt and McQueen,
1972), Switzerland (Klein et al., 1976), and Israel (Levy et al.,
1977) have consistently documented an association between age
and an increased incidence of adverse drug reactions.
The data on outpatients are limited. Two studies demon-
strated an increase with age (Kellaway and McCrae, 1973; LumIey
et al., 1986) ~d two demonstrated no effect of age (Klein et al.,
1984; Muiroy, 1973~. In one of the studies that did not show an
age effect, the results suggested that the elderly might be unable
to distinguish drug side effects from symptoms of "old ages and
unable to communicate adverse effects to their providers (Klein et
al., 1984~.
Limitations of the data on adverse drug reactions in the elderly
have been enumerated (Klein et al., 1981; Nolan and O'Malley,
1987b; Vestal et al., 1985~. Most studies have involved hospitalized
patients. True populations at risk, which would include patients
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ENVIRONMENT, AGING, AND THE AGED
101
talking drugs in the community as well as patients in the hospital,
frequently have not been studied. Patients have not been strat-
ified according to severity of illness or concurrent drug therapy.
Unmedicated control groups have not been included.
Despite the lirn~tations, the available data indicate that sev-
eral risk factors are associated with adverse drug reactions, in-
cluding age, sex, drug dosage, previous drug reaction, impairment
in hepatic or renal function, length of hospital stay, and multiple-
drug therapy (Vestal et al., 1985~. In addition, age differences in
physiology and pharmacology might help to explain the apparent
propensity of the elderly to suffer adverse reactions to drugs.
LIFESTYLE
Deliberate Chemical Exposure
Life-styTe is important in determining the types and quantities
of chern~cal agents (other than pharmaceuticals) that are deliber-
ately brought into contact with the human body. Some of the
agents reflect cultural trends, others are more individual.
The chemicals and their uses are diverse. Specialized com-
ponents of the diet have become popular in the United States,
although scientific data to justify their use are generally lack-
ing. Some people are convinced of the merits of an exclusively
or predominantly vegetarian diet; others use supplements that in-
clude pure preparations of vitamins, amino acids, minerals, and
other compounds, as well as many complex chemical mixtures
represented by "unusual" plant and other materials or extracts.
Whether such materials have any effect on the aging processes, ei-
ther adverse or beneficial, generally has not been tested. Similarly,
their toxic effects are usually unstudied.
Another important source of deliberate human exposure to
chemical agents comes from the use of various types of fragrances
and cosmetic agents. These are often complex chemical mixtures
whose major ant] minor components are untested beyond acute
toxic potential. Studies involving repeated application to the skin
of experimental animals have sometimes revealed dermal and neu-
rologic damage.
Deliberate chemical exposure of human subjects occurs in a
number of other settings, many of which are influenced by individ-
ual preferences and life-styI~for example, use of mouthwash and
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102
AGING IN TODAY'S ENVIRONMENT
oral deodorants, antiseborrheic shampoos, sunscreen and suntan
lotions, and insect repellents.
[earned Heiplessness
Aging is associated with a Toss of control over homeostatic
responses, mobility, and cognitive function, for example. In physi-
ologic terms, the loss of control leads to a narrowing of homeostatic
reserve and, in behavioral terms, to helplessness. The tendency of
fondly and friends, as well as members of the health professions, to
urge accommodation rather than resistance to progressive incur-
sions on functional capacity leads to "learned helplessness." The
acceptance of helplessness leads not only to greater helplessness,
but also to increased susceptibility to disease.
A dramatic example of the relationship between learned help-
lessness and disease occurs in rats subjected to the unyoked electric-
shock paradigm of Weiss (Sklar and Anisman, 1979; Visinta~ner et
al., 1982~. Two rats are connected (yoked) in series to a random
electric-shock generating system. Both rats have levers in their
cages, but only one lever functions as a switch for the electric cir-
cuit. When the functional switch is pressed, the electric shock to
both rats is turned off. However, only the rat with the functional
switch is in control; the other is subjected to "learned helpless-
ness.~ A third rat is placed in the cage, but Is not subjected to
electric shock. The effect of these environmental manipulations
on susceptibility to disease is striking. For example, if the dose
of cancer ceils that kills 50% of the rats not subjected to electric
shock is given to rats that have learned helplessness, 80~o of the
animals die. The same dose of cancer cells kills only 20%0 of the
rats in control.
