Complex Mixtures Methods for In Vivo Toxicity Testing (1988) / Chapter Skim
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2. Concepts for Analyzing Human Exposure to Complex Chemical Mixtures
2. Concepts for Analyzing Human Exposure to Complex Chemical Mixtures
Pages 10-38
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From page 10... ...
The prediction of human health risks uses a "weight-of-evidence" approach that considers data from various sources—epidemiology, analyses of accidental or intentional human exposures, animal tests, cell culture studies, metabolic and mutagenic assays, and so on and weights the data from all those sources in relation to their relevance to human populations (WHO, 1981; Ballantyne, 19851. For any chemical exposure, an effect of concern must be identified and a dose-response relationship must be estimated.
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From page 11... ...
Those discussions include not only the complexity of the materials to which people are exposed and the complexity of the exposed populations, but also the interactive effects that can ensue from exposure to mixtures of biologically active substances.. In theory, the most relevant effects data are those generated from human exposures.
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From page 12... ...
The two most commonly used surrogates for dose are exposure and biologic fluids from exposed persons, which can provide evidence that absorption has taken place or that biologically effective doses have been delivered. Dose surrogates can include the presence ofthe chemical of interest itself in blood, urine, or exhaled air or the presence of metabolites or enzymes induced by uptake of the chemical.
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From page 13... ...
The research cited above on roofers exposed to BaP indicates that their ambient exposures are considerably higher than those of cigarette smokers. However, the rate of lung cancer is much higher for cigarette smokers than for roofers.
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From page 14... ...
as an indicator for the various sulfur oxides, and the mass concentration of suspended particulate matter (PM) for all pollutants present as droplets or solid particles.
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(1984) have recently demonstrated selective hepatic and adipose retention of specific chlorinated dibenzofurans from complex mixtures of them and PCBs found at Yusho, Japan.
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A model to predict the percentage deposition of particles in various regions of the respiratory tract was developed by the Task Group on Lung Dynamics (ICRP, 1966) of the International Commission on Radiological Protection.
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Few generalizations about absorption rates are possible for individual chemicals, let alone for complex chemical mixtures. Particles that do not dissolve at deposition sites can be translocated to remote retention sites by passive and active clearance processes.
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Inhaled materials that affect mucocilia~y clearance rates include cigarette smoke (Albert et al., 1974, 1975) , sulfuric acid (Lippmann et al., 1982; Schlesinger et al., 1983)
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From page 19... ...
Cigarette smokers, for example, who switch to filtered brands reduce exposure to the total mixture, but not necessarily to the key toxic ingredients; the obvious way to decrease exposure to the toxic ingredients is to decrease or cease smoking. Decreases in the exposure of workers and the general public to coke-oven emissions are accomplished by controlling all the emissions, not only the most toxic fractions.
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From page 20... ...
Some examples are lung cancer resulting from exposure to cigarettes and radon daughters (Little et al., 1965; Rajewsky and Stahlhofen, 1966; Pershagen et al., 1987) , lung cancer due to cigarette-smoking and asbestos exposures (Selikoff et al., 1968; Berm et al., 1972; Hammond and Selikoff, 1973)
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From page 21... ...
Toxicologic testing of joint effects of two or more chemical exposures, under carefully controlled conditions, would help answer many of the outstanding questions. Toxicologic evaluation of complex mixtures can address many of the questions raised specifically by epidemiologic studies of workplace and other exposures to mixtures.
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CONSIDERATIONS IN QUANTITATION OF HUMAN EXPOSURES IN EPIDEMIOLOGIC STUDIES Documented effects of environmental chemicals on humans seldom contain quantitative exposure data and only occasionally include more than crude exposure rankings based on known contact with or proximity to the materials believed to have caused the effects. Interpretation ofthe available human experience requires some appreciation of the uses and limitations of the data used to estimate the exposure side of the exposure-response relation.
