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Animal Studies of PCBs and Lung Cancer, 1 to 31
This may not be a complete list of all animal lung research
involving PCBs. For more animal studies, visit the TOXNET
database operated by the National Library of Medicine (the source of these
abstracts.) Keep in mind that these studies are not all equal in size or
quality. Some animal research was published in peer-reviewed journals,
while others were simply presented at conferences. A few are duplicates
by the same author (one conference-based, another published) but we presented
both because the descriptions were slightly different. Please note:
there are 62 studies in total, on two webpages - see continuation
link at bottom.
Study #1
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PCB treatment of newborns increased the cancer-causing ability
of a tobacco chemical in one strain of mice but not in another
The transplacental tumorigenicity of the tobacco-specific
carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was assessed
in three strains of mice: A/J; C3H/He x C57BL/6 F1 (hereafter called C3B6F1);
and Swiss outbred [Cr:NIH(S)]. NNK (100 mg/kg) was administered i.p. on
Days 14, 16, and 18 of gestation to A/J and C3H/He mice and on Days 15,
17 and 19 of gestation to the Swiss mice. The effects of postnatal treatment
with tumor-promoting agents, including 0.05% sodium barbital in the
drinking water until death or a single dose of Aroclor 1254 (a mixture
of polychlorinated biphenyls, PCB) given on Postnatal Day 8 or 56,
were also examined. Progeny were sacrificed at age 24 wk (A/J) or 72 wk
(C3B6F1 and Swiss). Significant incidences of tumors occurred in the lungs
of strain A/J progeny and in the livers of male C3B6F1 and Swiss progeny.
Lung tumor incidence was 8 of 34 (24%) in the female offspring of the A/J
mice treated with NNK, compared with 1 of 39 (3%) in controls (P less than
0.05). A 2-fold difference in lung tumor incidence in male offspring of
NNK-treated (4 of 23, 13%) versus control (3 of 48, 6%) A/J mice was not
of statistical significance. However, the incidence of lung tumors in NNK-exposed
progeny A/J mice in both sexes combined (12 of 66, 18%) was also significantly
greater than in controls (4 of 87, 5%). The incidence of liver tumors in
the male C3B6F1 mice exposed transplacentally to NNK was 12 of 30 (40%)
compared to 8 of 46 (17%) in controls (P less than 0.05). No effects
of postnatal sodium barbital or PCB were observed on transplacental
NNK tumorigenicity in C3B6F1 mice. The combined incidence of liver
carcinoma in male mice in all NNK-treated groups (13 of 141, 9%) was significantly
greater (P less than 0.05) than in controls (5 of 144, 3%). In male
Swiss mice exposed transplacentally to NNK, the incidence of liver
tumors was 3 of 57 (5%) compared to 0 of 35 controls, and postnatal
treatment with PCB on Day 56 caused a significant increase (5 of 26, 19%)
(P less than 0.05) in the incidence of NNK-induced liver tumors. The
combined incidence of liver tumors in the male offspring of the Swiss mice
treated with NNK, with or without PCB, was 8 of 83 (10%) which was significantly
greater (P less than 0.05) than in controls (0 of 66). The mothers in all
NNK-treated groups of all three strains developed lung tumors in high incidence
and multiplicity, and C3H mothers also presented a significant number of
liver tumors. Taken together, the results of this study demonstrate that
NNK is a transplacental tumorigen in the mouse, with activity that is relatively
weak compared with the adult and is demonstrable only in fetal target organs
of high sensitivity. (Anderson et al, 1989a)
Study #2
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PCB treatment of newborns increased the cancer-causing ability
of NNK (a tobacco chemical) in one strain of mice but not in another
Both cigarette smoke and nitrosamines have been suggested
as contributors to human risk of perinatal cancer initiation. The transplacental
(TP) carcinogenicity of NNK was tested in A/J, (C3H/He x C57BL/6)F1, and
Swiss (NIH S) mice. Three doses of 100 mg/kg were given ip during the last
week of gestation. In A/J offspring killed at 24 wks, 12/66 (18%) had a
lung tumor, vs 4/87 (5%) of controls (p less than 0.05). In C3B6F1 male
offspring at 72 weeks, TP NNK resulted in 12/30 (40%) with liver tumor
vs 8/46 controls (17%) (p less than 0.05). Postnatal treatment of these
mice with Na barbital (0.5% in the drinking water) or a single 500 mg/kg
dose of a mixture of polychlorinated biphenyls (PCB) did not alter liver
tumor numbers. NNK-exposed Swiss male offspring also developed liver tumors,
in significantly greater numbers after PCBs given on day 56 (5/26, 19%)
vs 3/57 (5%) for NNK only (P = 0.056). Total liver tumor incidence for
both NNK groups, 8/83, was significantly greater than for controls, 0/66.
