Monitoring Human Tissues for Toxic Substances (1991) / Chapter Skim
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3. Toxicologic Issues
3. Toxicologic Issues
Pages 45-70
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From page 45... ...
Tissue-monitoring data alone can alert those concerned with public health to the need to conduct studies on specific environmental chemicals. Three examples that illustrate the importance of tissue monitoring are monitoring of blood to determine the extent of lead toxicity in the United States, monitoring of fish and wildlife to determine concentrations of pesticides in tissues, and monitoring of acute tissue damage to identify conditions common to such damage.
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From page 46... ...
Clearly, tissue monitoring can be of great value for associating adverse health effects with exposure to environmental chemicals, but several problems arise in attempts to understand the association. Most toxicologic concerns are related to chronic diseases that can take decades to develop (e.g., dementias, necrologic disorders, cancer, osteoporosis, and arthritis)
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From page 47... ...
Concentrations of environmental chemicals in human tissues can be used to assess the likelihood that disease will result from chemical exposures. The monitoring of human tissues for toxic substances is concerned primarily with measurement of exposure, although some information is relevant to biologic effects.
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From page 48... ...
It is important to distinguish between the current use of human-tissue monitoring data and their potential use in risk assessment. Data on tissue concentrations of xenobiotics constitute measures of internal dose and so can help to identify a hazard (i.e., a qualitative risk)
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From page 49... ...
For example, it is not possible to "back-calculate" the history of exposure from a single blood sample. Thus, the use of tissue monitoring data to estimate potential risks with the conventional approach is not always accurate.
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From page 50... ...
Sensitive physicochemical and immunologic methods can detect and measure very low concentrations of foreign substances in the body. Exhaled air, blood, and urine are ordinarily used, but other body fluids such as breast milk, semen, and adipose tissue have also been used.
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From page 51... ...
Because estimates of the amount of the chemical present in the entire body are rarely possible, and may not be as useful, a particular tissue is typically chosen as an indicator of body burdens or stores of the chemical. The specific tissue chosen in biologic monitoring may be selected because this tissue accumulates the chemical (e.g., adipose tissue for some pesticides; bone for lead or strontium)
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From page 52... ...
Markers of Biologically Effective Dose Markers of biologically effective dose measure the amount of a pollutant or its metabolites that has interacted with cellular macromolecules at a target site or an established surrogate. Measures of biologically effective dose include DNA adducts and hemoglobin adducts in a range of cells and tissues, including peripheral blood, bone marrow, lung macrophages, buccal mucosa, placental tissue, and lung tissue.
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From page 53... ...
Because of the 3-month lifespan of hemoglobin, these assays reflect relatively recent exposures, while DNA adducts can assess exposure integrated over a much longer period. Markers of Early Biologic Effect Whereas markers of biologically effective dose indicate an interaction with critical macromolecules that might potentially result in disease, these markers may also be repaired, or otherwise "lost." In contrast, markers of early biologic effect indicate the occurrence of irreversible toxic interactions either at the target or an analogous site.
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From page 54... ...
. Elevated frequencies of chromosomal aberrations and/or SCEs have been observed in persons exposed to ionizing radiation or to a variety of chemicals including vinyl chloride, styrene, ethylene oxide, and organophosphates (Evans, 1982; Vainio et al., 1984~.
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From page 55... ...
A large number of factors influence this reaction, including age, genetic makeup, gender, developmental stage, physical activity, and normal physiological states such as pregnancy and lactation. Susceptibility to the effects of a chemical results from differences in transfer of the toxic chemical from the external dose to the internal dose, the biokinetics of distribution among and within tissues, and the responsiveness of the target tissue.
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From page 56... ...
is a new approach using recombinant techniques to detect DNA conformations associated with genetic predisposition to cancers such as retinoblastoma (Francomano and Kazazian, 1986~. Summary Although many biologic markers are in the validation stage, they have considerable potential in risk assessment and environmental epidemiology (reviewed in Perera, 1987; Hulka and Wilcosky, 1989~.