It seems reasonable to conclude that some of the increased
intrinsic susceptibility to disease that is manifested in the elderly
could be related to environmental influences that result in learned
helplessness among physiologically comprorn~sed and behaviorally
impaired people.
Atrophy of Disuse
Life-style can inevitably affect aging processes and the aged
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ENVIRONMENT, AGING, AND 17IE AGED
103
through occupation, recreational activities, exercise habits, eat-
ing and drinking habits, tobacco smoking, exposure to stress-
almost any behavior that creates contact between the person and
the environment. Elements of life-style can increase or decrease
risks of acquiring age-related degenerative diseases. They can also
conceivably accelerate or delay physiologic and anatomic changes
associated with the passage of years. Clear examples are the va-
riety of age-related- diseases induced by toxic chern~cals in tobacco
smoke and the decrease in risk of cardiovascular disease produced
by regular exercise.
Atrophy of disuse is a consequence of life-style and therefore
belongs among factors responsible for extrinsic aging. Decline in
the vigor, health, and well-being of the aging and the aged is
tacitly assumed to be due to intrinsic aging, but these unfavorable
changes result largely from atrophy of disuse. The debilitated
state resulting from atrophy of disuse conceivably contributes to
susceptibility to age-related diseases; however, such effects are
difficult to dissect from the general complex of events that make
up intrinsic and extrinsic aging.
In a study of some 17,000 middle-aged and older Harvard
alumni over several years, Paffenbarger et al. (1984) found a 49~o
excess risk of coronary heart disease among people who led seden-
ta~y life-styles (Butler and Lewis, 1986~.
Spoor Pollutants
The indoor environment is a subject of growing concern. Dur-
ing the last decade, health experts and regulatory officials have rec-
ognized that indoor exposures can have a greater effect on human
health and comfort than outdoor pollutants. Americans spend
up to 80~o of their time indoors in homes, in public buildings,
in offices or other places of work, or in various modes of trans-
portation. Those who are most susceptible to the health effects
of pollution—the very old, the very young, and the chronically
ill might spend even more of their time indoors.
No federal standards for indoor air—apart from industrial
workplace standards exist. Yet the concentrations of some pol-
lutants in office buildings, homes, and public places are known
to exceed their primary ambient-air quality standards. Modern
energy-conservation measures that reduce ventilation can cause
"sick buildings" and the related health effects.
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104
AGING IN TODAY'S ENVIRONMENT
Indoor pollutants of concern identified by the National Re-
search Council (1981a) and in other reports include radon and its
decay products, asbestos, tobacco smoke, formaldehyde and other
organic compounds, the gases from combustion (principally nitro-
gen dioxide and carbon monoxide), and microorganisms and aller-
gens. There is little epidemiologic information on the health effects
of chronic, low-level exposure to any of these pollutants except to-
bacco smoke (National Research Council, 1986~. What data exist
have been derived principally from occupational exposures—to
uranium, pesticides, and asbestos, for example and most involve
acute exposures.
For some pollutants, human discomfort provides a useful in-
dicator of environmental contamination. Discomfort gives imme-
diate incentive to avoid or correct environmental deficiencies and
can lead to closer investigation of their source. Unfortunately, the
populations that are most susceptible to the effects of pollution
knight be the least able to do anything about it. The elderly com-
monly have diminished sensory perception and are less able to
detect contaminants in their environment. People who seldom go
outside into fresh air or who are chronically exposed to carbon
dioxide or carbon monoxide might also have diminished sensory
capacity.
Temperature
Conditions for thermal comfort appear to vary little, if at all,
with such factors as geographic location, sex, ethnic background,
and even age (ranger, 1972~. Aging merits some special con-
sideration: the basal metabolic rate decreases progressively, but
evaporative heat loss does also. These two changes tend to offset
each other to a limited extent that is difficult to assess, because
the elderly spend much more time than the young in sedentary
activities. Furthermore, with the energy conservation practices
now common indoors during winter, the elderly have a narrower
temperature range, which limits their thermal resistance (Sacher,
1979~.