The NNK mothers all developed lung tumors in high incidence; the C3H mothers
presented liver tumors also. Thus NNK is a weak transplacental carcinogen
for sensitive fetal target organs in the mouse. (Anderson et al, 1989b)
Study #3
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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.
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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
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the fetus may be much more sensitive than adults
Literature on fetal metabolism of carcinogens since 1980
has been systematically listed and selectively discussed. The published
data continues to support the conclusion that animal and human fetal tissues
have the capacity to metabolize carcinogens, but at a low rate compared
to the adult. Metabolism of low-molecular-weight chemicals, including nitrosamines,
appears only near term in the rodent and is poorly inducible transplacentally;
these agents are correspondingly relatively ineffective as fetal carcinogens.
Metabolism
of aromatic carcinogens, by contrast, appears early in gestation and is
highly inducible transplacentally in rodents by chemicals such as polycyclic
aromatic hydrocarbons (PAH) and tetrachlorodibenzo-p-dioxin, resulting
in dramatic percent increases in enzyme activity. Transplacental induction
has not been unequivocally demonstrated for the human fetus. Phase II enzymes,
metabolizing aromatic compounds to water-soluble forms, generally have
higher constitutive activity but lower degree of inducibility in the fetus,
compared with phase I (activating) enzymes, and appear to show quantitatively
different patterns in the human compared with the rodent. Specific and
sensitive new technologies, including 32P-postlabelling, immunodetection
of specific proteins, and use of cDNA probes, are beginning to be applied
to fetal systems and are providing a more definitive and detailed understanding
of the ontogeny and modulation of fetal carcinogen metabolizing enzymes.
Fetal and maternal metabolism of PAH, especially methylcholanthrene (MC),
have been found to be important determinants in susceptibility of the fetus
to tumorigenesis. In particular, we have utilized a mouse model system
wherein a single dominant gene, Ah, confers responsiveness to induction
of PAH metabolism by cytochrome Pl(450) (IA1); the recessive allele, Ah,
is associated with nonresponsiveness. In appropriate backcrosses between
C57BL/6 (AhAh) and DBA/2 (AhAh) mice, responsive and nonresponsive fetuses
were carried together in mothers who were, themselves, either responsive
or nonresponsive. In both cases, responsive fetuses later developed more
lung and liver tumours after transplacental MC, compared with nonresponsive
littermates. Fetuses of responsive mothers, however, experienced a lower
cancer risk than did those of nonresponsive mothers at a comparable MC
dose. Pretreatment of the pregnant mice with the noncarcinogenic inducer,
beta-naphthoflavone (BNF) had a uniform protective effect for all of the
fetuses, especially the responsive ones, if the mother was responsive.
For nonresponsive mothers, by contrast, BNF pretreatment led to an enhancement
of tumorigenesis, in the responsive fetuses only, under certain conditions
of dose and fetal sex. Taken together these complex results show that (a)
increased maternal metabolism protects the fetus and (b) increased fetal
metabolism potentiates the action of the carcinogen under certain conditions,
but may also, under other conditions, be protective. The transplacetal
exposure to MC also had a permanent positive imprinting effect on the capacity
of the livers of those exposed to metabolize MC, as adults 13 months later.
