Polycyclic Aromatic Hydrocarbons Evaluation of Sources and Effects (1983) / Chapter Skim
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7 SOME FACTORS THAT AFFECT SUSCEPTIBILITY OF HUMANS TO POLYCYCLIC AROMATIC HYDROCARBONS
7 SOME FACTORS THAT AFFECT SUSCEPTIBILITY OF HUMANS TO POLYCYCLIC AROMATIC HYDROCARBONS
Pages 349-382
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From page 349... ...
Protein deficiencies can lower AHH activity,l°l and the type of dietary protein can affect AHH activity.36 Nutrient deficiencies are observed in both childrenl25 and adults;189 deficiencies in iron, vitamin A, and vitamin C are the most prevalent. Whether these deficiencies play a role in PAH-related effects in humans is not known.
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From page 350... ...
normal lung tissue ~ Lung cancer Lymphocytes 39 Absolute AHH activity dominantly inherited; values given relative to "standard" panel; no AHH values presented Lung cancer Lymphocytes 4 Lung cancer Antipyrine 71 Leukemia Lymphocytes 11 7-12 Inducibility determined by noninduced AHH activity Antipyrine half-life related to cancer and smoking Susceptibility related to low ARH ~..
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From page 351... ...
In six cancer patients. Nine hospitalized patients used.
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From page 352... ...
oo c ~: ~o 0 O c c' · - 0 u ·~4 ~u .
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0 c ~: 0 0 0 · a ck o z tJ w 0 o cL o c e e .
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From page 354... ...
0 10 20 3040 SO 60 ~ 100 Percent of Population FIGURE 7-1. Interplay between genetically controlled variations and environmental exposure leading to cancer susceptibility.
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From page 355... ...
To AL To Jig ~ O t To ~ ~ KE ~ ..
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From page 356... ...
1 1L c ~ ~ ~ ~ In In ~ c a Id ED z ~ ¢ = 1 lo ~ ~IHHY 7-18 .
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From page 357... ...
Cytotoxic, mutagenic, or carcinogenic effects are thought to result from nonrepair or misrepair of particular DNA damage. Reprinted with permission from Roberts;157 copyright Academic Press.
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From page 358... ...
Genetic control of interindividual variations in the inducibility of aryl hydrocarbon hydroxylase in cultured human lymphocytes. Cancer Res.
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From page 359... ...
Meredith-Brown. Large interindividual variations in metabolism of benzo~a~pyrene by peripheral lung tissue from lung cancer patients.
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From page 360... ...
Makala. Induction of aryl hydrocarbon hydroxylase activity and pulmonary carcinoma.
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From page 361... ...
Aryl hydrocarbon hydroxylase activity in lymphocytes from lung cancer patients and normal controls. Oncology 33:105-109, 1976.
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From page 362... ...
Aryl hydrocarbon hydroxylase in buman bronchial epithelium and blood monocyte.
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From page 363... ...
Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer -- analysis of cryopreserved lymphocytes. Cancer Res.
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From page 364... ...
Aryl hydrocarbon hydroxylase activity in pulmonary macrophages and 1Ymohocvtes from lung cancer and non-cancer patients.
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From page 365... ...
Analysis of aryl hydrocarbon hydroxylase activity in human lung tissue, pulmonary macrophages, and blood lymphocytes. Cancer 41:2292-2300, 1978.
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From page 366... ...
Questionable relation of aryl hydrocarbon hydroxylase to lung cancer risk.
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From page 367... ...
Kauppila. Maternal cigarette smoking, placental aryl hydrocarbon hydroxylase and neonatal size.
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Aryl hydrocarbon hydroxylase is inhibited by antibody to rat liver cytochrome P-450. Science 208 :1031-1033, 1980.
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From page 369... ...
Polynuclear aromatic hydrocarbons of tobacco smoke: Isolation and identification. Beitr.
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Aryl hydrocarbon hydroxylase inducibility in carcinoma of renal pelvis and ureter. Lancet 2:612-617, 1977.
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II. Differences in metabolism to water-soluble products and aryl hydrocarbon hydroxylase activity.
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From page 373... ...
SOURCES, ATMOSPHERIC PERSISTENCE, AND TRANSFORMATIONS OF PAHs The emphasis of this report is on PAHs emitted from mobile sources, but these substances are ubiquitous -- they are found in terrestrial and aquatic plants, in soils and bottom sediments, and in fresh and marine waters, as a result of emission from both mobile and stationary sources. The total annual release of benzo~a~pyrene (BaP)
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From page 374... ...
Extracts of particles from spark-ignition and diesel exhaust are mutagenic to Salmonella typhimurium in forward- and backward mutation assays and in several animal-cell model systems. The extracts were directly active in the bacterial assay, whereas emission from coke ovens, roofing tar, cigarette-smoke condensate, wood combustion products, and Pap 8-2 lo.
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From page 375... ...
The mouse skin tumorigenesis model has been used to assay the carcinogenicity of extracts of various particles. The condensates from spark-ignition engine exhaust proved carcinogenic in this model; those from diesel exhaust were less active.
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From page 376... ...
The epoxides may give rise to bans dial derivatives in reactions catalyzed by the membrane-bound enzyme epoxide hydratase; these dial derivatives may be excreted unchanged or conjugated as glucuronides. Secondary metabolism by the cytochrome P-450-dependent monooxygenases yields very reactive diolepoxides that can spontaneously rearrange to electrophiles that can interact with macromolecular nucleophiles, such~as DNA.
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From page 377... ...
Although it has been proposed that aryl hydrocarbon hydroxylase activity in lymphocytes and monocytes of lung-cancer patients 8-5 Hi;
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From page 378... ...
Susceptibility to PAH-induced effects may be controlled at the level of uptake into specific cells, metabolic activation or inactivation, DNA repair, expression of DNA damage and its progression to the phenotype of a mutant cell, and immunocompetence of the person. Several of these steps (perhaps all)
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From page 379... ...
On the basis of what is currently known, research should be conducted to discover practical and economical adjustments in engine design for reducing particulate and gaseous PAH emission. In vitro mutagenesis tests could be used to determine the types of adjustments that influence the concentrations of PAH chemicals active in these short-term tests.
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From page 380... ...
A model for promotion other than the mouse skin tumorigenesis system is needed. Of special interest would be a promotion system using human cells.
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From page 381... ...
With appropriately designed cell-model systems that use various cell types, the relationship of in vivo repair of PAH metabolite-DNA adducts should be examined and an activity profile developed for the individual known active PAHs. Animals other than mice and rats should be used to examine PAH metabolite-DNA adduct formation and the mechanisms by which phenolic antioxidants and inducers of aryl hydrocarbon hydroxylase (AHH)
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From page 382... ...
· Reassess the role of genetically mediated differences in AHH -responsiveness in determining cancer susceptibility by using multiple human tissues and multiple enzyme end points (assay for PAH receptors in human tissue; assay for total and specific cytochrome P-450s by monocLononal antibodies; assay for AHH expression of these genes; use of lymphoid, epidermal, and fibrobLastic cells as sources of tissues for enzymatic assays; and use of multiple functional assays for AHH, e.g., fluorimetry, high-performance liquid chromatography, and UNA binding and repair)
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