EPA/600/P-03/004A
November 2005
Final Report
AGING AND TOXIC RESPONSE:
ISSUES RELEVANT TO RISK ASSESSMENT
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC 20460
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DISCLAIMER
This document has been reviewed in concordance with U.S. Environmental Protection Agency
policy and approved for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
Preferred citation:
U.S. EPA (Environmental Protection Agency). (2006) Aging and toxic response: issues relevant
to risk assessment. National Center for Environmental Assessment, Washington, DC;
EPA/600/P-03/004A. Available from: National Technical Information Service, Springfield, VA,
(202) 564-3261 and online at http://www.epa.gov/ncea.
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CONTENTS
LIST OF TABLES iv
PREFACE v
AUTHORS, CONTRIBUTORS, REVIEWERS, AND ACKNOWLEGEMENTS vi
EXECUTIVE SUMMARY vii
1. INTRODUCTION 1
2. DEFINING THE AGING POPULATION 3
3. PHYSIOLOGICAL CHANGES AND AGE-RELATED DISEASES AND CONDITIONS ...A
3.1. GENETIC AND CELLULAR STRUCTURE AND FUNCTION 4
3.2. NERVOUS SYSTEM 6
3.2.1. Cognitive Function 7
3.2.2. Motor Function 9
3.2.3. Sensory Function 10
3.3. CARDIOVASCULAR SYSTEM 12
3.4. GASTROINTESTINAL SYSTEM 18
3.5. RESPIRATORY SYSTEM 19
3.6. HEPATIC SYSTEM 21
3.7. RENAL SYSTEM 22
3.8. IMMUNE SYSTEM 24
3.9. SKIN 25
3.10. BODY MASS 26
3.11. MUSCULO-SKELETAL SYSTEM 27
3.12. ENDOCRINE AND REPRODUCTIVE SYSTEMS 29
3.13. BASAL METABOLISM 31
4. POLYPHARMACY IN THE ELDERLY 32
5. EXAMPLES OF ENVIRONMENTAL AGENTS AS RISK FACTORS FOR DISEASES IN
THE ELDERLY 33
5.1. Metals 33
5.2. Pesticides 34
5.3. Air Pollution 35
6. ANIMAL MODELS FOR THE STUDY OF AGING 37
6.1. IN VITRO MODELS 38
6.2. NONMAMMALIAN SPECIES 39
6.3. MAMMALIAN SPECIES 39
7. AGE-RELATED RISK ASSESSMENT ISSUES AND RESEARCH NEEDS 42
REFERENCES 46
in
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LIST OF TABLES
Table 1. Physiological changes related to toxicokinetics in the elderly
IV
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PREFACE
In 2002, EPA launched the Aging Initiative to develop a National Agenda for the
Environment and the Aging to help guide the Agency's efforts to protect the health of older
persons. This document, Aging and Toxic Response: Issues Relevant to Risk Assessment, is
intended to orient EPA scientists and risk assessors to physiological and biochemical factors in
the elderly that may influence their responses to exposures from environmental chemicals.
Although it is not a comprehensive review of literature, the document identifies several data gaps
and research needs that may inform the Office of Research and Development's Research
Initiative on Aging in conducting research for better characterize risk to the elderly population
from exposure to environmental agents.
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AUTHORS, CONTRIBUTORS, REVIEWERS, AND ACKNOWLEDGEMENTS
The U.S. EPA's Risk Assessment Forum (RAF) and the National Center for Environmental
Assessment (NCEA), both within the Office of Research and Development, are responsible for
the preparation of this document. The RAF initially contracted with Versar, Inc. (EPA Contract
No. 68-99-238, Task 15), and the Work Assignment Manager for this contract was Gary
Kimmel, NCEA. Versar subcontracted to Edward J. Masoro, University of Texas Health Center,
Austin, TX, and Janice B. Swartz, Northwestern University, Chicago, IL. The February 2001
Versar report "Exploration of Aging and Toxic Response" was posted on the NCEA webpage and
remains available at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=29411. NCEA's
Washington Division subsequently sought to further the topical discussion of aging. The 2001
draft report was enhanced by updating a significant number of references and related discussion,
as well as reorganizing the material, to produce this November 2005 report "Aging and Toxic
Response: Issues Relevant to Risk Assessment'.
AUTHORS for the 2005 report:
Rebecca C. Brown
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
Babasaheb Sonawane
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
CONTRIBUTORS
Marquea D. King
Office of Pollution Prevention and Toxics
U.S. Environmental Protection Agency
Washington, DC
REVIEWERS
U.S. Environmental Protection Agency Reviewers
Stanley Barone NCEA, ORD
Robert Benson Region 8
Barbara Glenn National Center for Environmental Research, ORD
Kathryn Guyton NCEA, ORD
Larry Hall National Health & Environmental Exposure Research Laboratory, ORD
Lee Hofmann Office of Solid Waste & Emergency Response
Doug Johns NCEA, ORD
Carole Kimmel NCEA, ORD
Gary Kimmel NCEA, ORD
Susan Makris NCEA, ORD
Deirdre Murphy Office of Air Quality Planning & Standards, Office of Air & Radiation
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AUTHORS, CONTRIBUTORS, REVIEWERS, AND ACKNOWLEDGEMENTS, cont.
Edward Ohanian Office of Water
Dharm Singh NCEA, ORD
James Walker NCEA, ORD
Edward Washburn Office of Science Policy, ORD
External Reviewers*
Kannan Krishnan University of Montreal, Montreal, Canada
Ed Levin Duke University Medical Center, Durham, NC
Randy Strong University of Texas Health Science Center, San Antonio, TX
* The external reviewers were independently selected by the Eastern Research Group under EPA
Work Assignment No. 88, Contract No. 68-C-02-060. The external peer review contract was
managed by Nagalakshmi Keshava, NCEA, ORD, Washington, DC.
ACKNOWLEDGEMENTS:
Thanks to Emily Newell, NCEA, ORD, Washington, DC, for her editorial assistance.
Vll
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EXECUTIVE SUMMARY
Aging and Toxic Response: Issues Relevant to Risk Assessment was prepared to provide a
very broad overview of the functional, physiological, and biochemical changes that occur in
elderly persons, and the major age-associated diseases and conditions in order to better
understand the age-related toxicokinetic and toxicodynamic impacts of environmental agents.
Elderly people can be vulnerable to environmental challenges due to their age-altered
physiological processes and exposure patterns. In addition, the presence of age-associated
diseases or conditions may increase susceptibility to the harmful effects of specific agents.
Therefore, special consideration of the elderly population is needed in assessing risk from
exposure to environmental agents.
A few examples of biological responses to exposure to environmental agents in the
elderly population are provided, along with a succinct discussion of various animal models used
to study the aged response to environmental agents. There is also recognition of risk assessment
issues and relevant research needs.
This document is not meant to be a comprehensive review of the literature for the topic
areas discussed. Instead, it is intended to orient the reader to the general subject of aging and
potential toxic responses, particularly the identified physiological factors likely to influence the
risk of exposure to environmental agents in elderly populations.
Vlll
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1. INTRODUCTION
Americans aged 65 years and older are a growing segment of the U.S. population.
Various federal government organizations, including the U.S. Environmental Protection Agency
(EPA, or Agency), recognized the challenges confronting older Americans. Attention to the
possible health effects on elderly Americans from environmental exposures began with the
publication of Aging in Today's Environment (Committee on Chemical Toxicity and Aging,
1987) and Principles of Evaluating Chemical Effect on the Aged Population (WHO, 1993). In
2002, EPA launched the Aging Initiative to develop a National Agenda for the Environment and
the Aging to help guide the Agency's efforts to protect the health of older persons. In response
to these efforts, the National Academy of Sciences convened a workshop entitled The
Differential Susceptibility of Older Persons to Environmental Hazards in December 2002 (NAS,
2002).
During certain life stages, particularly in early development (U.S. EPA, 2005a) and later
life, individuals can be differentially exposed to and affected by a variety of toxicants in their
environment. In the aging population, exposures may be related to disease and nutritional status,
occupation (NRC and IOM, 2004), and lifestyle choices (e.g., smoking, consumer product use,
subsistence activities, hobbies) (Verbrugge et al., 1996), and the effects of these exposures may
accumulate throughout an individual's life (U.S. EPA, 2003). In addition, early-life exposures
may impact the occurrence of later health conditions (Barker, 1998). Due to the gradual decline
in physiological processes, and the increase in age-associated diseases and conditions, the elderly
have or may have increased susceptibility to health effects from exposure to environmental
agents.
The growing proportion of Americans in the aged demographic group heightens the need
to understand the potential impact of environmental influences on this sector of the population.
In 2002, 35.6 million persons in the U.S. were aged 65 years and older, accounting for about
12% of the total population; by 2030, the older population will more than double to 71.5 million
(U.S. AoA, 2004). Worldwide, the number of persons aged 60 years and older is estimated to be
more than 600 million, and that number is projected to grow to almost 2 billion by 2050, when
the population of older persons will be larger than the population of children (0-14 years) for the
first time in human history (WHO, 2002).
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Subpopulations within the elderly population can be delineated by gender or
race/ethnicity and are important distinctions. Women make up 58% of the population aged 65
years and older and 69% of the population aged 85 years and older (FIFARS, 2004). The U.S. is
becoming more racially and ethnically diverse; in 2003 non-Hispanic whites made up about 83%
of the population aged 65 years and older, but this proportion is expected to decline to 61% by
2050 (FIFARS, 2004). In addition, genetic polymorphisms related to metabolic capacity within
the aged population may influence the toxicity caused by exposure to a parent chemical or a
reactive intermediate.
Chapter 2 of this document defines the terms and age groupings for aging research.
Chapter 3 discusses the physiological changes that occur in the elderly and highlights age-related
diseases and conditions in each system. Chapter 4 highlights the impact of pharmaceutical use
on the response to environmental toxicants. Chapter 5 gives examples of environmental
contaminants of concern to the elderly population. Chapter 6 succinctly discusses various animal
methodologies and models used in aging research. Chapter 7 evaluates and identifies risk
assessment issues for the aged population and future research needs.
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2. DEFINING THE AGING POPULATION
When referring to older humans, the terms "aged," "elderly," "geriatric," and "senescing"
are used interchangeably. In the U.S. and many other countries, the aged population is defined
as those aged 65 years and older, based on the traditional age of retirement from the work force.
However, there is no general agreement on the start of this stage of life. For example, the United
Nations defines people aged 60 years and older as elderly (WHO, 1993).
One concern about grouping all the elderly into one broad category is that because
physiological changes occur variably after 65 years of age. Therefore, the creation of
subcategories of age groups has been proposed: 65-74 years, young-old; 75-84 years, old; 85-99
years, old-old; and over 100 years, oldest-old (Spirduso, 1995). Most gerontologists refer to
persons in the last group as "centenarians," and this group has recently been the subject of much
research in an attempt to discover the basis of their extreme longevity. This document, for the
most part, addresses all elderly as one age category: 65 years and older.
Physiological deterioration does increase with age (Crome, 2003), with the percentage of
persons requiring help from others for basic life activities increasing from about 9% in the 65-74
years age range to 20% in the 75-84 years age range and to 50% in those 85 years and older
(Jette, 1995). However, these age-based subcategories do not account for the variability that
occurs among individuals of the same age (U.S. EPA, 2002). To address this issue, the term
"biological age" is used to describe the functional ability of one individual when compared with
another individual of the same chronological age. "Usual aging" is said to occur in individuals
who function well but who may exhibit modest deterioration of the physiological systems;
"successful aging" occurs in those who will continue to live in a healthy manner (Rowe and
Kahn, 1998). Finally, the descriptive terms "fit" and "frail" refer to the maintained levels of
independence for daily living (Geller and Zenick, 2005).
Animal models employed for research on aging are discussed in Chapter 6. The terms
"elderly," "aged," and "geriatric" are not usually used for animals and there are no generally
agreed-upon criteria available for determining old age for animal species. Using life table
characteristics as a guide, an animal is deemed "old" if its age is greater than the median length
of life of the population, and it may be placed in the category of "oldest old" if it is older than the
age of the 10th percentile survivors.