This effect was relatively small (15-30%) but consistent and of statistical
significance, and was dependent on induced metabolism of the MC by either
fetus or mother. BNF did not have an imprinting effect. Thus induced metabolism
in mother and fetus was clearly an important modulating factor for both
tumorigenesis and imprinting in the fetus. Detailed biochemical and molecular
analysis is indicated. Transplacental BNF and MC were found to result
in a 20-40 fold induction in aryl hydrocarbon hydroxylase, an activity
of P1(450), in fetal liver and lung, compared with 2-fold in adult liver.
This increase was preceded by synthesis of mRNA for P1(450), detected with
a cDNA probe in Northern and slot blots. Kinetics of induction of both
RNA and enzyme activity differed for MC and BNF, with a more rapid response
and decline for MC. A phase II conjugation enzyme, UDPG transferase, was
not induced in fetal liver by MC but showed a significant 2-fold increase
after BNF. The high percent increase in expression of the P1(450) gene
in Ah responsive mice, resulting in activation of MC, in the fetus may
explain the unique influence of this gene in fetal tumorigenesis. (Anderson
et al, 1989c)
Study #4
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PCBs promote NDMA (tobacco chemical) initiated lung tumors
after a single dose
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average tumor numbers were enhanced 4-fold
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nonmetabolized PCB congeners retained in the tissues continuously
stimulated tumor growth
Swiss-mice were exposed to N-nitrosodimethylamine (62759)
(NDMA) to initiate lung tumors which were subsequently promoted by a single
dose of a Aroclor-1254 (11097691) given at 250 or 500mg/kg, 4 days
later. Alveologenic adenomas thus generated increased in number over the
following year reaching a four fold enhancement in average tumor number
compared
to those animals receiving only NDMA. The nonmetabolized polychlorinated
biphenyl (PCB) congeners retained in the tissues continuously stimulated
tumor growth. After a 500mg/kg dose of Aroclor-1254, nine congeners
accounted for more than 90% of the PCBs 1 day after treatment. Concentrations
in the lung and liver were equivalent 1 day after treatment, but the amount
in lung declined during the first week. When given singly, 2,2',3,4,4',5'-hexachlorobiphenyl
promoted lung tumors. No promotion was noted following exposure to 2,2',4,4',5,5'-hexachlorobiphenyl
(35065271) which actually abrogated the positive effect of the 2,2',3,4,4',5'-hexachlorobiphenyl.
A single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) caused a
significant elevation in immunochemically detected protein and enzymatic
activity of cytochrome-P450IA1 (P450IA1) in the lung for at least 12 weeks.
The results of the study confirmed that PCBs promote NDMA initiated
lung tumors after a single dose. Involvement of the Ah receptor and/or
P450IA1 was suggested by the promotion by an Ah receptor antagonistic congener
given alone; abrogation of this promotion by simultaneous treatment with
an Ah antagonistic congener; selective retention in lung of two congeners
that are Ah receptor agonists; and sustained induction in lung of P450IA1
enzyme activity for at least 30 weeks after a single PCB dose. (Anderson
et al, 1991)
Study #5
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PCBs alone produced a slightly significant increase of tumors
in newborns
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PCBs administered after NDMA initiation in newborn mice resulted
in a substantial increase in lung tumors
A study was conducted on Swiss-mice to determine the tumor
promoting effects exerted by treatment with polychlorinated biphenyls (PCBs),
such as Aroclor-1254 (1336363), after initiation with a nitrosamine, N-nitrosodimethylamine
(62759) (NDMA). NDMA was injected into male mice on postnatal day four
at 5mg/kg. Aroclor-1254 was given on day eight at 250mg/kg by gavage as
a promoter. Mice were sacrificed at 16, 28, 52, or 72 weeks of age. Lungs,
liver tissue, and carcasses were retained for PCB content analysis. PCB
amount and composition were determined by extraction and gas chromatography
with electron capture detection. PCBs alone produced slightly significant
increase of tumors compared to controls; however, PCBs administered
after NDMA initiation in neonatal mice resulted in a substantial increase
in lung tumors. At 28 weeks, the incidences of lung tumors rose two
and a half fold due to PCB injection, and multiplicities of lung tumors
increased four fold at 28 and 52 weeks. Liver tumors were found in 52 week
old mice at a 39% incidence, and only in mice administered with both NDMA
and PCBs. Over 90% of the detected PCBs in mice carcasses belonged to eight
congeners. There was a positive association between lung tumor number
at 28 weeks and relative percentage of the congener 2,2',4,4',5-pentachlorobiphenyl
in the carcass. The authors conclude that PCBs act as lung and liver
tumor promoters in mice. (Anderson et al, 1994)
Study #6
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sequential exposure to PCBs and tobacco chemicals may result
in increased tumor yield, but with chemical-, sex-, and age-dependent differences
The yield of tumors after perinatal carcinogens may be increased
by subsequent exposure to tumor promoters. Polychlorinated biphenyls (PCBs)
are of special concern because of their ready delivery in breast milk.