Sensory adaptations in sedentary older persons might be se-
verely diminished, and a person could fail to notice the symptoms
of impending hypothermia until they became severe.
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ENVIRONMENT, AGING, AND ME AGED
Radon
105
The radioactive gas raclon and its decay products have drawn
considerable attention in recent years after discoveries of very high
indoor concentrations in some parts of the country. Exposure to
high concentrations of radon and its progeny causes lung cancer.
Most of the data on the health effects of radon progeny come
from studies of underground miners whose occupational exposures
were 10~1,000 times those of the general population. However,
homes in some locales have recorded radon concentrations higher
than those in mines. Data on Canadian uranium miners indicate
an excess of lung cancers even in the group with the lowest cumu-
lative dose a dose that would be in the same range as the lifetime
cumulative close from many home exposures.
A few epidemiologic studies of nonoccupational radon expo-
sure have been done, but most have failed to control for smoking.
However, it appears that both active smoking and passive smok-
ing increase susceptibility to the effects of radon, because radon
progeny adhere to respirable particulate matter in tobacco smoke.
Nero et al. (1986) recently reviewed the associated risks.
Formaldehyde
There are many sources of formaldehyde exposure in the in-
door environment. Particleboard, paneling, plywood, and urea-
formaldehyde foam insulation can be important sources of va-
pors. Because of their extensive use of particleboard, with its high
surface-to-volume ratio, mobile homes have been found to have
much higher concentrations of formaldehyde than conventional
homes. In addition, cosmetic products, especially shampoos, are
a source of skin exposure, and cigarette smoke contains 10-15 mg
of formaldehyde per cigarette.
Formaldehyde, a contaminant of concern to all populations,
might be particularly important in the health and comfort of el-
derly people and people with chronic respiratory problems. The
present Occupational Safety and Health Administration standard
for formaldehyde is 3 ppm. However, the National Institute for
Occupational Safety and Health has recommended that occupa-
tional exposure be reduced to the lowest feasible, to minimize
the risk of cancer (U.S. NIOSH, 1981~. Potential carcinogenic-
ity has been reviewed by the International Agency for Research
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106
AGING IN TODAY'S ENVIRONMENT
on Cancer (1982~. In addition, people have reported mild ear,
nose, and throat discomfort and other symptoms at led than 0.5
ppm. Between 10 and 20% of the general population might be
susceptible to the effects of formaldehyde and react acutely at any
concentration.
The principal effect of formaldehyde at low concentrations is
irritation of the eyes and mucous membranes. Human eyes are
very sensitive to airborne formaldehyde; they can be irritated by
atmospheric concentrations of 0.0~0.5 ppm and in some cases
respond to 0.01 ppm when formaldehyde ~ mixed with other pol-
lutants. At relatively low concentrations (0.1 ppm), it can irritate
upper airways; it more frequently does so at 1-11 ppm (NRC,
1981a). In some susceptible persons, an allergic reaction might
occur at very low concentrations, causing bronchoconstriction and
asthmatic symptoms.
Combustion Products
The two indoor combustion products that most often cause
concern about health effects on those exposed are nitrogen dioxide
(NO2) and carbon monoxide (CO). The amount of NO2 formed
in unvented indoor combustion devices Is not usually sufficient
to cause acute toxicity; however, NO2 concentrations equal to or
greater than the current ambient-air quality standard of 0.05 ppm
are not unusual in kitchens with gas cooking (NRC, 1981a). In
animal studies, NO2 has been shown to produce transient and long-
term damage to small bronchial airways and alveolar tissue (WHO,
1977~. In addition, changes in nonciliated cells, destruction of
Type ~ epithelial cells, and proliferation of Type IT cells after
relatively low exposures (2 ppm for 4 hours) suggest that chronic
exposure couIcl lead to chronic bronchitis and the development of
emphysema (Evans and Freeman, 1980~. Resistance was weakened
in animals chronically exposed to NO2 at low concentrations with
bacterial aerosol challenge (Gardner et al., 1979~.