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3. PHYSIOLOGICAL CHANGES AND AGE-RELATED DISEASES
AND CONDITIONS
The progressive modification of structure and function with age involves alterations not
only at the genetic, molecular, and cellular levels, but also at the level of the tissues, organs,
systems, and the entire organism. The processes of how a toxicant affects the body are known as
toxicokinetics (TK) and toxicodynamics (TD). TK, also referred to as pharmacokinetics, is the
determination and quantification of absorption, distribution, metabolism, and excretion of
chemicals. TD, also referred to as pharmacodynamics, is the determination and quantification of
the sequence of events at the cellular and molecular levels leading to a toxic response to
environmental agents.
Age-related changes in TK (Calabrese, 1986; Hattis and Russ, 2003) and TD (Roberts et
al., 1996) have been studied, but given the interindividual variation in physiological changes, the
degree to which a given elderly individual will exhibit TK and TD changes cannot be predicted
solely on the basis of chronological age. The natural physiological deterioration in organs and
tissues of elderly individuals may lead to increased responses toward xenobiotics that may
additionally be compounded by the preexisting conditions of the individual. Also, genetic
polymorphisms affect individual responses to environmental chemicals, although the database
for such variation within the elderly population is quite limited (Dybing and Soderlund, 1999).
In the following sections, each organ or system is discussed in reference to age-related
changes in its structure or function, not only as an inherent part of aging, but in response to
environmental agents. The focus throughout this document is on the normal processes of aging
and how these may alter risk, with a few examples of disease states or conditions that can also
alter risk. Although it is important to differentiate between age-related pathology and true
physiological aging, this is often difficult because the majority of age-related changes increase
the vulnerability of an aging organism to disease and, ultimately, death.
3.1. GENETIC AND CELLULAR STRUCTURE AND FUNCTION
In general, genetic damage increases with age, including the frequency of DNA adducts,
point mutations, microsatellite expansions and contractions, amplifications and contractions of
DNA sequences, gene rearrangements, and chromosomal aberrations (Burkle, 1996). Telomere
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length appears to decrease with increasing age, although the functional consequences are not
clear. The rate of cellular repair decreases with age, and the occurrence of incomplete or
inaccurate repair increases with age; this results in an increase in structural changes in the DNA
or associated proteins. Genetic transcription may increase, decrease, or remain unaffected with
age. In addition, the rate of gene expression or protein synthesis generally declines with age
(Van Remmen et al., 1995).
A number of changes occur at the cellular level, leading to changes in structure or
function of various organ systems. Cellular signal transduction plays a key role in functional
regulation (Lodish et al., 1995) and may be altered during aging (Yeo and Park, 2002).
Alterations in apoptosis have been suggested to play a major role in aging (Holt, 1995; Warner,
1999).
The elderly may be more vulnerable to chemical exposure because of a decreased
capacity to repair DNA damage caused by mutagens. Decreased immunologic defenses may
also increase the vulnerability of the elderly to chemical carcinogens. Also, the elderly have a
decreased ability to detoxify free radicals and other reactive metabolites that can initiate
carcinogenesis, promote proliferation of initiated cells, and drive progression to the malignant
phenotype (Balducci et al., 1986; Rikans and Hornbrook, 1997). On the other hand, other
physiological changes in the elderly may reduce their vulnerability to certain chemical
carcinogens, including decreased capacity for metabolic activation, increased capacity for
deactivation, decreased enteric absorption, and reduced capacity for cellular proliferation
(Balducci et al., 1986).
Cancer is characterized by abnormal cells with partial or complete lack of structural
organization and functional coordination with normal cells and tissue that grow more rapidly
than normal cells; it is predominantly a disease of the aged (Dix, 1989). The accumulating
abnormal growth forms a distinct mass (tumor), which can be either benign or malignant.
Benign tumors are noncancerous; malignant growths invade and destroy the tissue in which they
originate and can metastasize to other sites in the body via the bloodstream and lymphatic
system.
Fundamental aspects of cancer development in the elderly are not well understood (Lee
and Wei, 1997). The increase of cancer incidence with age may be related to decreased immune
function, a longer duration of exposure to carcinogens due to increased length of life, increased
susceptibility of cells to carcinogens, and several other biological factors (Cohen, 1994).
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Because cancerous growths can continue long after the initiating stimulus ceases and they
typically occur over many years, latency is an important consideration.
Examples of cancers that occur at a higher frequency in the elderly include those of the
lung (Connolly, 1998), pancreas (Braganza and Sharer, 1998), skin (Chuttani and Gilchrest,
1995), colon (Wald, 1998), prostate (George, 1998), breast (Mansel and Harland, 1998), and
uterus, ovaries and cervix (Brown and Cooper, 1998). Both the incidence of and mortality from
cancer are higher in the elderly population, potentially due simply to the increasing length of life
expectancy. Also, research seems to indicate that environmental exposure early in life is a key
risk factor for cancer diagnosis later in life (Perera, 1997, 1998). Because the role of
environmental agents in cancer risk is complex, a detailed discussion of cancer is beyond the
scope of this document.
3.2. NERVOUS SYSTEM
The central nervous system (CNS) may undergo progressive deterioration at all levels of
organization: structural, biochemical, and functional. On the structural level, only a modest
decrease in brain weight actually occurs with advancing age. However, the volume of the
cerebrospinal fluid (CSF) does increase with age, with a concomitant decrease in brain volume
(Stafford et al., 1988). Although generalized age-associated loss of neurons is small, the key
issue is the decline in the number of synapses with advancing age (Masliah et al., 1993). Some
localized brain regions suffer a more substantial loss of neurons than do others (Katzman, 1995);
more specifically, motor neurons that supply skeletal muscle are lost with aging, although no
available evidence suggests that this results in functional changes.
Aging alters the biochemistry of the neurotransmitter system in both the brain and the
peripheral and autonomic nervous systems (Collins and Cowen, 1998; Cotman et al., 1995). For
example, glutamate, N-methyl-D-aspartate, and kainic acid-binding receptor binding all change
with age, as does the level of gamma amino butyric acid in the CSF. The elderly have higher
blood levels of the sympathetic neurotransmitter norepinephrine than do younger people,
probably due to an increased rate of release of norepinephrine by sympathetic nerve fibers,
although a decreased clearance of norepinephrine from the circulating blood may also be
involved. In addition, the response to the sympathetic neurotransmitter is impaired at advanced
ages in a number of important target sites, e.g., the heart.
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Carrier-based transport may be somewhat compromised (e.g., decreased transport of
choline and glucose), and the blood-brain barrier may be more vulnerable to damage in elderly
individuals. Most of the studies examining blood-brain barrier function and aging have failed to
show any significant age-related alterations in permeability to lipophobic substances and high-
molecular-weight solutes in the absence of neurological disease (Johnson and Finch, 1995;
Mooradian, 1988). However, when exposure is concurrent with a chronic disease that may
damage the integrity of the barrier (e.g., Alzheimer's disease, hypertension, diabetes, stroke),
chemicals may more freely penetrate the blood-brain barrier in the elderly. Also, there is some
evidence that exposure to these agents early in life may cause later neurological impairment
(Barone et al., 2001; Landrigan et al., 2005; Logroscino, 2005).
3.2.1. Cognitive Function
Cognition refers to processes of the mind such as perceiving, remembering, thinking,
learning, and creating. Aging impacts three aspects of cognition: attention, memory, and
intellectual functions. Attention, the ability to focus on and perform a simple task without losing
track of the task objective, does not undergo an appreciable age-associated change. Because this
process involves the circuitry of the brain stem and the thalamus, it appears that these brain
regions remain functionally intact in the elderly (Albert and Moss, 1995). However, other
aspects of attention and response inhibition involving frontal lobe functioning and, presumably,
dopamine modulation of frontal activity do appear to undergo an age-related decline (Volkow et
al., 1998). Other aspects of intellectual function, such as executive function requiring abstraction
and mental flexibility, can also be affected by aging and are associated with a subtle decline in
dopaminergic modulation also in frontal cortical activity (Volkow et al., 1998).
Memory, on the other hand, progressively deteriorates in the elderly, with impairment
evident in 15% of men and 11% of women aged 65 years and older and more than 33% of all
elderly aged 85 years and older (FIFARS, 2004). However, many types of memory are not
impaired in the healthy elderly, such as short-term memory (Smith and Earles, 1996) and the
initial processing of sensory information.
In the absence of disease, intellectual functions can be rather well maintained in the
elderly (Kausler, 1994). Although some kinds of learning become increasingly difficult with
increasing age, e.g., learning tasks that require great perceptual speed and a high level of
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physical coordination, some aspects of intellectual function may actually improve (e.g.,
creativity), although speed of performance may markedly deteriorate with advanced age. With
respect to semantic knowledge (verbal ability in vocabulary, information, and comprehension),
intellectual performance changes little during adult life. Procedural memory, which requires the
use of both learned motor and cognitive skills (e.g., typing or riding a bicycle), does not
deteriorate in the normal elderly, but the functional ability to perform them may be affected by
aging.
Alzheimer's disease (AD) affected nearly 4.5 million Americans in 2000, and the
affected population is expected to increase to 13.2 million by 2050 (Hebert et al., 2003). In
2002, AD was responsible for 3.2% of all deaths among the elderly (Anderson and Smith, 2005).
AD typically involves the degeneration of neurons in the cerebral cortex and the hippocampus,
and the morphologic hallmarks of the disease are senile plaques (containing the core protein
beta-amyloid surrounded by swollen degenerating nerve terminals and glia cells) and
neurofibrillary tangles (found inside the axons and dendrites of brain neurons). With further
progression, deficits occur in the ability to communicate orally and in writing, recognize familiar
objects by sight, and copy simple drawings. The individual often remains alert and cognizant
until the terminal stages (Terry and Katzman, 1992).
A number of environmental exposures have been studied to examine the relationship with
the development of AD (Brown et al., 2005), including aluminum and pesticides. A genetic
predisposition for the development of AD also appears to exist; in particular, the epsilon-4 allele
of the apolipoprotein E gene has been found to increase the risk of the disease at advanced ages.
In addition, AD in women may be related to the loss of estrogen after menopause (Kawas et al.,
1997).
Other dementias. Dementia is prevalent in the older population, with 15% of men and
11% of women experiencing moderate or severe memory impairment and the prevalence
increases with age (FIFARS, 2004). However, although memory loss is the most common
symptom of dementia, it does not necessarily indicate a diagnosis of dementia.
The most common disease that can cause dementia is AD, followed by vascular dementia
(VaD). Other diseases that can cause dementia include Lewy body dementia, frontotemporal
dementia, Huntington's disease, and Creutzfeldt-Jakob disease. VaD is related to a reduced
blood flow to the brain (Hershey and Olszewski, 1994), and the subtype multi-infarct dementia is
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caused by blood vessel obstructions, many too small to have produced a major clinical problem.
A history of strokes or transient ischemic attacks may be present.
A number of environmental risk factors may be associated with cognitive decline,
including polychlorinated byphenyls (PCBs) (Schantz et al., 2001), metals, pesticides, and
solvents (Baker, 1994). For VaD, these include occupational exposure to pesticides, plastic, or
rubber (Hebert et al., 2000; Lindsay et al., 1997).
3.2.2. Motor Function
The elderly have some loss in ability to precisely control skeletal muscle activity,
resulting in a variety of deficits in motor performance ability. These deficits are due to age-
associated deterioration of the central processing system, as well as to changes in sensory and
muscle function.
Reaction time - the time from stimulus to initiation of a motor response, such as the
contraction of a skeletal muscle - slows with advancing age (Spirduso, 1995). Although this is
due in part to the slowing of both the muscle contraction and the peripheral nerve impulse
conduction velocity, the slowing of central processing is the primary defect. Reaction time in the
elderly is slowed even more when the individual is confronted with a choice of alternative
responses or if the movement complexity increases. Reduced speed appears to enable the elderly
to maintain accuracy of movement.
Mobility changes only moderately in the elderly who are free of discernible diseases. In
particular, the speed of walking decreases with age; this occurs to a larger degree in women than
in men (Fernandez et al., 1990). Although a slow gait is likely due to reduced muscle strength
and joint deterioration as well as impairment of balance and posture (Walker and Rowland,
1991; Woolacott et al., 1986), it may also enhance the ability of the elderly to monitor the
environment, thus enabling them to avoid hazards. A number of environmental risk factors have
been associated with a decline in motor function, including metals such as lead and manganese,
pesticides, and solvents.
