Complex Mixtures Methods for In Vivo Toxicity Testing (1988) / Chapter Skim
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Appendix B: Case Studies Establishing Active Agents and/or Interactions in Complex Mixtures
Appendix B: Case Studies Establishing Active Agents and/or Interactions in Complex Mixtures
Pages 133-167
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From page 133... ...
in ambient air and their effects on mortality and respiratory disease morbidity is a classic case of exposure to complex mixtures in which identification of causal factors has proved extremely difficult. Epidemiologic research has been critical in determining the relative roles of SO2 and PM, whereas laboratory inhalation studies have been critical in identifying active components in the PM.
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From page 134... ...
performed regression analyses between daily mortality and four different components of PM: total suspended particulate matter (TSP) , inhalable particulate matter (IP)
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From page 135... ...
The only experimental inhalation studies producing effects of possible relevance to the human experience have been those involving acidic aerosols, either alone or in complex mixtures. Some recent animal inhalation studies by Amdur (1985)
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From page 137... ...
The significance of the changes in particle clearance rate in the lungs from repetitive daily exposures to acidic aerosols, in terms of the pathogenesis of chronic respiratory disease, is not yet clear. But the close correspondence between the effects of cigarette smoke and H2SO4 aerosol on mucocilia~y clearance after both short-term and long-term exposures, the similarities between the epithelial changes after repetitive H2SO4 inhalation in rabbits and those seen in the lungs of young smokers in postmortem examinations, and the wellestablished role of smoking in the etiology of chronic bronchitis combine to suggest that chronic bronchitis could result from long-term repetitive exposures to H2SO4 (Lippmann et al., 1982~.
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From page 139... ...
After adjustment for age, bodymass index, all measured nutritional factors, and blood biochemistry factors were adjusted for a multiple linear regression model, the relations of both systolic and diastolic blood pressures to blood Pb were statistically significant (p < 0.011. In an examination of the NHANES II population in the age range from 12-74, Harlan et al.
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From page 140... ...
The result of combined exposures is to increase the number of carcinomas, and this increase is interpreted as additive by several investigators, whereas others consider the effect as multiplicative. Exposure to radon daughters and cigarette smoke also appears to decrease the latency induction period for lung cancer.
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From page 141... ...
These investigators found more lung cancers in nonsmoking radon-daughter-exposed dogs than in a group exposed to cigarette smoke. These findings were interpreted as "protective" effect.
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From page 142... ...
Despite the fact that uranium miners smoked more than the comparably aged nonminer U.S. males, the excess exposure to cigarette smoke explained only a small part of the observed increase in lung cancer.
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From page 143... ...
The animals receiving the combination of smoke and radiation had an increased yield of lung cancers, which appeared earlier than with radiation alone. In summary, epidemiologic studies of exposure to radon daughters and cigarette smoke have demonstrated two effects.
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From page 144... ...
There is no evidence, however, that cigarette-smoking accelerates or modifies the extent of fibrosis produced by asbestos exposure. Animal studies, when properly designed, have demonstrated the production of primary lung cancer, pleural mesotheliomas, and asbestosis.
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From page 145... ...
Studies have not established a threshold quantity of asbestos required to increase Me risk of lung TABLE B-2 Age-Standard~zed Lung Cancer Death Ratesa for Cigarette Smoking and/or Occupational Exposure to Asbestos Dust Compared win No Smoking and No Occupational Exposure to Asbestos DusP Exposure History to Cigarette Death Mortality Mortality Group Asbestos? Smoking?
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From page 146... ...
The risk of developing lung cancer after cessation of cigarette-smoking in asbestos-exposed workers appears to decrease in a manner similar to that seen in non-asbestos-exposed cigarette smokers who stop smoking. These findings have been observed by Hammond et al.
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From page 147... ...
evaluated the discriminatory power of various pulmonary Function tests to distinguish the effects of smoking from those of asbestos exposure. Decreases in diffusing capacity for carbon monoxide and decreases in vital capacity were the best measures of severity of obstructive and restrictive lung disease in persons with combined exposures, but these tests do not clearly distinguish between the two agents.
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From page 148... ...
Those changes had no relation to radiologic categories of pneumoconiosis, cumulative asbestos exposure, or pulmonary functional abnormality. There is apparently a lack of uniform results concerning the effect of asbestos and cigarette-smoking on T-lymphocyte number and activity.
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From page 149... ...
The relative risk (risk ratio) is commonly used in epidemiologic studies as a measure of risk.