A 1981 study by Mostardi et al. compared the health of chil-
dren attending two schools, one of which bordered an industry and
had comparatively high concentrations of NO2 and sulfur dioxide.
The study found a higher incidence of acute respiratory illness and
significantly compromised pulmonary function among the children
attending the school near the industry. That finding is important
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ENVIRONMENT, A GINO, AND LIE A GED
107
because recent evidence has suggested that frequency and sever-
ity of acute respiratory illness in childhood are related to chronic
obstructive lung disease in adulthood.
The second import ant product of combustion, CO, is found
in cigarette smoke and fossil-fuel combustion effluents, and thus is
found commonly indoors in a broad range of concentrations. The
principal health effect of CO is impaired oxygen transport. CO is
readily absorbed from inspired air and binds to hemoglobin with
over 200 times the affinity of oxygen. Doses are cumulative, so
exposure to CO at even Tow concentrations in the air can result in
substantial carboxyhemogIobin concentrations in the blood. Al-
though healthy people are not greatly affected by exposure to CO
at low concentrations, those with limited cardiovascular reserve
can be at greater risk because their blood has reduced oxygen-
carrying capacity. In addition, CO has been implicated in the
pathogenesis of atherosclerosis.
Asbestos
Asbestos has been widely used in public and private buildings,
in insulation and fireproofing materials, in ornamental decoration
and soundproofing, and on surfaces In public areas. An extensive
program has recently been undertaken to identify and remove it
from school buildings.
The relationship between exposure to asbestos and Jung can-
cer is well known. Asbestosis, mesothelioma, and gastrointestinal
tract cancers have been found in excess among workers occupation-
ally exposed to asbestos. Less is known about the health effects of
exposures to asbestos and other fibrous materials in environments
other than the workplace.
Environmental Tobacco Smoke
Tobacco smoke is a major source of pollution in the indoor
environment. Nonsmokers absorb measurable amounts of CO and
nicotine and can absorb small amounts of other constituents from
environmental tobacco smoke (ETS). ETS contains several other
known hazardous pollutants, but few studies have been done on
exposure to them by this route.
Many of the chemicals identified in cigarette smoke are irritat-
ing to the nose, throat, and eyes. Studies of the long-term effects
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108
AGING IN TODAY'S ENVIRONMENT
of passive smoking have suggested that it can cause small-airway
dysfunction, which ~ an early precursor of clinically important
chronic obstructive lung disease. Exposure to ETS appears to
cause some increase in systolic blood pressure, especially in chil-
dren. As mentioned above, carboxyhemogiobin concentration can
be increased by exposure to tobacco smoke, which would reduce
the maximal exercise capacity in normal adults. Some people are
allergic to ETS, although documentation on the numbers of these
people is inadequate.
Chronic exposure to tobacco smoke apparently can impair
immune system function. Laboratory studies on mice have found
that chronic tobacco-smoke exposure accelerated many of the im-
munologic changes associated with aging, including marked mod-
ifications of the responses associated with the T-lymphocyte arm
of the immune system and of the systemic clearance mechanisms.
Populations that might be more susceptible than others to
the effects of ETS include children, people with coronary arterial
disease, and people with chronic Jung disease. Patients with com-
prom~sed heart or lung function suffer earlier onset of angina or
clyspnea, respectively, after exposure to ETS.
Pesticides
A wide variety of pesticides are available for use in the home
and in public and office buildings. They are assumed to be an
important source of exposure to known hazardous substances.
About 9 of 10 households in the United States use some type of
pesticide in the house, garden, or yard; nearly 84~o of this use is
in the house. A study conducted in South Carolina (a region of
heavy pesticide use) by Kie! et al. (1969) found that one-third of
the families that used pesticides applied them during each week
of the year. A study by Savage et al. (1981) surveyed 10,000
households in different regions of the United States and found
over 500 pesticide formulations being used. Many people did Lot
know what pesticide they had used (e.g., Bug sprayed. Interviews
with members of 8,254 households yielded the recording of use or
storage of 1,756 containers of unknown insecticides.
Representative terms from entire chapter:
aging processes