Parkinson's disease (PD) currently affects approximately 500,000 people in the U.S.,
and about 50,000 new cases are reported annually, with an average age of onset of 60 years. PD
is a motor disorder with symptoms that include tremors at near rest, rigidity (resistance to passive
movement of limbs), slowness in initiating movements, deterioration of postural reflexes, lack of
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facial expression, and rapid, small steps with decreased associated movements such as arm
swinging (Mutch and Inglis, 1998). This is a progressive disease, resulting in severe disability
and ultimately death. The rate of progression varies among individuals, with death occurring
within 5 years in 25% of the cases and within 10 years in 60% of the cases.
There is a clear association between the loss of dopamine receptors in the brain
(nigrostriatal projection) and motor task performance as is seen in PD. Neurons in the substantia
nigra that send axons to the striatum are lost, resulting in a decrease in the release of the
neurotransmitter dopamine in this brain region (Volkow et al., 1998).
Although some genetic polymorphisms are linked to PD, the majority of PD cases are
sporadic (Checkoway et al., 1998). Risk factors for PD include increasing age and
environmental exposure (Ben-Sholom, 1997; Brown et al., 2005; Tanner and Goldman, 1996),
including pesticides (Abbott et al., 2003), metals such as manganese, solvents, farm or rural
residence, farming occupation (Petrovich et al., 2002), or drinking well water. In fact, only
approximately 10% of PD cases are related to occupational exposures (Semchuk et al., 1992).
Environmental toxicants may interact with genetic predispositions, e.g., pesticide exposure and
glutathione-S-transferase polymorphism (Menegon et al., 1998). In addition, there is some
evidence for early-life exposure to environmental agents and later development of PD
(Logroscino, 2005).
Stroke refers to a sudden or relatively rapid occurrence of inadequate blood flow to the
brain caused by the blockage or rupture of a brain blood vessel, resulting in brain cell death and
neurological impairment (Ebrahim, 1998). Importantly, strokes can allow the blood-brain barrier
to be breached, potentially leading to increased cerebral exposure to toxicants (Cipolla et al.,
2004). Strokes may occur at any age, but are most common in the elderly. In the U.S., the
incidence of stroke is about 700,000 per year, and more than 160,000 deaths annually are
attributed to strokes. More than half the survivors have functional impairments, ranging from
inability to function in the work force to loss of ability to carry out activities of daily living.
Also, an estimated 20% of all dementia cases are thought to be due to stroke (Barba et al., 2002).
3.2.3. Sensory Function
Impairment of the sensory system occurs in almost all elderly people. Indeed, studies
show that virtually all sensory modalities decline in acuity with age (Pathy, 1998). The sensory
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system includes vision, hearing, touch, taste, and smell, and it can be affected by exposure to
metals and solvents (Gobba, 2003).
Vision. Age-related sight impairment occurs in 16% of men and 19% of women
(FIFARS, 2004). A number of changes occur in the visual system with age (Scialfa and Kline,
1996). Visual acuity, the ability to see objects in fine detail, decreases with increasing age and
likely results from a decrease in the number of neurons making up the optic nerve. Loss of rods
results in a reduced ability to adapt to low-intensity light. The reduced ability of the elderly to
discriminate colors in the green-blue-violet region of the visible light spectrum does not appear
to be due to a defect in the cones; rather it relates to a yellowing of the lens with increasing age
(Hood et al., 1999), which also may underlie the increased susceptibility to glare. Those over
age 50 years have some loss in depth perception, for reasons that remain to be identified.
Vision impairment can be caused by a decrease in resting pupil size, which reduces the
illumination of the retina and the ability of the lens to become more spherical when the person is
looking at near objects. This decrease is due to a change in the physical properties of the lens
and in the function of the ciliary muscles, and it progresses with age. Several visual disorders
occur much more commonly in the elderly than in the young, including cataracts (Young, 1991),
glaucoma (Shiose, 1990), and age-related macular degeneration (Brodie, 1998). Visual function
can be disturbed from exposure to metals, solvents, and pesticides (Gobba, 2003).
Hearing. Age-related hearing impairment (presbycusis) is found in nearly one-half of all
elderly men and one-third of all elderly women (FIFARS, 2004). Many changes related to
hearing loss occur in the structures of the inner ear (Willott, 1991). Cilia, which encode high-
frequency sound, atrophy, auditory nerve cells are lost, blood supply to the cochlea is reduced,
and the structure of the basilar membrane is altered. Age-related hearing loss due to changes in
the external and middle ear appears to be of minor importance. In some individuals, altered
functioning of the vestibular apparatus in the inner ear related to balance and sensory perception
may be involved in the feeling of light-headedness and vertigo.
Many elderly people have difficulty in distinguishing spoken words, a problem magnified
by background noise (Bergman et al., 1976). In addition, hearing loss is likely to contribute to
an age-associated decline in cognitive ability in some individuals.
Although normal aging can cause hearing loss, exposure to toxicants such as solvents,
gases such as carbon monoxide (CO), and metals such as lead and manganese (Gobba, 2003;
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Johnson andNylen, 1995; Rybak, 1992). In addition, chemicals (e.g., solvents) may interact
with lifetime noise exposure and result in hearing loss (Gary et al., 1997).
Touch. Aging alters the cutaneous sensory system by decreasing the number of some
sensory receptors (Pacinian and Meissner corpuscles) (Meisami, 1994). However, little change
with age occurs in the number of other receptors (Merkel discs) and free nerve endings.
Particularly in the hand region, sensitivity to touch decreases with age, as does the ability to
distinguish between two spatially distinct points of contact. As an individual ages, decreased
perception of ambient temperature is experienced. High-frequency vibration is sensed to a lesser
degree with increasing age by the Pacinian corpuscles, particularly in the feet and legs.
Although the ability to detect the onset of pain is not affected by age, whether the elderly are
more or less tolerant of pain is debatable. The ability to sense limb movement and reproduce
changes in limb position (proprioception) appears to deteriorate with advanced age (Skinner et
al., 1988). Metals, solvents, and pesticides may impair the touch sensation (Gobba, 2003).
Taste and Smell. Because of methodological difficulties in testing, the effects of age on
taste and smell are not well understood (Bartoshuk and Duffy, 1995). However, age seems to
have a greater effect on the sense of smell than on taste (NIDCD, 2002a), with the sense of smell
starting to decline around age 60 (NIDCD, 2002b). Loss of taste and smell can lead to
inappropriate eating habits, malnutrition, weight loss or gain, weakened immunity, and increased
exposure to toxicants (Santos et al., 2004). For instance, individuals who are not able to smell
natural gas may have prolonged exposure and increased risk than those with the ability to smell.
Some causes of taste and smell loss include medication, disease, infection, dental problems, head
injury, smoking, and vitamin deficiencies, as well as metals (e.g., cadmium) and solvents
(Gobba, 2003; NIDCD, 2002a, 2002b; Schwartz et al., 1990).
3.3. CARDIOVASCULAR SYSTEM
In healthy individuals, the heart increases modestly in size over time (Folkow and
Svanborg, 1993), primarily due to an increase in the thickness of the wall of the left ventricle of
the heart resulting from hypertrophy of the wall's cardiac muscle cells. The age-associated
increase in heart mass is far greater in people who suffer from hypertension.
The conductile system of the heart also undergoes age-associated changes (Fleg et al.,
1988). After age 60, the number of cells in the sino-atrial (SA) node progressively declines.
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Some decrease in the resting heart rate with increasing adult age also occurs, and this appears to
be due in part to a change in the SA node's pacemaker function. Some change with age also
takes place in the atrio-ventricular node and its connection to the conductile system of the
ventricles, causing a minor delay in the progression of action potentials from the atria to the
ventricles. Increasingly common with aging are abnormal rhythms (arrhythmias) of the heart,
such as a too rapid (tachycardia) or a too slow (bradycardia) heart rate, or the occurrence of
pacemaker cells at sites other than the SA node. Sudden death due to an arrhythmia may be
relatively common in the elderly (Cleland et al., 2002).
The pump function of the heart also changes with increasing age (Lakatta, 1995). The
blood flow into the left ventricle during diastole becomes slower, but this is compensated for by
the increased amount of blood pumped by the left atrial contraction in late left ventricular
diastole. Thus, at rest, the total amount of blood entering the left ventricle during diastole is
similar for old and young people of the same size and gender. The stroke volume in resting
healthy people is similar for young and old of the same size and gender, as is the cardiac output.
However, there is one difference between the healthy young and old in the pump function of the
left ventricle: the contraction of the left ventricle is prolonged with increasing age, and this
prolongation helps the healthy elderly maintain a stroke volume similar to that of the young.
Although only small age-related changes in the functioning of the heart as a pump occur in
healthy people at rest, substantial differences emerge when a person is challenged.
Arterial blood vessel structure changes with age (Kottke, 1985). With increasing age, the
diameter of the lumen of the large arteries increases. The walls of these arteries increase in
thickness and become stiffer. Although the lumen diameter of the smaller peripheral arteries
shows less of an increase, wall thickness shows a greater increase. These age-related changes in
arterial structure are due to several factors: a decrease in elastin relative to collagen in the arterial
walls, an increased mineralization of the elastin with calcium and phosphorus, and an increase in
sustained contractile activity of smooth muscle in the walls of the arteries. One of the hallmarks
of aging of the cardiovascular system is the increased velocity of the pulse wave, which stems
from the increased stiffness of the arterial walls. Arterial impedance does not increase through
middle age because the increase in arterial wall stiffness is compensated for by the increase in
the arterial lumen. However, at advanced ages, impedance increases because the effect of the
increased stiffness prevails.
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The influence of aging on capillaries is an understudied subject (Folkow and Svanborg,
1993). In some tissues, the number of capillaries decreases at advanced ages, but the limited
information available indicates that no change occurs with age in either structure or function. In
addition, an age-associated vein distensibility occurs; this interferes with the proper functioning
of the valves and, as a result, fluid tends to collect in the legs. As peripheral vascular resistance
increases with age, blood perfusion to the organs decreases (Lakatta, 1995).
The sympathetic nervous system plays an important role in the response of the
cardiovascular system to challenges, and its influence is reduced with age (Lakatta, 1993). The
intrinsic ability for muscle contraction or relaxation does not change, but alterations in the
processes linking the receptor with the contractile or relaxation mechanisms do occur with age.
These changes contribute to altered baroreflex responses that often impair the ability of elderly
individuals to adapt to cardiovascular stressors. Because of the age-related decline in beta-
adrenergic function, the maximal heart rate in response to exercise decreases with age.
Beta-adrenergic dilatation and alpha-adrenergic constriction of veins is decreased at
advanced ages. A decline occurs in the beta-adrenergic receptor function (Turner and Scarpace,
1996; Podrazik and Schwartz, 1999); this impaired stimulation of the heart is not due to a
decrease in the number of receptors, but to an alteration in the cellular signal transduction
response to receptor stimulation. Importantly, there are persistent effects after developmental
exposure to nicotine (Navarro et al., 1990) and chlorpyrifos (Slotkin et al., 2002).
Release of norepinephrine from adrenergic nerve terminals within the cardiovascular
system is the primary mechanism for increasing heart rate and blood pressure in order to increase
organ perfusion. Systolic, diastolic, and mean blood pressure all increase with aging (Svanborg,
1989). The increase in mean and diastolic pressure is primarily due to increased resistance of the
arterioles. The increase in systolic pressure stems from the increased stiffness of the walls of the
arteries as well as to increased resistance of the arterioles. Although some studies have not seen
an age-associated increase in blood pressure, body weight, physical exercise, smoking, and lead
have been shown to increase blood pressure in the elderly (Svanborg, 1996).
In young adults, the need to increase the cardiac output during exercise is met by an
increase in the activity of the sympathetic nerve fibers to the heart, which increases the heart rate
and stroke volume, the latter because of the increased contractility of the ventricular cardiac
muscle cells. In the healthy elderly, heart rate and ventricular contractility increase much less in
response to exercise because of decreased effectiveness of the sympathetic nervous system. This
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is compensated for by an increase in the blood volume in the chamber of the left ventricle at the
end of diastole, causing an increase in the length of the left ventricular muscle cells. Within
limits, an increase in the length of the cardiac muscle cells increases the force of contraction.
Therefore, in the elderly, an increase in stroke volume during exercise is secondary to the
increase in diastolic volume of the left ventricle. Thus, the healthy elderly can increase cardiac
output in response to exercise, but by a different mechanism than that of the young. However,
this compensatory ability is compromised in the elderly who suffer from age-associated
cardiovascular disorders. A number of environmental factors can lead to cardiovascular
conditions, including metals such as lead and air pollutants.