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From page 57... ...
CHOICE OF TISSUES TO MONITOR Background A monitoring program to survey xenobiotic chemicals in human tissues should provide an estimate of chemical concentrations in the tissues selected, identify the tissues and toxic effects relevant to each chemical, and identify potential risks. Those objectives are seldom achieved in the laboratory, and they are even less likely to be achieved in a survey of tissues from the general population.
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From page 58... ...
Tissues reach equilibrium at rates that depend in large part on the concentration of the chemical in blood, the rate of blood flow to the major tissue depots, and the tissue volumes. Final tissue-to-blood ratios reflect the affinities of the chemical for the individual tissues; the ratio for lipid-rich tissues is very high for highly lipophilic chemicals.
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From page 59... ...
TOXICOLOGIC ISSUES O 59 1 'a If Lid Bile _ ~ Fat i' , , ,,,.,.,.,, . Muscle Skin Gut Tissue Gut Lumen Feces Kidney I Urine FIGURE 3-1 Schematic diagram for a typical whole-body physiological pharmacokinetic model.
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From page 60... ...
60 to A Al a: A, 'v ~ .Q o ~ Hi Hi o a Hi ·o o ~ ~ ~ ~ ~ ·~= == ~ ~ al to ~ ~ ·- ~ ~ ~ om no a m o Cat o x Ct ._ TO ~ Ox US U)
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From page 61... ...
~ 61 on Do .O on ~ I' ~ — — C;S ~ E ~ ~ E o E ·E o.
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From page 62... ...
That relationship accounts for the observation that rats exposed to DOT at nontoxic concentrations for 3 months died of DDT intoxication when placed on a restricted diet that reduced their total body fat and consequently ~ncreased concentrations (Kimbrough, 1982~. Blood If blood-to-tissue ratios are known, determination of the blood concentration of a chemical can provide accurate estimates of other tissue concentrations.
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From page 63... ...
But breath analysis can yield estimates of relatively constant exposure, as sometimes occurs in the home or workplace. An important advantage for blood collection, in contrast to collection of adipose samples from cadavers, is that samples to be obtained from living persons, so that interviews can be conducted with sample donors to obtain demographic and environmental information, which permits examination of causal relationships and risk factors.
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From page 64... ...
Included in the questions that should be studied with great care are to what extent freezing/thawing will change concentrations of volatile contaminants; whether and how cells should be separated from plasma or serum to minimize analytical effects; and how samples should be stored before analysis, including temporal effects on volatile chemical concentrations. Adipose Tissue Adipose tissue contains the highest concentrations of some of the most persistent chemicals in the environment, including halogenated aromatic hydrocarbons.
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From page 65... ...
Lean tissues are generally available for assay only from autopsies; however, once a collection system is established for collecting adipose tissues at autopsy, then other solid (lean) tissues, such as liver and kidney, can be collected without much additional expense or effort.
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From page 66... ...
That is particularly true of highly lipophilic substances, such as halogenated aromatic compounds. Halogenated insecticides and other halogenated organic compounds are easily detected in human hair by simple extraction and analysis with gas chromatography (Matthews et al., 1976~.
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From page 67... ...
An essential part of monitoring exposure of the general population is a survey of chemical concentrations in human tissues. The original NHMP program was required to concentrate on chemicals in human adipose tissue.
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From page 68... ...
Blood con on shady besuppl~d by the Rued collection of adipose Sum in port to muffin Rich c~r~ while new long~errr~ series of blood meosur~ e established and us puff because some ~n~ meres ace most convene us fat As discussed elsewhere, fat samples are necessarily nonrandom and nonrepresentative, so careful study of the relation between blood concentrations and fat concentrations is needed to validate the latter. Measurements of nonrandom adipose tissue (as in the present CHATS)
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From page 69... ...
TOXICOLOGIC ISSUES Age priority smelly be given to the cdl~on of mashed adipose and blood specimen for fun ~1~1 analyses. Matched speamens offatf~m airiest ~ ~ nut also be us~lfor if.
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