A single dose of the PCBs mixture Aroclor 1254 promotes lung and liver
tumors initiated neonatally in mice by N-nitrosodimethylamine (NDMA). In
this study NDMA or the tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)
were given transplacentally or neonatally (i.p., day 4) to Swiss mice,
followed by Aroclor 1254 (i.g., 500 mg/kg) on day 56. At one year of age,
the PCBs treatment significantly increased the incidence of primary lung
tumors initiated in fetal males by NDMA (10 mg/kg, day 19), from 0 to 40%.
PCBs after NNK (100 mg/kg, gestation days 15, 17, 19) increased lung tumor
multiplicity 4-fold. Both liver tumors (adenomas and carcinomas) and lung
tumors after neonatal NDMA (10 mg/kg), but not after NNK (50 mg/kg), were
promoted 2-fold in males by PCBs. Neither chemical caused tumors in female
fetuses, but lung tumors initiated with NNK and liver tumors caused by
NDMA in female neonates were promoted 2- to 3-fold by Aroclor. These data
confirm that sequential exposure to these 2 classes of environmental carcinogens
may result in increased tumor yield, but with chemical-, sex-, and age-dependent
differences. (Anderson et al, 1993)
Study #7
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significant lung tumors developed in male fetuses exposed
to NNK or NDMA (tobacco chemicals), followed by exposure after birth to
PCB Aroclor 1254.
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exposure to NDMA in the womb yielded no tumor increase unless
further exposed to PCB Aroclor 1254, when 36% developed lung tumors
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later PCB exposure doubled the incidence of lung tumors in
newborn mice exposed to NDMA
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PCB effects depend on the timing of PCB exposure and sex
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single doses of PCBs into the digestive system were enough
to cause the lung cancer effect
The tumor promotabilities of the polychlorinated biphenyl
(PCB) mixture Arochlor-1254 (11097691) (ACL) on mouse lung and
liver tumors initiated by N-nitrosodimethylamine (62759) (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) administered transplacentally and neonatally were compared. Adult
female Swiss-mice were treated with NNK on gestation days 15, 17, and 19
and on day 19 with NDMA in saline. In another group, pregnant mice were
untreated but their offspring were injected intraperitoneally with either
NDMA (5mg/kg) or NNK (50mg/kg). On day 56, progeny of treated mothers and
treated neonates were given a single intragastric dose of ACL (500mg/kg).
Animals were killed at 52 weeks of age and complete necropsy was performed,
followed by histopathological examination of lungs, livers, and any other
suspected tissues. Results showed that the majority of tumors were primary
lung and hepatocellular tumors, the latter being predominantly
adenomas. Significant numbers of lung tumors appeared in male fetuses
exposed to NNK or NDMA, followed by postnatal exposure to ACL. The
NNK exposed mice showed a three to fourfold elevation in incidence and
multiplication of tumors compared to NNK or ACL control groups. Transplacental
exposure to NDMA yielded no tumor increase unless further exposed to
ACL, when 36% developed lung tumors. Females developed only
slight, but statistically insignificant, increases in tumor development
when subjected to NDMA or NNK alone or followed by ACL. In contrast to
transplacental exposure, the neonatally exposed mice showed an increase
in liver and lung tumors on NDMA exposure and these doubled in number
when followed by ACL exposure. NNK had less of an effect which was
not changed when followed by ACL exposure. The authors conclude that the
magnitude of the PCB effect on lung and liver tumors initiated by nitrosamines
is dependent on time of initiation and sex of the animal.