Heart failure involves a decline in the pump function of the heart, which can result in
several systemic problems and potentially death. A person with heart failure may have
inadequate oxygen delivery to the tissues, pulmonary congestion, systemic venous congestion, or
all three life-threatening conditions (Lye, 1998). It is an age-associated syndrome in that 75% of
the patients suffering from heart failure are over age 60 years. The two major causes of this
syndrome are coronary heart disease and hypertension. Lesions in the heart valves, not an
uncommon problem in the elderly, are also a potential cause.
Coronary heart disease and atherosclerosis are two major age-associated medical
problems. Coronary heart disease is often caused by an inadequate supply of oxygen to the heart
muscle (Shephard, 1997). The coronary arterial system can be subject to atherosclerosis, a
progressive process involving plaques that narrow the lumen of the coronary arteries and can
impede blood flow in the arteries in which they occur, particularly by serving as sites of clot
formation (Crow et al., 1996). In addition, atherosclerotic plaques commonly occur in the
internal carotid arteries near their origin in the neck, the middle cerebral arteries, the vertebral
arteries, and the basilar arteries. As these plaques grow in size with increasing age, they often
become sites for formation of blood clots that cut off the blood supply to regions of the brain.
If atherosclerosis is sufficiently great, the heart muscle suffers from ischemia, leading to
the death of heart cells, referred to as myocardial infarction (MI). An MI can be sudden when, in
addition to an atherosclerotic plaque, it involves a thrombus or an embolus. Both the incidence
and the prevalence of coronary heart disease increase with increasing age. The prevalence is
50% in the age range from 65 to 75 years and 60% in those over 75 years of age. The major risk
factors include elevated systolic blood pressure, high levels of low density lipoproteins, left
ventricular hypertrophy, diabetes mellitus, elevated plasma glucose levels, smoking and air
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pollution. Although in healthy people only modest changes in heart pump function occur with
aging, coronary heart disease can cause serious deficits that range from difficulty in exercising to
decreased function at rest. There is evidence that there may be fetal origins to both coronary
heart disease (Barker, 1995) and atherosclerosis (Palinski andNapoli, 2002).
Hypertension and hypotension are blood pressure conditions common in the elderly
(Scott, 1998). Hypertension - persistently elevated blood pressure - occurs in approximately
50% of the elderly (FIFARS, 2004). There are two basic forms of hypertension. One involves
elevation of both the systolic and diastolic blood pressures (defined numerically as a systolic
pressure above 140 mm Hg and a diastolic pressure above 90 mm Hg). The other form (isolated
systolic hypertension) is systolic pressure above 160 mm Hg and diastolic pressure below 90 mm
Hg. Both forms of hypertension increase the risk of stroke and heart attacks.
Orthostatic or postural hypotension, a drop in systolic pressure of more than 20 mm Hg
for at least 1 minute, occurs in about 60% of the population over age 65 (MacLennan et al.,
1980). By decreasing blood flow to the head, hypotension is a contributor to falls among the
elderly. Hypotension is caused by altered reflex responses to a falling blood pressure, the most
important being the blunting of the arterial baroreceptor reflex, which readjusts the blood
pressure by modifying both heart rate and resistance of the arterioles. The elderly are also prone
to postprandial hypotension (a fall in blood pressure an hour or so after eating); this is due to an
inability to compensate for a decrease in the resistance of the arterioles of the gastrointestinal
(GI) tract by increasing the resistance of the arterioles of other regions (Lipsitz et al., 1983).
There is some evidence that blood pressure in adults is linked to early growth factors (Lackland
et al., 2003).
Anemia is commonly found in the elderly, although whether anemia occurs as a normal
result of aging is debated. Anemia is a decrease in the normal concentration of red blood cells
(erythrocytes), as measured by the hemoglobin count, that leads to the decrease of oxygen
transported in the blood. This results in fatigue, weakness, and reduced mobility. It has been
theorized that the disruption of proinflammatory cytokines response (e.g., interleukin [ILJ-6)
could be one explanation (Ershler, 2003). Causes include blood loss, nutritional deficiencies
(iron, vitamin Bi2, folate), chronic diseases such as chronic kidney disease, diabetes, cancer,
cardiovascular disease (see above), rheumatoid arthritis, and gastrointestinal conditions, as well
as medical treatments. In turn, anemia can increase the risk of cardiovascular disease (Pereira
and Sarnak, 2003). Anemia in the presence of chronic kidney disease (McCullough and Lepor,
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2005) may increase the risk of dementia (Atti et al., 2005). Those with anemia are at particular
risk from exposure to CO.
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3.4. GASTROINTESTINAL SYSTEM
The processing of food by the GI system involves the following activities: motor activity
of the GI tract, glandular secretion, digestion, and absorption of substances from the lumen of the
GI tract into the blood or lymph. Although the healthy elderly carry out these functions rather
well, some age-associated changes in each of the functions do occur (Holt, 1995).
More than 25% of all U.S. adults aged 65 years and older have no natural teeth (FIFARS,
2004), and the skeletal muscles involved in mastication become weaker with aging, which can
result in a reduced ability to chew and consequential malnutrition. Secretion of saliva may or
may not decrease with age in the healthy elderly, but disease states or medications often alter
salivary secretion.
Although the ability to digest carbohydrates, protein, and fat is not compromised at
advanced ages (although people genetically susceptible to lactase deficiency have a
progressively reduced ability to digest lactose with aging), the capacity to absorb these
substances decreases with age. However, this poses little problem for the elderly because of
increased gastric residence time (Evans et al., 1981; Horowitz et al., 1984), which generally
increases the absorptive capacity to excess of what is needed. The slower transit time through
the stomach and lower GI tract increases the time available for absorption and potentially
increases the maximal plasma concentration and the length of time of maximal plasma
concentration. In general, the extent to which chemical absorption is affected by age (Calabrese,
1986) depends on the nature of the foreign substance and the degree to which any elderly
individual has compromised GI function. The absorption process may also be extended due to
reduced gut motility.
Various xenobiotics may impair nutrient intake by altering GI acid and enzyme
production, reducing appetite, slowing gut motility and gastric emptying, and reducing
absorption (Iber et al., 1994). Reduced absorption of nutrients, in combination with reduced
food intake, leads to decreased levels of vitamins in the body (Balducci et al., 1986; Schumann,
1999). Both vitamin and protein malnutrition in the elderly can have a severe impact on hepatic
metabolism and clearance (Iber et al., 1994; Thomas, 1995).
Significant age-associated change in gastric emptying occurs only when a meal is very
large, and constipation and diarrhea do not occur more frequently in the elderly unless related to
a disease. However, the elderly are more prone to fecal incontinence because of both higher
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rectal pressures when the rectum is distended by a fecal mass and reduced force of the anal
sphincter.
Atrophic gastritis can reduce gastric secretion of hydrochloric acid, and the prevalence
and severity do increase with age. This inflammatory disease, probably caused by an
autoimmune mechanism, leads to destruction of the parietal cells, which secrete hydrochloric
acid. These parietal cells also secrete intrinsic factor, and their loss can also result in pernicious
anemia. Lower stomach pH and decreased active intestinal transport may reduce the absorption
of both xenobiotics as well as essential vitamins such as A, Bl, B12, folate and calcium
(Saltzman and Russell, 1998). Additionally, gallstones, which are more prevalent at advanced
ages, may prevent bile from reaching the lumen of the GI tract.
Dysphagia, or swallowing difficulties, are minor and do not cause significant functional
difficulties in the healthy elderly. However, dysphagia can arise with age-associated diseases
that adversely affect motor nerve control of the swallowing process (e.g., stroke, PD,
amyotrophic lateral sclerosis). Reduced compliance of the upper esophageal sphincter, which
interferes with the passage of the food bolus from the throat down into the esophagus, is
somewhat common in the elderly. Another swallowing disorder, achalasia, relates to a reduced
esophageal peristaltic wave production when swallowing and a failure of the lower esophageal
sphincter to open; as a result, the food bolus tends to remain lodged in the esophagus. The
prevalence of this disorder increases with age.
3.5. RESPIRATORY SYSTEM
Pulmonary function declines in the elderly due to loss of elastic recoil and weakness in
diaphragmatic, chest wall, and abdominal muscles that result in decreased gas exchange (Turner
and Scarpace, 1996). The great reserve function of the lung permits reasonable physical capacity
in healthy individuals despite these age-related changes, and training can improve aerobic
capacity and endurance. However, when there is a need for increased breathing (e.g., exercise,
high altitude), the lungs may not be able to keep up with the demand.
After about age 20, a healthy individual stops making new alveoli and the lungs begin a
slow process of losing some of their tissue. Due to the loss of alveoli and lung capillaries over
time, the amount of oxygen diffusing from the air sacs into the blood decreases. However, the
transport of oxygen from the lungs to the tissues and of carbon dioxide from the tissues to the
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lungs is not affected by aging. It is normal for healthy older people to have a reduced response
to both decreased oxygen and increased carbon dioxide levels resulting in an increased rate and
depth of breathing. In spite of age-related changes in the thorax-lung air pump, alveolar
ventilation in the healthy elderly is not sufficiently altered so as to limit vigorous exercise.
However, diffusion of oxygen may decline due to disruption of alveolar walls resulting from
inflammatory insults or environmental pollutants. These changes are relatively minor, and
sufficient lung surface area is available to allow gas exchange and the exposure to environmental
agents. In those suffering from age-associated diseases, anemia can cause reduced gaseous
transportation (Cohen and Crawford, 1992).
The volume of air exhaled progressively decreases (with residual air in the lungs
increasing with age), and the rate of airflow slowly declines. This is due to the increased
resistance to airflow in the bronchioles, the change in elastic properties of the lungs, and the
decrease in the force generated by the respiratory muscles. The vital capacity - the volume
exhaled following maximal inspiration and maximal expiration - decreases with age as the
diaphragm and muscles between the ribs (intercostals) weaken. A change in lung capacity can
also occur due to loss of bone mass of the ribs and vertebrae and mineral deposits in the rib
cartilage. With aging, the airways tend to collapse more readily, particularly when an older
person breathes shallowly or is in bed for a prolonged time (Rossi et al., 1996).
With aging, the body's defenses against lung infection may weaken and lead to an
increased risk of lung infections. The cough reflex may not trigger as readily, and the cough
may be less forceful. The cilia are less able to move mucus up and out of the airway. The nose
and breathing passages secrete fewer antibodies that protect against viruses and are therefore less
able to meet challenges to the system, such as pneumonia secondary to bacterial and viral
infections. There is evidence that early developmental growth may have an adverse effect on
lung development (Maritz et al., 2005). Environmental factors that can lead to lung disease
include solvents (Jones and Brautbar, 1997), asbestos, and ambient air pollutants.
Asthma in the elderly is not uncommon, with 7% of men and 9% of women reporting
symptoms (FIFARS, 2004). It is, however, often confused with chronic obstructive pulmonary
disease (see below), possibly due to changes in the lung function as well as changes in the
immune system (Vignola et al., 2003). For example, in older individuals there is a decrease in 0-
2 receptors in the smooth muscles lining the airways, with cholinergic receptors becoming the
dominant smooth muscle receptors as aging progresses (Morris, 1994).
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Chronic obstructive pulmonary disease (COPD) refers to the combined occurrence of
chronic bronchitis and emphysema (Morris, 1994) and is the fourth leading cause of death in the
U.S., with 119,000 dying from COPD in 2000 (NIHLB, 2003). Alone, chronic bronchitis occurs
in 5-7% of all elderly adults, and emphysema (often associated with smoking) is diagnosed in 4-
7% of all adults over age 65 years (FIFARS, 2004). In COPD, the bronchial lining undergoes
progressive changes, including gradual loss of cilia and thickening of the epithelium by
proliferation of mucosal cells. The emphysema component involves dilation and disruption of
alveolar walls. Thus, unlike in most elderly, the deterioration of pulmonary function in those
suffering from COPD markedly limits their functional abilities and can lead to cardiovascular
disease (Curkendall et al., 2005), which can be exacerbated by exposure to ozone.