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From page 150... ...
It would not be correct, for example, to TABLE B-4 Relative Risks of Oral Cancer According to Level of Exposure to Smoking and Alcohola Smoking (cigarette equivalents/day) o 1.00 1.40 1.60 2.33 Alcohol, oz/day < 20 20-39 - 40 o <0.4 0.4-1.5 21.6 1.52 1.67 4.36 4.13 1.43 3.18 4.46 9.59 2.43 3.25 8.21 15.5 a Adapted from Rothman and Keller (1972)
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From page 151... ...
TRIHALOMETHANES AND OTHER BYPRODUCTS OF CHLORINATION IN DRINKING WATER This case study demonstrates how epidemiologic methods have been used to evaluate human risk from exposure to complex mixtures of chlorination byproducts in disinfected drinking water. It is generally accepted that the practice of chlorine disinfection, used since 1909 in the United States (Johnson, 191 1)
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From page 152... ...
In the face of these difficulties, comparisons of risk between groups or individuals exposed to chlorinated surface water, as opposed to persons who used groundwater, could be as valid and useful as comparisons based on actual THM measurements. Just as toxicologic assessment of chlorination byproducts and other chemicals in drinking water have evolved from crude evaluations of complex mixtures to identification of individual chemicals, so epidemiologic studies have progressed from broad assessments, with little ability to distinguish specific exposures or control for potential confounders, to more refined "analytic"
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From page 153... ...
Salg (1977) examined the association between water-quality factors and cancer mortality in the 346 counties of the Ohio River drainage basin, using as exposure variables the percentage of each county's population served by surface water.
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From page 154... ...
showed no association of risk with several different measures of past THM intake. Dose differences between exposed and unexposed persons in Wisconsin might not have been as large as in North Carolina, because relatively uncontaminated surface waters were used for drinkingwater supplies in Wisconsin and had lower concentrations of chlorination byproducts.
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From page 155... ...
COKE-OVEN EMISSIONS The following discussion of the toxic effects of coke-oven emissions is presented to demonstrate that animal toxicity testing of complex mixtures is a valid means of predicting human disease resulting from environmental exposure to these mixtures. From a toxicologic point of view, coke-oven emissions and related agents, such as coal tar, are probably the most widely studied complex mixtures.
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From page 156... ...
For 70 years, investigators have been producing skin cancer in experimental animals by dermal application of coal tar or coal-tar extracts. The results are consistent with observations of increased scrotal cancer in chimneysweeps made two centuries ago, but are not confirmed by modern epidemiologic studies of coke-oven workers.
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From page 157... ...
The above discussion of coke-oven emissions demonstrates that data generated by animal toxicity testing of complex mixtures can be a reasonable predictorofhuman disease, if the mixture being tested in the laboratory is representative of mixtures in the human environment, if studies are properly designed to detect diseases, and if we are aware that the specific diseases and target organs in test animals can vale from those in humans. COAL-MINE DUST The studies of lung disease in coal miners have focused principally on chest x-ray alterations, pulmonary function deficits, chronic bronchitis, and pathologic alterations of lung tissue.
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From page 158... ...
However, the greatest decrement in LEVI was found in workers with chronic bronchitis, and it could not be explained solely on the basis of dust exposure and cigarette-smoking. In a longitudinal study of 1,677 active coal miners without PMF, Love and Miller (1982)
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From page 159... ...
. Most of the studies focused on active miners and therefore might have analyzed a self-selected group of people who can tolerate dust exposures without significant effects on pulmonary function.
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The monkeys developed macules thatlooked similar to those seen in coal miners' lungs. Rats did not develop macules with the same appearance as those in coal miners, probably because the anatomy of the rat lung is considerably different from that of the human lung.
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From page 161... ...
1978. A case control study of gastrointestinal and urinary tract cancer mortality and drinking water chlorination, pp.
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1985. Underground mining, smoking, and lung cancer: A case-control study in the iron ore municipalities in northern Sweden.
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1982. Case-control cancer mortality study and chlorination of drinking water in Louisiana.
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1977. Ohio drinking water source and cancer rates.
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From page 165... ...
1977. Cancer Mortality Rates and Drinking Water Quality in the Ohio River Valley Basin.
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From page 166... ...
1986. The relationship of blood lead to blood pressure in a longitudinal study of working men.
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From page 167... ...
1983. Matched pair case control study of drinking wafer chlorination and cancer mortality, pp.
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