Aging in Today's Environment (1987) / Chapter Skim
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4 Principles of Toxicology in the Context of Aging
4 Principles of Toxicology in the Context of Aging
Pages 46-71
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From page 46... ...
Toxicology, more than most disciplines of biology, depends on comparison of experimental results with large data bases acquired through the application of standard test protocols to large numbers of chemicals and types of radiation. To study both the possible exacerbation of aging processes by environmental agents and the potential of increased toxicity for elderly people, mechanisms of aging must be considered with respect to their similarity to mechanisms of toxicity of known toxic agents.
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From page 47... ...
Furthermore, aging cannot be readily arrested and is present during any wholeanimal experiment. Thus, all toxic processes induced by external agents can interact with aging processes, and the possible impact of this interaction would be greater with chronic exposures or toxic effects whose latency includes a substantial portion of the life span.
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From page 48... ...
Conversely, diverse toxic agents sometimes produce similar pathologic effects; that is, the processes that manifest some effects can be triggered by different agents. All tissues deteriorate during aging.
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From page 49... ...
~ How can environmental agents, particularly pharmaceuticals, that hold increased hazard for the aged be identified? Most toxicity Is measurer]
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From page 50... ...
Many toxic chemicals are converted to less toxic, or in some cases more toxic, chern~cals by the same pathways that are responsible for the biotransformation of drugs, so data on drugs have relevance for toxicologic concerns. For information on aging and drug disposition, several comprehensive reviews of geriatric pharmacology are available (Greenblatt et al., 1982; Schmucker, 1978, 1985; Vestal and Dawson, 1985~.
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From page 51... ...
The main sites of absorption of toxic agents are the skin, lungs, and gastrointestinal tract. Many toxicants can be absorbed through the skin and enter the bloodstream.
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From page 52... ...
Such binding is of particular concern to toxicologists and medical scientists, because toxicants bound to those proteins can be displaced by other chemical agents and, once released, go to target organs and produce injury there. The distribution of toxicants depends on their ability to cross cell membranes and on their affinity for various body components.
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From page 53... ...
is reduced by 1~15% between the ages of 20 and 80 years; lean body mass in proportion to body weight is also diminished with age, and body fat is increased. These changes can be predicted to cause higher blood concentrations of substances that are distributed mainly in body water or lean body mass.
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From page 54... ...
However, storage of the chemical in tissue depots or the toxicity of unmeasured, activated, intermediate chemical forms is sometimes more important. Processes of metabolism and elimination can be altered in the elderly, but the evidence of altered hepatic drug metabolism in humans is indirect.
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From page 55... ...
Nevertheless, the possibility of the greatly reduced capacity of some elderly patients to r~etabolize and eliminate drugs should be taken into consideration when prescribing drugs for the elderly. This can be done either by slightly reducing the dosage of potent drugs with low therapeutic indexes or by watching the patients very carefully, to ensure therapeutic efficacy of prescribed medications and to detect undesirable drug-related side effects early.
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From page 56... ...
That decrease results in higher blood concentrations after equivalent doses in the elderly than in the young. Acute alcohol exposure inhibits and chronic exposure induces oxidative drug metabolism in the normal liver.
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From page 57... ...
Therefore, in clinical practice it is essential to measure plasma concentrations of potentially toxic drugs and adjust doses accordingly to achieve therapeutic concentrations. Not only geriatric patients, but fetuses, neonates, and children show rates of drug elimination that differ from those in normal adults and that can vary greatly with drug and person.
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From page 58... ...
MECHANISMS OF TOXICITY AT THE MOLECULAR, CELLULAR, AND TISSUE LEVEL The mechanisms by which toxic agents exert their actions are extremely diverse. Such mechanisms vary between specific agents and between doses of a given agent.
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From page 59... ...
The search for toxic mechanisms that are shared by aging and by specific toxic agents should include agents whose action is very broad, because aging broadly affects all tin sues. Breadth of action can result from different types of mechanisrns, however.
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From page 60... ...
In considering the possible effects of any toxic agent on aging and the aged, we must view such an induced response as part of a series of toxic actions and as depending on dose, mode of exposure, duration of exposure, species exposed, and period of observation. Other toxic agents are probably more specific in their initial actions and in their effects.
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From page 61... ...
It is important, however, in understanding the toxic mechanism acting at the tissue level to determine its etiology at the cellular and molecular levels. To return to the example of ionizing radiation, the induced failure of the lining of the gut to perform its barrier function Is the direct result of failure of stem cells to proliferate, which causes sloughing of the intestinal mucosa.
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From page 62... ...
Qualitative differences among subjects in pathways of drug metabolism and quantitative differences in the activities of the enzymes that catalyze those reactions and pathways could be involved in the regulation and control of such tissue damage. Thus, genetic differences among subjects can render some more and others less sensitive to the toxicity of different reactive metabolites.
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From page 63... ...
. In the past 20 years, genetic factors that directly affect xenobiotic response and disposition in humans have been discovered
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From page 64... ...
In some people under some conditions, genetic factors are the major or even sole cause of such interindividual differences. For example, when age, sex, diet, and exposure to environmental chemicals that activate or inhibit the hepatic drug-metabolizing enzyme system remain constant among human subjects, large interinctividual variations in response to and disposition of xenobiotics remain.
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From page 65... ...
Acetophenetidin-induced methemoglobinemia Polymorphic serum aryl esterase activity Deficient N-hydroxylation of amobarbital Polymorphic hydroxylation of debrisoquine in man Polymorphic hydroxylation of mephenytoin Aberra I Normal Location Catalase in erythrocytes N-Acetyl transferase in liver Pseudocholinesterase in plasma Mixed-function oxidase in liver th at parahydroxyl at es phenytoinb Mixed-function oxidase in liver that hydroxyl at es b bishydroxycoumarin Mixed-function oxidase in liver t hat de -ethyl at es acetophenet idinb Serum aryl esterase (paraoxonase) Mixed-function oxidase in liver that N-hydroxylates amobarbitalb Mixed-function oxidase in liver that 4-hydroxylates debrisoquine Mixed-function oxidase in liver that hydroxylates S-mephenytoinb aAutosomal recessive, unless otherwise noted.
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From page 66... ...
conditions mentioned above are rare and make only a few drugs toxic, they probably contribute in only a minor way to the major medical problem of adverse drug reactions. However, another development in pharmacogenetics suggests that genetic differences that directly affect xenobiotic disposition play a prominent role in commonly encountered forms of drug toxicity.
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From page 67... ...
Biologic markers in humans, animals, or other biota can serve as measures of exposure to or injury by a xenobiotic by indicating internal or circulating dose, stored body burden, dose at a target tissue, or the early onset of a pathologic effect. The concept of biologic markers grew out of cancer research that sought to identify the role of exogenous agents or host factors as causes of human cancer.
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From page 68... ...
, and potential or actual health impairment. Markers of susceptibility indicate individual or population physiologic differences that affect response to environmental agents, regardless of exposure.
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From page 69... ...
Markers of biologically effective dose include such target-organ characteristics as rates of metabolic activation and detoxification, pre-existing susceptibilities, and reserve capacity. Markers of potential health impairment include early biologic responses, such as alterations in the functions of target or nontarget tissue shortly after exposure.
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From page 70... |
From page 71... ...
Tests for environmental agents are generally performed at dosages much higher than those to which human populations are exposed. Data from such tests must be extrapolated to predict human responses to dosages experienced in the environment.
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