Pneumonia is the leading causes of death among the elderly, accounting for 3.2% of
mortality in this age group (Anderson and Smith, 2005). Influenza, which can often be
prevented by use of vaccines, often leads to pneumonia. Although bacteria, virus, or fungi often
cause this condition, exposure to environmental etiologic pollutants including particulate matter
(PM) < 10 urn in diameter (PMi0) (Fischer et al., 2003; Zanobetti et al., 2000), nitrogen dioxide,
and CO (Fischer et al., 2003), can increase risk of disease
3.6. HEPATIC SYSTEM
In healthy individuals, liver function appears to be relatively well preserved in aging.
Hepatic blood flow decreases as a function of age by as much as 40% by age 70 (Marchesini et
al., 1988; Wynne et al., 1988). Other morphological changes that can lead to reduced hepatic
metabolism include a decrease in overall liver mass, number of hepatic cells (Lakatta, 1995;
Wynne et al., 1988), and number of mitochondria, as seen by the gross appearance of atrophy.
Although mitochondrial integrity and enzymatic activity appear to remain unchanged with aging
(Ananthatraju et al., 2002), hepatic regeneration after injury is delayed in the elderly (Popper,
1986). In fact, livers from elderly individuals appear to regenerate much better when
transplanted to a younger donor. No decline seems to occur in hepatic protein content,
immunohistochemical content, or in vivo enzyme activity in the elderly.
After GI absorption, most xenobiotics pass through the liver, the central metabolic organ
of the body, before entering the systemic circulation and reaching a site of action. Hepatic
microsomal enzymes, particularly cytochrome P-450s, play a key role in xenobiotic metabolism.
Phase I reactions (e.g., oxidation, hydrolysis, reduction), first-pass hepatic metabolism, and
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serum albumin binding capacity (Tepper and Katz, 1998) are reduced with age, but a consistent
decline in Phase II reactions (e.g., glucuronidation, sulfation) has not been observed.
Subfamilies of cytochrome P-450 that may decline with age in humans (Lakatta, 1995) include
CYP2A6, CYP3A, and CYP2C, (Knodell et al., 1988; Robertson et al., 1988; Sotaniemi et al.,
1996), but possibly not CYP2D6 (Wood et al., 1979). These changes may contribute to the age-
related hepatic clearance, although this decrease is primarily due to the losses in liver mass and
hepatic blood flow (Wynne et al., 1988). Environmental contaminants such as solvents
(Brautbar and Williams, 2002) can lead to liver toxicity.
Cirrhosis is a common liver disease caused by the replacement of normal hepatic tissue
with fibrous tissue. It is the 12th leading cause of death, which occurs within a year of diagnosis
for 60% of patients. Blockage of the bile duct can lead to primary biliary cirrhosis. Other major
causes include alcoholism and hepatitis, along with autoimmune conditions, infectious agents,
and xenobiotics (Kita et al., 2004).
3.7. RENAL SYSTEM
Several structural and functional changes occur in the kidneys with increasing age
(Epstein, 1996; Lindeman, 1995). The mass of the kidneys decreases progressively starting in
young adulthood, primarily in the cortex, with little loss occurring in the medulla. Renal blood
flow is reduced by 40-50% by age 60, mostly associated with the constriction of the kidney
arterioles, which increases the resistance to blood flow through the kidneys. This reduction in
renal blood flow results in a greatly reduced glomerular filtration rate (GFR), with the elderly
having about 70% the rate of younger adults; however, this may not occur in all people
(Lindeman et al., 1985). The number of functioning nephrons also declines with age (Papper,
1973; Lindeman, 1990).
Tubular secretion and reabsorption are also reduced with aging. Most of the renal
transport systems involved in tubular reabsorption and secretion continue to function effectively
in the healthy elderly. Hydrogen ion concentrations in the blood of healthy individuals increase
by 6-7% in the elderly as a result of altered kidney function (Frassetto and Sebastian, 1996). In
addition, the kidneys of the elderly excrete a large acid load much more slowly than do those of
the young (Adler et al., 1968). The elderly are also less able than the young to cope with water
deprivation, primarily due to a decrease in the ability of the kidney to generate urine that is
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highly concentrated (high osmolality) because of decreased response of the kidneys to the
hormone vasopressin (Kugler and Hustead, 2000).
Elderly individuals tend to excrete many xenobiotics and their metabolites at a reduced
rate. Sixty-six percent of the healthy elderly have evidence of impaired renal function, resulting
in a persistence of xenobiotics that are dependant on inactivation and excretion by the kidney
(Dybing and Soderlund, 1999). In addition, exposure to solvents (Brautbar, 2004) or lead may
result in renal interstitial fibrosis and nephrosclerosis and could accelerate the age-related decline
in kidney function. Superimposing chronic diseases of the elderly, such as heart failure, may
accelerate these changes in kidney function (Cody, 1993).
Hyponatraemia and hypernatraemia, a deficiency or excess of sodium in the blood
respectively, can result from changes in kidney function relative to water and electrolyte
metabolism (Kugler and Hustead, 2000). One reason why the elderly are at higher risk of
sodium imbalance is a reduced thirst sensation (Kenney and Chiu, 2001). The kidney does show
a reduced ability to maintain sodium balance, independent of dietary sodium. The decreased
ability to conserve sodium may be due in part to intrinsic changes in the kidney transport
systems; however, much of the decrease appears to be the result of an age-related decline in the
response of the renin-angiotensin-aldosterone system to low sodium levels. The decreased
capacity for excreting sodium appears to arise from decreased renal blood flow and glomerular
filtration rate with increasing age. This can result in CNS dysfunction due to the impact of an
acute disease or the medications used to treat the disease (Miller, 1997).
Urinary incontinence occurs in an estimated 15-30% of community-dwelling elderly,
and the prevalence is much higher in nursing home residents (Maione-Lee, 1998). Common
causes are urinary infections, medications, psychological disorders, restricted mobility,
endocrine disorders, and stool impaction. Enlargement of the prostate, which begins at about age
45, can often cause obstruction of urinary flow in elderly men (George, 1998). The ability to
void may be lost, which can be fatally destructive to the kidneys unless appropriate medical
intervention is employed immediately. In addition, diabetes is a common cause of long-term
urinary incontinence.
Diabetes is increased in the elderly, with 14-18% affected (FIFARS, 2004). It is
responsible for 3% of all deaths in this age group (Anderson and Smith, 2005). In particular,
Type 2 diabetes (noninsulin-dependent diabetes mellitus) increases in prevalence with increasing
age (Halter, 1995). In addition to a marked insulin resistance, the ability of the pancreas to
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secrete insulin in those with Type 2 diabetes is also impaired. However, little insulin resistance
is present in the elderly who are physically fit and relatively lean; the major causal factors appear
to be the decrease in physical activity and the increase in body fat associated with aging. There
is evidence that early fetal nutritional status may lead to diabetes in later life (Barker, 1999).
3.8. IMMUNE SYSTEM
The function of the immune system often diminishes with age (Hausman and Weksler,
1985; Miller, 1996; Vignola et al., 2003). Although the spleen and lymph nodes do not alter in
size, the thymus continuously decreases in size, and the cellular elements of this gland are
gradually replaced by adipose tissue. Altered immune response is due in part to altered
intracellular signaling in macrophages and neutrophils, reduced apoptosis in neutrophils, and
decreased stimulation of T and B cells by dendritic cells (Plackett et al., 2004) as well as
alteration of IL-10, IL-12, and antigen presentation by dendritic cells (Uyemura et al., 2002).
The ability to increase the number of T-lymphocytes that can respond to a particular antigen is
impaired (Uyemura et al., 2002), and the amount of antibody secreted by a given number of B-
lymphocytes decreases with age. Zinc, an essential compound for immune function, is reduced
in the body with aging, although it can be restored by supplemental intake.
The deterioration of the immune system undoubtedly contributes to increasing
susceptibility to infections and illnesses in the elderly. Importantly, the loss of immune
functionality could be a factor in the increasing incidence of cancer with age. Specifically, the
deterioration of immune surveillance may result in failure to effectively eliminate mutant cells,
thereby increasing cancer risk; however, the validity of this scenario has yet to be established.
Autoimmune Diseases. The age-associated rise in autoimmune diseases such as
rheumatoid arthritis, systemic lupus erythematosus, and glomerulonephritis results from
deterioration of the immune system, which also increases morbidity and mortality from such
diseases. Environmental risk factors include mercury, pesticides (Holsapple, 2002), iodine, vinyl
chloride, organic solvents, silica, particulates, ozone, and ultraviolet radiation (Powell et al.,
1999).
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3.9. SKIN
A number of naturally occurring age-related changes occur in the skin. The thickness of
the flat keratinocytes at the surface of the skin does not change with age, but the rate of shedding
and replacement of these cells decreases. Thus, in the elderly, these cells remain longer at the
surface of the skin, which increases the likelihood of accumulating damage. The number of
melanocytes decreases with increasing adult age by 10-20% each decade, increasing the
damaging action of ultraviolet light. At advanced ages, the epidermis contains 20-50% fewer
Langerhans cells than at young ages.
With increasing age, the structure of the basement membrane alters, decreasing the extent
of interaction between the dermis and the epidermis and increasing the likelihood of injuries
causing the two layers to separate. The thickness of the dermis is about 20% less in the elderly,
and the dermis is stiffer and less malleable, making it more vulnerable to injury. Many of the
changes in the dermis are due to alterations in the fibrous proteins (collagen and elastin) of the
dermis' extracellular matrix; fine wrinkles are probably related to these alterations. The small
blood vessels of the dermis change and the number of hair follicles declines.
Physiological functions of the skin are also altered during aging (Chuttani and Gilchrest,
1995). The barrier function is changed, and body water loss through the epidermis is decreased
with increasing age. A 15% age-associated reduction occurs in both the number and the
functional capacity of the sweat glands. In addition, with advancing age, subcutaneous fat
increases in some regions of the body (the waist in men and the thighs in women) and decreases
in others (face, hands, shins, and feet).
The inflammatory response of skin to harsh chemicals is less intense in the elderly. Also,
vitamin D production declines with age, and decreased exposure to sunlight and reduced
cutaneous synthesis may impair vitamin D status. Common risk factors associated with age-
related skin conditions include smoking and exposure to sunlight (Kennedy et al., 2003).
Areas of the skin exposed to sunlight may deteriorate prematurely more than areas that
are protected, a phenomenon called "photoaging" (Scharffetter-Kochanek et al., 2000), as
opposed to "intrinsic aging" (Chuttani and Gilchrest, 1995). Chronic photo damage is estimated
to cause more than 90% of cosmetic skin problems. It leads to coarseness of the skin, dilation of
groups of small cutaneous blood vessels, irregular pigmentation, and deep wrinkles. It also
causes a decrease in the number of epidermal Langerhans cells. Damage to the elastin and
collagen in the dermal extracellular matrix probably underlies many of the cosmetic problems.
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Pressure sores (i.e., decubitus ulcers or bedsores) are a major concern for the elderly
(Bennett and Bliss, 1998), particularly for those with decreased mobility or diabetes. Additional
risk factors are friction and moisture, particularly moisture due to fecal or urinary incontinence.
The mildest form occurs as a redness of the skin area; if the lesion becomes more severe, it
progresses to a loss of epidermal and dermal structures. Ultimately, full-thickness skin loss and
tissue necrosis can occur, resulting in a severe lesion.
3.10. BODY MASS
Body mass, commonly referred to as body weight, consists of both lean and fat body
mass (Forbes and Reina, 1970; Holloszy and Kohrt, 1995; Seidell and Visscher, 2000). During
adult life, the lean body mass (which is greater in men than in women) declines by about 0.3%
per year in men and 0.2% per year in women. Much of this decrease in lean body mass is due to
the loss of muscle mass, but a loss of bone and other tissue is involved. Although individuals
who continue to exercise have a greater lean body mass at any age than those of similar size who
are sedentary, even athletes progressively lose lean body mass.
Although lean body mass is decreasing, percentage fat content of the body increases with
age, and the distribution of body fat changes, with a preferential accumulation of fat in the
abdominal region. However, many elderly individuals lose body weight, and this can potentially
mobilize lipophylic substances back into the bloodstream. Also related to the reduction in lean
body mass, is the decrease in total body water content in the elderly. The decrease in
intracellular water causes polar compounds to be less well distributed but to be present at a
higher concentration in the remaining body water (Greenblatt et al., 1982).
