• PCB treatment of newborns increased the cancer-causing ability of a tobacco chemical in one strain of mice but not in another
• PCB treatment of newborns increased the cancer-causing ability of NNK (a tobacco chemical) in one strain of mice but not in another
• the fetus may face increased cancer risks when exposed (through the mother’s exposure) to chemicals which induce enzymes which metabolize other chemicals to become carcinogenic.
• metabolism of aromatic carcinogens appears early in gestation and is highly inducible transplacentally in rodents by chemicals such as dioxin, resulting in dramatic percent increases in enzyme activity
• the fetus may be much more sensitive than adults
• PCBs promote NDMA (tobacco chemical) initiated lung tumors after a single dose
• average tumor numbers were enhanced 4-fold
• nonmetabolized PCB congeners retained in the tissues continuously stimulated tumor growth
• PCBs alone produced a slightly significant increase of tumors in newborns
• PCBs administered after NDMA initiation in newborn mice resulted in a substantial increase in lung tumors
• sequential exposure to PCBs and tobacco chemicals may result in increased tumor yield, but with chemical-, sex-, and age-dependent differences
• significant lung tumors developed in male fetuses exposed to NNK or NDMA (tobacco chemicals), followed by exposure after birth to PCB Aroclor 1254.
• exposure to NDMA in the womb yielded no tumor increase unless further exposed to PCB Aroclor 1254, when 36% developed lung tumors
• later PCB exposure doubled the incidence of lung tumors in newborn mice exposed to NDMA
• PCB effects depend on the timing of PCB exposure and sex
• single doses of PCBs into the digestive system were enough to cause the lung cancer effect
• PCBs (Aroclor-1254) were used to induce enzymes which facilitated the mutagenicity of small particulates, which may contribute to the induction of lung cancer
• depletion of vitamin-A in the lung increases susceptibility to lung cancer
• pentachlorophenol (usually contaminated with dioxins) was associated with airborne particulate matter which was associated with depletion of vitamin-A [PCBs are also usually contaminated with dioxins)
• PCBs play a role in levels of cytochrome-P450 enzymes in the lungs
• the lung enzyme, cytochrome P450 1A1, was significantly increased by PCBs
• cytochrome P450 IIB1 was significantly elevated
• total PCB lung content decreased with half lives of 17 and 9 weeks
• lower chlorinated PCBs cleared more rapidly that highly chlorinated compounds
• regulation of lung enzymes following PCBs involves interactions between specific PCB congeners
• the Ah receptor is not involved in PCB suppression of the lung enzyme, cytochrome CYP2B
• regulation of the lung enzyme, cytochrome CYP1A1, does appear to involve the Ah receptor
• PCBs decreased the cytochrome P4502B by about 50-60% in both strains of mice
• kidneys are more sensitive than lungs to PCB enzyme induction, but the effect is more persistent in lungs
• PCB Aroclor 1254 was a potent enzyme inducing agent in the lungs
• mutational activation of the K-ras oncogene often occurs in human and mouse lung adenocarcinomas
• PCBs caused an increase in membrane/cytosol ratio in mouse lungs
• PCBs and dioxins can induce the K-ras p21 oncogene [cancer gene] or increase its membrane level in certain mouse strains, but these properties are not fully dependent on Ahr receptor type
• K-ras p21 induction may be related to lung cancer
• HPOP and BOP (two tobacco carcinogens) required the presence of lung enzymes induced by PCBs in order to show positive mutagenic activity
• lung abscesses and pneumonia have been observed in mammalian species exposed to PCBs
• a uteroglobin lung protein has been identified which, although not a receptor, has served to specifically concentrate methylsulfone metabolites of PCBs in lung Clara cells
• enzymes induced by PCBs increase the mutagenicity of nitrosamines
• PCBs and dioxin together increased the incidence of lung and palate/nasal turbinates or tongue cancer in both sexes 
• respiratory tract biotransformation of many man-made toxic chemicals found in inhaled environmental pollutants is generally considered essential for the mutagenic, carcinogenic, and/or toxic response of lung tissue to these chemicals.
• mouse lung tissue enzymes induced by PCBs were used to test metabolic behavior of several toxic compounds
• PCB induced enzymes help promote mutations induced by cigarette smoke condensate
• metabolic activation is required before NNK (a tobacco chemical) will induce lung tumors
• PCBs induce the enzyme (cytochrome P450) which metabolically activates NNK
• PCBs were used to stimulate lung enzymes used to test whether a class of chemicals caused mutations
• PCBs strongly stimulated the activity of the NADPH-requiring enzymes responsible for ICR deactivation, which may relate to lung cancer.
• PCBs are a weak inducer of aryl hydrocarbon hydroxylase (AHH) activity in rabbit lung
• Furans caused a 3-fold increase in AHH activity in the lung [PCBs are generally contaminated furans.]
• PCB and furan pretreatments caused a greater than 15-fold and about 3- to 4-fold increase in the formation of the tumor-causing metabolites
• PCBs caused a 75% decrease in formation of K-region metabolite, BP-4, 5-deydrodiol
• NNK (a tobacco chemical) required bioactivation by enzymes in order to cause mutations (which might lead to cancer)
• PCBs were used to induce enzyme production which led to this bioactivation
• PCBs combined with main-stream and side-stream cigarette smoke condensates to induce AHH activity in the lung
• one lung lesion with adenoma (cancer) was induced by PCBs in a small test population of mice
• PCB may promote (but not initiate) lung tumors induced by 1-nitropyrene
• PCB may not induce K-ras mutation directly
• when both PCBs and 1-nitropyrene (a pollutant) were present both the number and size of tumors were significantly more
• thymidine incorporation into lung DNA was significantly increased by PCB injection
• PCBs reduced DNA I-compounds, which may correlate with lung cancer
• 2 PAH’s [air & water pollutants] caused increased mutations and increased DNA adduct levels if the test included lung microsomes from PCB-treated animals