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Many epidemiologic studies of complex mixtures are based on occupational exposures. These involve repetitive daily exposures lasting up to about 8 hours, with uptake predominantly by inhalation, but sometimes also by skin absorption.
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In assessing or accumulating exposure histories or estimates, it is important to collect evidence on the frequency and magnitude of the occasional or intermittent releases associated win process upsets. SOME STATISTICAL ISSUES IN QUANTITATION OF EXPOSURE The preceding discussions have addressed some complications in the assessment of exposure for complex mixtures, including the parameters of exposureresponse relations and measurement of exposure.
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This problem can be regarded as one of experimental design, and statistical literature on methods of determining designs that are "optimal" for some prespecified criteria, which account for both cost and accuracy, could play an important role in the design of future exposure-response studies. PREDICTIVE VALUE OF LABORATORY STUDIES FOR HUMAN EFFECTS OF ENVIRONMENTAL EXPOSURES The rationale for using animal studies to evaluate the human risks associated with environmental pollutants is that evolution has endowed mammalian species with similar genetic, biochemical, and physiologic makeups.
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From page 26... ...
For that reason, successful extrapolation of animal toxicity data to humans requires comparing animal and human toxicity data and elucidation of toxicokinetic events that are relevant to interspecies variability in toxicity. The process is aided by knowledge gained from surveys of occupationally exposed persons and from both unintentional and carefully controlled experimental human exposures.
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From page 27... ...
, can produce ciliastasis and inflammatory reaction in the respiratory tract. When cigarette smoke is inhaled chronically in amounts generated from one to two packs per day for 20 or more years, chronic lesions develop in several organs, including the lung and cardiovascular system, and neoplasms develop that are not predictable from any of the acute lesions.
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From page 28... ...
In spite of the previously described difficulties associated with the identification of human carcinogens, 30 chemicals or chemical mixtures and 9 industrial processes have been identified as definitive human carcinogens studies on humans have confirmed that the agents cause cancer in those who are exposed (IARC, 1982; Vainio et al., 1985; Rall et al., 19871. A review of IARC monographs found 288 chemicals, industrial processes, and complex mixtures for
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From page 29... ...
. The use of laboratory animals has been of limited value in the study of combined exposures, such as exposure to radon daughters and cigarette smoke and to asbestos and cigarette smoke (see Appendix B for details)
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SUMMARIES OF EXAMPLES OF HUMAN EXPOSURES TO COMPLEX CHEMICAL MIXTURES The final section of this chapter contains eight summaries of situations in which there has been an apparent nonconcurrence between human and animal health responses. (For readers interested in additional information, more detailed descriptions are provided in Appendix B.)
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From page 31... ...
The evidence for the independent role of lead comes primarily from NHANES II, a national population-based study that included a substudy on blood lead, blood pressure, and dietary factors. Supporting evidence for the influence of blood lead on blood pressure comes from a series of recent epidemiologic studies of occupationally exposed populations.
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From page 32... ...
RADON DAUGHTERS AND CIGARETTE SMOKE Several investigators have speculated that cigarette-smoking and radon daughters have joint actions in the incidence of lung cancer among miners exposed occupationally. Both radon daughters and cigarette-smoking are known to increase lung-cancer incidence in humans independently, and their joint action produces no more than an additive cumulative incidence.
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From page 33... ...
The issue deserves much further attention, because exposures are so widespread and potential absolute risks so high. COKE-OVEN EMISSIONS Epidemiologic studies have shown an increased incidence of lung and genitourinary tract cancers in connection with exposure to coke-oven emissions, whereas experimental inhalation studies in animals have not produced comparable results.
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1974. Effects of cigarette smoke components on bronchial clearance in the donkey.
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1982. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Suppl.
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1965. Distribution of polonium2'0 in pulmonary tissues of cigarette smokers.
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1966. Polonium-210 activity in the lungs of cigarette smokers.
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From page 38... ...
1985. Data on the carcinogenicity of chemicals in the IARC Monographs programme.
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