Drugs and environmental chemicals with hydrophilic properties would be expected to
have a decrease in volume of distribution in the elderly. The distribution of lipophilic
environmental chemicals such as dioxins, PCBs, and other halogenated substances depends on
the adipose tissue content of the body. These changes mean that lipid-soluble compounds are
better distributed and retained longer in the elderly (Wills, 1984). However, weight loss often
seen in the elderly has the potential to mobilize stores of lipophilic toxicants.
Age-related changes in protein binding may be due to decreased liver production of
serum proteins or changes in drug affinity for the proteins (Wallace and Verbeeck, 1984).
Inadequate protein intake in the elderly may also contribute to decreased plasma protein
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synthesis as well as malnutrition, which can result in anemia. Serum albumin may decrease by
about 10-20% between ages 30 and 70 years, allowing for an increase in the amount of unbound
free drug in the plasma. Increased free drug/environmental chemical or their reactive metabolite
levels can enhance target organ responses and lead to adverse toxic reactions. The plasma
albumin fraction is responsible for most toxicant binding in the plasma.
Dehydration is a common reason for hospital admittance among the elderly. The
disturbance in fluid and electrolytes is due to already reduced water content in the body and renal
changes. In addition, the elderly individual may have a reduced fluid intake due to cognitive or
motor impairment, a desire to reduce incontinence, or a reduced thirst response (Kenney and
Chiu, 2001).
Obesity increases with age, and by 65 years approximately one-third of all U.S. adults are
considered obese (FIFARS, 2004). This may be somewhat due to the increase of sedentary
lifestyle with age as well increased calorie intake. Obesity is associated with increased risk of
heart disease, Type 2 diabetes, cancer, respiratory conditions, and osteoarthritis (FIFARS, 2004).
There is evidence that early growth may have an influence on obesity in later life (Oken and
Gillman, 2003).
3.11. MUSCULO-SKELETAL SYSTEM
By age 70, the height of men and women is 2.5-5% below its peak level (Spirduso,
1995), due primarily to the compression of the cartilaginous discs between the vertebrae and a
loss in vertebral bone. Bone loss and joint deterioration commonly occur with increasing age.
Bone loss is greater in women than in men, and the rate of loss accelerates after menopause; such
acceleration has been found to be due to low postmenopausal levels of estrogen. In the young
adult, remodeling of bone occurs by the process of bone resorption being balanced by bone
reformation, so that remodeling causes no change in the amount of bone. With advancing adult
age, the balance during remodeling shifts in favor of bone resorption (Kalu, 1995). Men start to
lose bone at later ages than do women, and in general the amount of loss is less for men than for
women.
A decrease in skeletal muscle mass (sarcopenia) occurs with increasing adult age (Lexell,
1995). A decrease in the number of muscle fibers is generally agreed to occur with increasing
age in many, but not all, skeletal muscles. Associated with this decline in muscle mass is an
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approximate 33% decrease in muscle strength (Hurley, 1995), along with a decrease in the speed
of movement.
With increasing age, the strength and speed of smooth muscle function are reduced
(Folkow and Svanborg, 1993). Some loss in the efficiency of sympathetic nervous system
control of venous smooth muscle may also occur. The extent to which skeletal muscle disuse is
responsible for the age-associated loss of skeletal muscle fibers is unknown, yet disuse will lead
to a decrease in muscle fiber size as well as a change in functional characteristics. However,
elderly persons who have been physically active or have undergone strength training can develop
muscle force as great as that of sedentary young adults (Evans, 1995) because the development
of increased muscle fiber size compensates for the reduced number of fibers. With increasing
age, most people adopt a more sedentary lifestyle (Rowe and Kahn, 1998); thus, some of the
changes in skeletal muscle function with advancing age are clearly due to lack of use.
Osteoporosis is characterized by low bone mass and increased susceptibility to bone
fractures from minor trauma (Riggs and Melton, 1988), and its prevalence increases with
advancing age. There are two major types of age-associated osteoporosis: Type I defined as an
increase in the rate of remodeling of bone, with bone resorption outpacing bone formation, and
Type II, defined as a decreased rate of bone formation. Type I is frequently associated with
fractures of the vertebrae and wrists, whereas Type II results mostly in vertebral wedge fractures
and hip fractures. Both are more common in women; the lower incidence in men is due to three
factors: greater bone density upon reaching maturity, shorter life expectancy, and the lack of a
rapid endocrine change equivalent to menopause.
Lifetime exercise and an adequate dietary intake of calcium minimize the occurrence of
osteoporosis, whereas alcoholic beverages, smoking, and caffeine are risk factors for
osteoporosis. The condition can lead to a release of toxins, such as lead, that are stored in the
bone. In addition, there are links between bone growth in early life and later development of
osteoporosis (Harvey and Cooper, 2004).
Osteoarthritis is the most common degenerative joint disease in the elderly (Felson,
1990; Radin and Martin, 1984) with approximately one-third of all elderly individuals
experiencing some arthritic symptoms (FIFARS, 2004). In the healthy elderly, the synovial
joints show deteriorative changes (Spirduso, 1995). Functionally, joint flexibility is lost,
reducing the range of motion and increasing the possibility of damage to the joints and the
muscles crossing the joints. In this disease, the cartilage of the joint changes in consistency,
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cracks, and wears away, ultimately exposing the bone surface to another bone. With time,
further changes in bone may occur, such as the development of bone spurs, abnormal thickness,
and fluid-filled pockets. Periodic or chronic inflammation can occur, which is accompanied by
pain. Although osteoarthritis can occur in any joint, it most commonly affects the joints of the
fingers, knees, and hips.
Gout results in joint inflammation and involves the formation of uric acid crystals in the
synovial fluid (Rubenoff, 1990). The joint in the big toe is the one most commonly involved,
although any joint may be affected. Gout is more common and occurs earlier in men than in
women, peaking in the fifth decade of life. Exacerbations and remissions characterize the course
of the disease. The major causal factor of gout is an elevation in plasma uric acid concentration,
which increases with age and in individuals who take diuretics thus probably accounting for the
age-associated characteristic of this disease.
3.12. ENDOCRINE AND REPRODUCTIVE SYSTEMS
In the healthy elderly, the functioning of the pituitary-thyroid axis is not markedly
different from that in the young (Mooradian, 1995). The concentration of serum thyroxine is not
affected by aging. The concentrations of triiodotyrosine and thyroid-stimulating hormone and
the rate of thyroid hormone production and degradation are either not affected or are modestly
decreased by aging. The secretion of thyroid-stimulating hormone by the pituitary in response to
the hypothalamic thyrotropin-releasing hormone is modestly decreased or unchanged by aging,
as is the response of the thyroid gland to thyroid-stimulating hormone. The ability of thyroid
hormone to suppress the pituitary secretion of thyroid-stimulating hormone is decreased at
advanced ages, as is the response of the basal metabolic rate to thyroid hormone. The
consequences to the healthy elderly, if any, of these modest age-related changes in the pituitary-
thyroid axis have not been defined.
The pituitary-adrenal axis refers to the influence of pituitary adrenocorticotrophic
hormone on the secretion of cortisol and dehydroepiandrosterone by the adrenal cortex. Little or
no increase in the level of plasma cortisol occurs with advancing age in nonstressed healthy
people, but under conditions of stress, plasma cortisol levels increase more in the elderly than in
the young, and the increase is more prolonged (Masoro, 1995). Whether the increased cortisol
response is beneficial or detrimental remains to be determined. The blood level of
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dehydroepiandrosterone peaks at ages 25 to 30 years and decreases thereafter, so by age 80 the
level is 10% of that at age 25 to 30 years (Yen and Laughlin, 1998). Low levels of blood
dehydroepiandrosterone have been associated with age-associated disorders, such as some forms
of cancer, dementia, cardiovascular disease, Type 2 diabetes, obesity, and osteoporosis.
Pituitary secretion of growth hormones decreases with increasing age, resulting in a
progressive decrease in the plasma levels of growth hormone and in insulin-like growth factor I,
the secretion of which is controlled by growth hormone (Bartke et al., 1998). Growth hormone
promotes the use of fat as an energy source, thereby sparing the use of protein. Thus the
decreasing level of growth hormone with increasing age may play a role in the age-associated
increase in body fat and decrease in muscle mass.
Marked age-related changes occur in the reproductive function of elderly women
(Sowers, 2000). Menopause is the natural permanent cessation of menstruation which occurs on
average at about 50 years of age and is completed for most women by age 65. Menopause is
believed to result primarily from the decreased ability of the ovaries to secrete estradiol. In the
years following menopause, plasma estradiol levels drop, and follicle-stimulating hormone and
luteinizing hormone levels are elevated. Also, pubic hair decreases, the vagina shortens and
loses elasticity and is at increased risk of bacterial and yeast infections and mechanical damage,
the oviducts shorten and their diameter decreases, breasts undergo atrophy of the glandular
structure with replacement by adipose tissue, the uterus reduces in size, and the cervix atrophies.
Although men do not undergo an andropause that is comparable to menopause, the male
reproductive system does undergo age-related changes (Plas et al., 2000). Atrophy of the
seminiferous tubules occurs with advancing age. Semen volume and sperm motility are
decreased, along with sperm concentration and count (Eskenazi et al., 2003). Plasma-free
testosterone declines after the age of 40, but some older men have levels well within the range
found in young men.
Hyperthyroidism and hypothyroidism are caused by excessive or decreased production of
thyroid hormones, respectively. Hypothyroidism affects up to 17% of the elderly, with a higher
incidence in women (Levy, 1991). Symptoms include decreased basal metabolism and skin
conditions. The most common cause is autoimmune thyroid conditions. Hyperthyroidism
affects up to 3% of the elderly (Levy, 1991). Symptoms of hyperthyroidism can include
cardiovascular effects, psychological disorders, weight loss, muscular weakness, increased
defecation, and visual effects and increased sensitivity to heat.
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3.13. BASAL METABOLISM
Total daily energy expenditure (i.e., daily metabolic rate) decreases with increasing adult
age (McCarter, 1995). However, if the basal metabolic rate is expressed per kilogram of lean
body mass, little age-related decline can be seen. Thus, the major reason for the decreased basal
metabolic rate is likely due to the change in body composition with age, namely the increasing
fat mass and decreasing skeletal muscle mass.
Fat oxidation is decreased in the elderly at rest and during exercise (Calles-Escandon and
Poehlman, 1997), likely due to the decrease of fat-free mass. With advancing age, the rate of
protein synthesis and protein degradation (turnonver) decreases (Van Remmen et al., 1995). As
they reside in the body, protein molecules are gradually damaged by oxidation, glycation, heat,
and other factors. Thus, by increasing the average length of time a protein spends in the body,
the age-associated decrease in the rate of protein turnover acts to increase the amount of
damaged protein molecules. The age-associated decrease in muscle mass probably relates, at
least in part, to the decrease in protein synthesis.
The use of energy may lead to the generation of reactive oxygen molecules (e.g.,
superoxide, hydrogen peroxide, and hydroxyl radicals), which cause damage to biological
macromolecules such as mitochondrial DNA (Balin and Vilenchik, 1996) in conjunction with
decreased protection from superoxide dismutase and glutathione (Bolzan et al., 1997), and such
damage does accumulate with increasing age.
With increasing age, the ability of the body to regulate temperature deteriorates (Collins
and Exton-Smith, 1983). The extent of this deterioration varies among individuals, depending on
health, physical fitness, and lifestyle factors. In a hot environment, the elderly have a reduced
ability to redistribute blood flow from the core of the body to the skin due to structural changes
in the skin blood vessels and to a decreased capacity to constrict the vessels supplying the
viscera, which also lead to a reduced sweating response. In a cold environment, the elderly show
a decrease in constriction of the skin blood vessels and a reduced shivering ability.
Hyperthermia and hypothermia are much more likely to occur in elderly people than in
young people. However, the main reason the elderly are more vulnerable to extremes in
environmental temperature is the lowered perception of ambient temperature, resulting in fewer
effective behavioral responses, such as seeking appropriate clothing or shelter.
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4. POLYPHARMACY IN THE ELDERLY
The elderly may suffer from numerous degenerative diseases that require the chronic
consumption of drugs intended to maintain organ function. Similar to toxicants, pharmaceuticals
interact with the physiological states of the elderly. Multiple prescription drug use
(polypharmacy) is high in the elderly; on average, a healthy individual filled 10 prescriptions in
2000, whereas those with comorbidities filled up to 57 prescriptions (FIFARS, 2004). Some
medications may more profoundly impact the elderly than they do younger adults due to
increased bioavailability, decreased metabolic ability, reduced volume of distribution due to
reduced total body water, reduced clearance, or a combination of these factors.