• PCB pretreatment inhibited (S)-nicotine oxidation
• Clara cells of the bronchiolar epithelium and Type II cells of the alveolar epithelium are possible target cells in lung cancer
• PCB feeding did not consistently change oxygen utilization, phagocytic activity or microbicidal activity in phagocytic cells. 
• certain individual parameters were altered by PCBs, but not in any temporal pattern.
• fibronectin, a surface binding glycoprotein, was significantly decreased
• certain PCB types did not increase tumor susceptibility in a certain mouse strain
• a certain protein in lung fluids binds selectively to certain PCB metabolites, causing PCB accumulation in the lung 
• the toxicological significance of this behavior is unknown
• PCBs caused proliferation and dilation of agranular endoplasmic reticulum throughout the apical cytoplasm of Clara cells in the lung
• ciliated cells were unaffected
• such PCB doses did not induce severe bronchiolar lesions in mice
• a certain protein in lung fluids binds selectively to certain PCB metabolites, causing PCB accumulation in the lung 
• the protein was localized in the secretory granules of the apical Clara cell cytoplasm
• the protein plays an important role in determining the in-vivo disposition of PCBs.
• dioxin increases the induction of enzymes in the lung, which alters the reactivity of certain air pollutants in the lung [PCBs are frequently contaminated with dioxins, and certain PCBs are dioxin-like]
• PCB binding protein is synthesized in or secreted from Clara cells. 
• studies of PCBs and lung toxicity should take methylsulfonyl PCBs into consideration.
• the PCB binding protein in the lung has been specifically identified
• Clara cell secretory protein may mediate the biological accumulation of potentially harmful PCB metabolites in the lung
• Clara cells contain a secretory protein of molecular weight 12800d that specifically binds PCB methyl sulfones with high affinity
• this protein plays an important role in the in-vivo disposition of these compounds
• PCBs accumulate and are retained longterm in the lungs’ tracheobronchial mucosa
• the PCB-binding protein complex has been shown to be subsequently secreted into the airway lumen and spread over the entire surface lining
• a structural relationship exists between the rat lung PCB binding protein and uteroglobin, a hormonally regulated steroid binding protein in rabbit lung
• certain PCB metabolites accumulate strikingly in rat lung tissue, due to a uteroglobin-like macromolecule in the lung
• immunological alteration may be different between peripheral blood and respiratory system as one of the target organs of PCBs and furans
• PCB pretreatment did not alter the 50% lethal dose of 1-nitronaphthalene
• PCB did prevent morphological signs of lung injury and any increase in either lung weight or enzyme activity in bronchoalveolar lavage fluid
• PCBs made liver injury worse
• both lung tumor incidence and multiplicity were significantly increased when mice exposed to environmental cigarette smoke were pretreated with PCBs, as compared to exposure only to environmental cigarette smoke
• PCB 52 and its oxide failed to induce lung cancer
• three P-450 enzymes induced by PCBs in rat lungs are involved in the activation of several procarcinogens such as polycyclic aromatic hydrocarbons [combustion byproducts]
• two PCBs produced greater lung enzyme activity than they did liver enzyme activity
• PCBs produced increases of two to five times control levels
• relative induction potency of PCBs appears to be tissue specific and EROD activity may not accurately reflect potency in non-liver tissues. 
• Dioxin Toxic Equivalency Factors (TEFs) proposed for PCBs may overestimate potencies by factors of ten to 1000.
• rates of individual BaP metabolite production are increased in lungs from mice pretreated with PCBs
• the existence of significant cytochrome P-450-dependent and conjugative BaP metabolism in the intact mouse lung is supported, similar to that examined in other species, and capable of contributing to the systemic metabolism of this carcinogen.
• PCBs are used to induce drug-metabolizing enzymes
• PCBs are very good inducers of AHH enzyme activity in certain mouse strains 
• strain of mouse and type of tissue are important variables in assessing the potential effect of microsomal enzyme-inducing PCBs on the metabolism of mutagenic substances.
• PCB induced enzymes enhanced the mutagenicity of 3 metabolites, but decreased mutagenicity of other metabolites
• PCB induced enzymes increased the mutagenic response due to several common air pollutants
• conversion of certain procarcinogens to active mutagens occurred only in the presence of enzymes
• enzymes induced by dioxins and PCBs strongly increased mutagenic activity of aromatic amines
• dioxin induced activity was higher than that of PCBs
• pretreatment of rats with PCBs markedly induced reductase (enzyme) activity in livers
• the effect in lungs was 6% of the effect in livers
• PCBs traveled to the lungs and other organs after injection intraperitoneally, though less than to the liver and kidneys
• PCB induced enzymes caused a noticeable accumulation of two common carcinogens in the lungs’ alveolar region
• irreversible binding in lung tissue was present in endothelial cells of arteries and veins, in the alveolar septal walls, and in type 2 pneumocytes
• PCB pretreatment enhanced the metabolic activation of 4-nitroquinoline diaphorase in the lung, leading to possible disorders in steroid homeostasis and cancer
• PCB induced enzymes converted a non-mutagenic chemical (phenanthridine) into a mutagenic one.
• the number of tobacco-initiated lung tumors in newborn mice were increased by PCBs 2.5-fold at 28 weeks, and fourfold at 28 and 52 weeks.
• PCBs promote lung tumors by triggering the early appearance of tumors which would otherwise occur in old age.
• Clara cell specific protein (CC10), also known as a PCB (a potent carcinogen)-binding protein, may be related to lung cancers

PCB enzyme induction will be used to test the metabolic activation of two lung carcinogens

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The Animal Studies 32 - 32

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