Some medications may decrease in effectiveness in elderly individuals. For example, the
elderly have lowered contractility and chronotropic responses in the heart to beta-adrenergic
stimulus and experience a lower impact on peripheral vasodilation (Cody, 1993; Podrazik and
Schwartz, 1999). The absorption of some prescription drugs used by the elderly may remain
unchanged, but the half-life may be extended and the clearance slowed, resulting in an increased
risk of associated adverse events. For example, angiotensin-converting enzyme (ACE) inhibitors
used for the treatment of heart failure can enhance the risk of severe chronic renal insufficiency
and renal failure due to decreased renal blood flow and tubular secretion in the kidneys. Calcium
channel blockers used for heart conditions are cleared primarily via hepatic metabolism, which
decreases with age, as does kidney function. Cipro, a treatment for bacterial infections (Lebel
and Bergeron, 1987), has significantly reduced renal clearance in the elderly due to a reduction
in the GFR and in tubular secretion, as well as reduced clearance through the hepatic, pulmonary,
and intestinal systems.
Interaction between drugs and environmental contaminants is a major concern for the
elderly, as are interactions between drugs (Cadieux, 1989; Lamy, 1990; Turner et al., 1992). Both
medications and environmental agents may alter the body's ability to process the other. Because
a larger research base exists for pharmaceuticals than for environmental contaminants, much can
be learned about TK changes due to exposure of xenobiotics from examining the literature on
pharmaceuticals.
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5. EXAMPLES OF ENVIRONMENTAL AGENTS AS RISK FACTORS FOR
DISEASES IN THE ELDERLY
The following examples were selected to represent some of the environmental agents and
environmental problems that are known to compromise the health status of the elderly
population.
5.1. Metals
A number of metals are recognized as affecting the neurological system and have been
suggested or implicated in having a role in the development of diseases of the elderly. In
particular, aluminum and mercury have been debated as a causal factor in neurological diseases
such as Alzheimer's disease, and mercury has been associated with heart attack risk in men
(Guallar et al., 2002). Other metals not discussed here but studied intensely for adverse health
effects include iron, zinc, copper, magnesium, and selenium.
Lead is a known toxicant that can be absorbed through the respiratory tract and the GI
tract. Lead first distributes to the soft tissue and then redistributes to the bone. Absorbed lead is
excreted predominantly through the urine; therefore, clearance in the elderly may be greatly
reduced due to a decreased glomerular filtration rate (GFR), a typical consequence of aging.
Lead can cause effects in many physiological systems. In the nervous system, symptoms
of lead exposure may be confused with effects of normal aging. Irritability, fatigue, decreased
libido, anorexia, sleep disturbance, impaired visual-motor coordination, loss of hearing (Rybak,
1992), and slowed reaction time are conditions that occur with lead poisoning but also with
advanced age. In the cardiovascular system lead exposure can increase blood pressure, and
precipitate congestive heart failure (Balestra, 1991) and may cause anemia by interfering with
heme synthesis, which can be exacerbated by poor nutritional intake. In the renal system,
chronic high-dose lead exposure may result in renal interstitial fibrosis and nephrosclerosis, and
such exposure has the potential to accelerate the age-related decline in kidney function.
The skeleton accumulates inorganic lead and holds 90% of the body's lead burden, given
that the half-life in bone is in years or decades as compared with one to two months in soft
tissues. Rapid release of this stored lead by skeletal disease could produce a considerable health
risk (Berlin et al., 1995; Silbergeld et al., 1988). Lead may also aggravate osteoporosis by
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inhibiting activation of vitamin D, uptake of dietary calcium, and aspects of bone cell function.
Modeling of bone loss with aging also suggests that loss of bone in women after menopause
could create a hazard related to release of lead into the blood (O'Flaherty, 2000).
Manganese (Mn) is essential to enzyme and membrane transport system function in all
mammalian tissues. However, as with many other essential metals (e.g., copper and iron), both
excess and deficiency in the body-burden of Mn, whether genetic or acquired, can seriously
impair vital physiological and biochemical processes. Mn toxicity is not widespread, but
excessive Mn exposure can occur, primarily from occupational exposure.
Mn exposure can occur via inhalation, oral ingestion, or intravenous administration.
After absorption into the blood by these alternate routes, brain uptake of Mn occurs via
transferrin receptors. Mn is apparently oxidized by ceruloplasmin, and the resulting trivalent Mn
binds to iron carrying the protein transferrin; transferrin-bound trivalent Mn is not as readily
removed by the liver as are protein complexes with divalent Mn, which is complexed with
plasma proteins that are efficiently removed by the liver. Mn is a potent neurotoxicant
(Cranmer, 1999) and clearly plays a role in the pathogenesis of neurodegenerative disorders
resembling idiopathic Parkinson's disease). Other neurological effects such as loss of hearing
(Rybak, 1992) are possible.
5.2. Pesticides
Pesticides are used to control various unwanted insects, rodents, plants, or molds. They
can be either persistent or nonpersistent, meaning that they either remain in the environment -
and therefore the body - for long periods of time or they are quickly metabolized. The use of
persistent pesticides is declining, and the use of nonpersistent pesticides is increasing in use.
Exposure can occur from residential use (e.g., gardening, pest control), occupational use
(e.g., farming, military), consumption of contaminated food or water, or from proximity to areas
where application occurs. It is important to note that certain pesticides were used in higher
frequency during the lives of those entering the elder years. For example, the application of
DDT in the U.S. has ceased, although many individuals now aged 65 and older have a history of
being directly exposed. Also, a number of Vietnam veterans were exposed to pesticides such as
Agent Orange, and the latent effects of exposure may be substantial. This could have a large
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impact on society since 9.5 million veterans were aged 65 years and older in 2000 (FIFARS,
2004).
Pesticides have been implicated as contributors to neurodegenerative diseases, including
Alzheimer's and Parkinson's diseases. There is considerable evidence that many pesticides can
cause a decline in cholinergic indices (choline acetyltransferase, acetylcholinesterase, and
muscarinic acetylcholine receptors), as occurs naturally with aging, suggesting that aging
humans may be more sensitive to organophosphate pesticides (Overstreet, 2000). There is also
evidence documenting the decline in cognitive function attributed in part to the decline in
cholinergic indices (Overstreet, 2000; Terry and Buccafusco, 2003), with studies reporting an
improvement in cognitive functioning following pharmaceutical treatment with
acetylcholinesterase inhibitors (Bullock and Dengiz, 2005; Ellis, 2005; Kaduszkiewicz et al.,
2005).
5.3. Air Pollution
Elderly individuals are vulnerable to the health effects of air pollution (Fischer et al.,
2003; Pope, 2000; Sandstrom et al., 2003) due to the reduced capacity of the respiratory and
cardiovascular systems, which results in increased symptoms, exacerbations of disease, and
mortality (Devlin et al., 2003). There is a large variation of exposure levels related to geographic
location, seasonality, use of personal care products, cooking, cleaning, transportation use,
housing (building materials, ventilation, heating, smoking, animals, pests), and recreational
choices. Under the Clean Air Act, EPA sets National Ambient Air Quality Standards (NAAQS)
for air pollutants deemed to be of particular concern to public health and the environment; these
include ozone (Os), PM, CO, sulfur dioxide (802), nitrogen oxides (NOx), and lead.
Exposure to Os is a known risk factor for acute exacerbation of cardiopulmonary
conditions in the aged population, leading to increased hospital admission (Delfino et al., 1998;
Schwartz, 1994; Yang et al., 2003) or mortality (Izzotti et al., 2000) due to, for instance, COPD
(Fischer et al., 2003). The Os 8-hour standard was exceeded for 46% of elderly adults in 2002
and has been increasing since 2000 (FIFARS, 2004), although many of these responses to
exposure are seen within NAAQS acceptable exposure range.
PM is a mixture of solid and liquid particles suspended in air that is emitted mostly from
combustion products from sources such as transportation, manufacturing, and energy production.
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PM standards were exceeded for 19% of elderly adults in 2002, although this number has
actually been improving since 2000 (FIFARS, 2004). Although acute exposure to PM can lead
to health effects (Hattis et al., 2001; Lippmann et al., 2003), both current and past exposures to
sources of PM are important considerations. Several recent studies suggest that PM is associated
with cardiovascular diseases (Anderson et al., 2003; Kunzli et al., 2005; Liao et al., 1999; Pope
et al., 2004; Utell et al. 2002) and respiratory diseases (Anderson et al., 2003; de Hartog et al.,
2003; Mann et al., 2002; Pope, 2000; Schwartz, 1994) in people age 65 and older.
Exposure to CO at all ages reduces the amount of oxygen in the blood, and it is a
particular concern for the elderly due to the common condition of anemia. CO can cause a
number of acute health effects, including fatigue, muscle weakness, shortness of breath, chest
pain in individuals with chronic heart conditions, headaches, visual or hearing (Rybak, 1992)
impairment, nausea, and dizziness. Behavioral effects include slowed reaction time, confusion,
and disorientation. In severe exposure, CO can cause loss of consciousness and death. These
effects can be exacerbated in elderly individuals due to their altered physiology and disease
states.
SO2 can have effects on the respiratory and cardiovascular systems (Venners et al.,
2003), particularly in individuals with preexisting diseases (e.g., asthma, COPD). Similarly,
NOx is associated with the exacerbation of respiratory (Simoni et al., 2003) and cardiovascular
conditions (Maheswaran et al., 2005), and elderly individuals may be particularly susceptible to
exposure.
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6. ANIMAL MODELS FOR THE STUDY OF AGING
Animal models, and particularly rodent models, have been and continue to be extremely
useful in defining and understanding the aging process and assessing the risk of environmental
agent exposure in the elderly. These models may provide insight on the interaction between
genetic, environmental, dietary, and disease factors and the normal aging process. Consideration
of the evolutionary mechanisms by which senescence evolves suggests that researchers need to
consider carefully the questions they wish to ask and choose their animal model accordingly
(Phelan, 1992).
Just as there is variability among humans, there is variability among different
experimental animal species as well as within a given species (e.g., strains). Therefore, it is
essential to be careful how one extrapolates information from animals to humans. In particular,
only a few experimental animal species (with the exception of nonhuman primates) live as long
as humans. Also, the timing and route of exposure in an animal experiment versus a human
scenario may be different, the TK and TD may be dissimilar, and the health outcomes may not
occur consistently. Therefore, these models may not be generalizable to aging in humans, but
they do allow basic theories of the molecular basis for aging to be tested.
In animal models, the role of restricting caloric intake is significant in the process of
aging because such restriction may increase life span, delay physiological deterioration, delay the
onset or slow the progression of most age-associated disease processes, and increase resistance to
the damaging affects of acute stressors (Masoro, 2000). Also, dietary restriction can improve
toxicant clearance, reduce the pathology associated with the toxicant, and even increase life span
relative to that of controls. However, tissue antioxidant defense against free radical damage may
be compromised under the nutritional deficiencies. In addition, there are relevant studies on
interaction(s) of caloric restriction and environmental exposure in aged animals that show that
the effect of some toxicants is reduced with caloric restriction (Apte et al., 2003; Maswood et al.,
2004). It is important to note that some toxicants may lead to reduced caloric intake or a
reduction in body weight.
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6.1. IN VITRO MODELS
In vitro cell culture and ex vivo models offer defined cells and environments in which to
explore specific genetic and cellular changes that occur during aging and study the mechanisms
of toxicity. In vitro techniques have been used to identify toxic hazards and investigate
mechanisms of toxicity (Cristofalo and Pignolo, 1995) in cells at various stages of proliferation
and senescence. Studies can be performed in cell cultures derived from humans or animals of
various ages in order to determine the vulnerability of these cells to free radical production
initiated by drug or environmental chemical exposure, although the age of the donor providing
the cells to be cultured can affect the success of the culture.
It is important to note that these systems supplement but do not replace experiments with
whole animals, and that their use in hazard identification in human health risk assessment has not
been widely accepted. This is due to the fact that a dose-response relationship obtained in vitro
may not correspond with in vivo results. The entire TK process that determines xenobiotic
concentration at the site of action in vivo cannot be accurately replicated in vitro, nor can in vitro
models capture individual variability of TK response.
Two types of cell cultures are generally used in aging research: primary cell cultures and
cell lines. Primary cell cultures are cells that are harvested directly from the organism's tissues,
dissociated into single cells before seeding into the culture vessel, and maintained in vitro for
periods beyond 24 hours. Cell lines are cultures that have been serially transplanted or
subcultured through a number of generations and can be propagated for an extended period of
time. In vitro systems often provide only partial answers to complex problems.
Stages in the cellular life cycle have been examined for possible mechanisms underlying
cell senescence. These possible mechanisms include studies of DNA repair, errors of protein
synthesis, and chromatin structure and function, as well as mechanisms modulating replicative
life span. The stages of a cultured cell are (1) outgrowth and establishment in the culture; (2)
vigorous proliferation that has a variable length, depending on the age of the tissue donor; (3)
declining proliferative vigor that includes cell death; and (4) emergence of an apparently long-
lived population that is unable to proliferate in response to mitogens.
Most cell types can be used in these models. Human diploid fibroblast cell models are
often used to study the mechanisms that underlie cellular senescence (Cristofalo et al., 1998). In
vitro studies of neurons are useful in controlling the response due to the fact that in vivo neuronal
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response may be mediated by nonneuronal cells or systemic biological processes that produce
toxic metabolites.
6.2. NONMAMMALIAN SPECIES
A number of nonmammalian species have been used to study the aging process. The
most common are fruit flies (Drosophila melanogaster) (Arking and Woodruff, 1998), nematodes
(Caenorhabditis elegans) (Reznick and Gershon, 1998), and zebrafish (Danio rerio) (Keller and
Murtha, 2004). At the cellular level, many of the phenomena related to fundamental aging
processes in mammals and nonmammals are similar, although the experimental results may be
difficult to generalize to mammals due to the vast difference in life spans.
The primary advantage of using nonmammalian species for aging research is the rate at
which genetic mechanisms can be studied (Liao and Freedman, 2002; Schwartz et al., 2004).
Specific genes may be manipulated to extend or shorten the life span, or genes involved in the
antioxidant defense systems can be tested to determine their effect on longevity and their
vulnerability to toxic exposure. In addition, these species may provide a suitable model for
examining the interaction between specific genes, environmental toxicants, and aging.
These species are particularly useful because (1) they have a short life cycle and life
spans, allowing for inexpensive multigenerational studies; (2) they have a simple multicellular
structure composed essentially of post-mitotic cells, which allows the examination of senescent
processes uncomplicated by the effects of cell division and replacement; and (3) they are
relatively easy to raise under well-defined and easily controlled nutritional conditions.
6.3. MAMMALIAN SPECIES
The aging animal as a model for the aging human may shed light on the aging process
and the accompanying physiological changes. Rats and mice offer models to study complex
changes in physiology and behavior and the indirect influences that organ systems have on each
other during the aging process. Nonhuman primate models can be used to examine the effect of
toxicant exposure on cognitive function in elderly animals. A main concern when using any
animal model is that the shorter life span makes them potentially less generalizable to the human
aging process.
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The choice of test species for aging study research should be based on the similarity of
TK or TD to humans, as well as the fact that not all species naturally demonstrate certain health
outcomes. For example, in rodents without genetic modification, atherosclerosis and
Alzheimer' s-type brain lesions do not spontaneously occur. Therefore, the mammal species has
to be selected carefully in order to observe the desired outcome.
Rodents, in particular rats and mice, are the most frequently used mammals for
experimental models of aging (Masoro, 1998), primarily because of their size and relatively short
life spans. Although a given phenotype may be similar among species, it is important to note that
the underlying mechanism of the effect may not be the same. Similarities among rats, mice, and
humans in aging phenotypic characteristics include
Low mortality between puberty and midlife and high mortality thereafter,
Marked increase in the prevalence of neoplasia after midlife,
Decreased cognitive impairment and increased motor deficits after midlife,
Total infertility of the female by about midlife and decreasing fertility of the male
with advancing age,
Increasing body fat mass through midlife and loss of body weight at advanced ages,
Impaired response to cold environment at advanced ages.
In rodent assays, both the genetic and the environmental factors related to the aging
process can be strictly controlled (van der Staay, 2002). Depending on the organ or system being
examined for age-related changes, a number of rat strains are available, such as inbred strains,
outbred strains, and natural populations that differ greatly in their genetic variability (Masoro,
1998). Heterozygous mice are more often being used in research (Lipman et al., 2004), with the
advantage that any observed effects are likely to be more generalizable. As models of human
aging, each strain possesses attributes that are suitable for particular lines of research but that
limit the system's value for other lines of research. Transgenic and knockout models are also
used (e.g., the long-lived p66shc knockout mice).
Rodent models have been used to support the connection between pesticide exposure and
Parkinson's disease (Cory-Slechta et al., 2005; Sherer et al., 2003), and new mouse models have
been established for human aging that express several aging phenotypes, such as atherosclerosis,
osteoporosis, skin atrophy, and pulmonary emphysema (Utsugi et al., 2000). These mouse
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models are expected to be important tools for aging research, particularly in studies that examine
the effect of aging on the immune system.
In addition to rodents, dogs, cats, rabbits, and nonhuman primates are used in a variety of
toxicological studies (Weindruch, 1995). Canines have moderate life spans, varying from about
12 to 20 years, depending on the breed (Cummings et al., 1996), and they are particularly used in
biomedical research for cardiology, toxicity, and safety testing.
Several nonhuman primate species have been used in aging research, with rhesus
monkeys being the best characterized and most extensively studied in biomedical gerontology
(Gallagher and Rapp, 1997). However, relatively few aging studies using nonhuman primates
have been performed because of the cost and limited availability of animals with known age and
health status (Weindruch, 1995).
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7. AGE-RELATED RISK ASSESSMENT ISSUES AND RESEARCH NEEDS
This document represents a broad overview of complex topics regarding the effect of
normal aging on the action of xenobiotics. One goal of the Agency's Aging Initiative is to
provide risk assessors with the tools needed to consider special sensitivities in order to conduct a
life stage-specific risk assessment. As a significant and potentially vulnerable segment of the
national population, the elderly represent a challenge in the measurement of exposure and the
evaluation of the effects of environmental exposures for assessing risk.
Characterization of exposure consists of numerous considerations from source to internal
dose, such as the pathway of exposure, including the description of the media (e.g., air, water,
food), exposure route (e.g., ingestion, inhalation, dermal contact), and scenario. Other
considerations for exposure include the frequency (e.g., intermittent, continuous) and length
(e.g., acute or chronic) of exposure, as well as aggregate and cumulative exposures (U.S. EPA,
1997e). Other factors that may affect risk at all life stages include occupational status, socio-
economic status, geographic location (e.g., climate), and individual behaviors and cultural
practices (U.S. EPA, 1997b). Exposure assessment can be made through biomarker information
achieved through biological monitoring (U.S. DHHS, 2005; McClearn, 1997; Pope et al., 2004).
However, due to the financial costs and participant burden, the sample size in such studies is
often very small. Some research needs related to exposure assessment include:
• Better characterization of factors that contribute to the exposure of elderly
populations to environmental agents, such as activity patterns and
microenvironments; and
• More research on biomarkers as a reliable measure of exposure.
Recognizing variability in TK and TD due to aging may help to explain interindividual
differences in susceptibility among exposed populations. By studying the physiologic changes
that occur during aging and the impact they have on TK and TD, this information can be used to
predict the potential for greater or lesser vulnerability to any type of environmental stressor
(Ginsberg et al., 2005). Table 1 summarizes the physiological changes seen in the elderly related
to TK (adapted from Geller and Zenick, 2005). In general, aging reduces the reserve capacity
that is available to adapt to environmental stressors.
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Table 1. Physiological changes related to toxicokinetics (TK) in the elderly
TK process
Absorption
Distribution
Metabolism
Excretion
Physiological changes in the elderly
Increased gastric residence time; decline in gastric acid production
Changes in dermal barrier function
Decrease in lung volume and ventilation rate
Decreased total body water (decreased volume of distribution; higher serum levels
for polar compounds)
Decreased muscle mass
Increased adipose tissue (higher accumulation of lipophilic compounds; slower
clearance rates)
Changes in plasma protein binding (e.g., decrease in plasma albumin)
Potential for increased permeability of blood-brain barrier with concurrent disease
Reduced liver volume and blood flow
Minor effects on Phase I and II metabolism
Decline in specific cytochrome P-450 activity
Potential for interactions of environmental toxicants with pharmaceutical agents
Significant effects in conjunction with age-associated disease.
Reduced renal blood flow, glomerular filtration
Reduced biliary excretion
Reduced pulmonary excretion
Source: Adapted from: Geller and Zenick, 2005.
Superimposed on the normal physiological changes due to aging are changes in
nutritional and disease status including: co-morbidity of diseases; the potential toxic effects of
various prescription drugs, and the increased probability for adverse interactions between drugs
or between drugs and environmental toxicants; and genetic polymorphisms. Any estimation of
the potential effects of environmental toxicants on the elderly must take each of these
circumstances into consideration.
Evidence that age-related changes in an environmental chemical's TK or TD can come
from several types of investigations relevant to risk assessment. Most studies of the
morphological and functional changes occurring with age are of a cross-sectional design, in
which measurements are made on subjects of different ages at a given point in time. A
disadvantage to cross-sectional studies is the lack of information on age-related changes in
individuals (Crome, 2003) or within a cohort. A cohort effect is the mutual experience related to
a particular situation, and a generational effect is related to the societal conditions of the time
(e.g., diet, education). The observed differences between the young and the old could be the
result of these experiences rather than of aging. For example, due to a longer life span, the
current aged population has had greater exposure to certain compounds such as lead and banned
pesticides such as DDT than those who will become aged in the future due to a cohort effect.
Therefore, it is important to note that although the toxic effect of these environmental agents
43
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remains the same, the exposure patterns may change over time. Another disadvantage to cross-
sectional studies is selective mortality or survivor effect. With increasing age, the fraction of a
cohort that is still alive decreases, which means that survivors at a given age may in many
regards be different than those who have already died.
Longitudinal studies of individuals circumvent some of these problems, but they are
costly and often have difficulty with retention of study participants over numerous years.
Although there are on-going longitudinal studies of human aging, this line of research has
primarily used, and will likely continue to use, the cross-sectional design. Similarly, biomarker
information can be useful in ascertaining effect (as well as for exposure) (U.S. DHHS, 2005;
McClearn, 1997; Pope et al., 2004), although the sample size for measures of effect may be very
small. Making this scientifically more challenging, there is potential for long latency periods
between exposures earlier in life and many health outcomes (U.S. EPA, 2005a, Figure 2.3), or
the latency period may be longer than the expected remaining life span (Landrigan et al., 2005).
In order to address these risk assessment concerns, some research needs include:
• A better understanding of the pathophysiological mechanisms of aging;
• Increased monitoring of the development and prevalence of chronic diseases,
particularly through the use of longitudinal studies;
• More chemical-specific toxicity data in human epidemiological studies in the elderly
population and in aged experimental animals;
• More dialogue between epidemiologists and mechanistic researchers of elderly
individuals;
• Focused research on the interactions between drugs and environmental contaminants;
Continued study of gene-environment interactions;
• More research on biomarkers as a reliable measure of biological age; and
• Improved understanding of latent effects from early life stage exposures.
The Agency recently explored age-related risk assessment concerns in the comprehensive
document^ Framework for Assessing Health Risks of Environmental Exposures to Children
(U.S. EPA, 2005a). In addition, risk assessment guidance exists for carcinogens (U.S. EPA
2005b), neurotoxicity (U.S. EPA, 1998), reproductive toxicity (U.S. EPA, 1996), and
environmental endocrine disruption (U.S. EPA, 1997a). However, specific guidance does not
exist for assessing health risk to the elderly.
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In order to improve our understanding of the interaction between biological aging and
exposure to environmental agents, these broad set of research need to be addressed. It is evident
that the aging population will require careful consideration regarding exposure, dose, and health
effects through targeted research in the aforementioned areas to better characterize potential risks
of environmental exposures and their interactions and relationships with genetic traits, nutrition,
and disease factors. It is critical that we gain a better understanding of these issues in order to
monitor and estimate differential exposures of the elderly population to environmental agents.
45
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