The effectiveness of sequential exposure to two environmentally relevant
compounds in the generation of hepatic and extrahepatic tumors in mice
is demonstrated. (Beebe et al, 1993)
Study #8
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PCBs (Aroclor-1254) were used to induce enzymes which facilitated
the mutagenicity of small particulates, which may contribute to the induction
of lung cancer
The mutagenicity of particulate matter collected in a steel
foundry was assayed. Samples were collected daily for 5 successive days
in April and November. The mass of particles collected was determined gravimetrically
for each filter, then extracted with methanol. Methanol was removed in
a rotary evaporator and the residue dissolved in dimethyl-sulfoxide. Mutagenicity
was assayed using Salmonella-typhimurium strain TA-98, with or without
S-9 supernatant fractions from Aroclor-1254 (11097691) treated male
Sprague-Dawley-rats. Colonies were counted with an automated colony counter.
There were considerable day to day variations in the total amount of mutagenic
activity detected as well as in the ratio of direct to indirect acting
material. Most of the direct acting material was associated with the largest
size class (greater than 7.7 micrometers). On 2 day, the remainder of the
direct acting mutagenicity was roughly equally distributed among the other
fractions while on 2 other days the remainder was largely found in the
smallest size class (less than 1.1 micrometers). Because the smallest class
size made up a relatively small proportion of the total mass, the highest
direct acting revertants per milligram particulate were found in this class.
In every case, however, the bulk of total indirect acting mutagenic
activity was associated with the smallest particles even though these
accounted for only 7 to 20 percent of samples. The average direct acting
mutagenicity per milligram in November samples was about 50 percent that
seen in April. The authors conclude that most of the mutagenic activity
of steel foundry particulates is associated with particles small enough
to penetrate the human bronchial tree. Particulate mutagens may contribute
to the induction of lung cancer in steel foundry workers. Daily and
monthly differences in particulates may be associated with differences
in mold and core making materials or the size of castings being poured.
(McCalla et al, 1983)
Study #9
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depletion of vitamin-A in the lung increases susceptibility
to lung cancer
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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)
The effects of airborne particulate matter (APM) on the metabolism
of vitamin-A (68268) and thyroid hormones were studied. Methanol extracts
were prepared from APM sampled outdoors in a rural area without industrial
pollution sources, from an indoor source polluted by wood combustion, and
from another indoor room polluted with cigarette smoke. The extracts were
fractionated and analyzed and their effects on transthyretin (TTR) and
thyroxine binding globulin (TBG) studied in-vitro using a binding inhibition
assay. To study the effects of APM in-vivo, Wistar-rats were injected with
APM extract and total triiodothyronine (TT3), total thyroxine (TT4), and
free thyroxine (FT4) were determined, as well as plasma, hepatic, and pulmonary
retinol and retinyl-esters. Significant reductions in the levels of
TT3, FT4, and TT4 were seen 6 hours after treatment of rats with APM. TT3
levels were still reduced 24 hours after treatment. A significant increase
in plasma retinol levels were seen 72 hours after treatment, while lung
retinol and retinyl-palmitate levels and liver retinol levels were
reduced. All APM extract samples inhibited thyroxine (T4) binding to TTR
in-vitro, and the neutral fraction of the extract accounted for most of
this inhibitory activity. None of the APM extracts inhibited the binding
of T4 to TBG. The acid fractions of the cigarette APM sample and the outdoor
APM samples were found to contain 6.6 and 0.23 nanograms of pentachlorophenol
(87865) per cubic meter of sampled air, respectively. The binding of T4
to TTR was unaffected by incubation with benzo(a)pyrene (50328), pyrene
(129000), or nicotine (54115). The authors conclude that APM may increasesusceptibility
to the development of lung cancer by depleting pulmonary vitamin-A. (Heussen
et al, 1993)
Study #10
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PCBs play a role in levels of cytochrome-P450 enzymes in
the lungs
The hazardous and toxicological aspects of polychlorinated
biphenyls (PCBs) and other polyhalogenated hydrocarbons were reviewed.
PCBs were manufactured in the United States under the trade name Aroclor
from 1929 to 1977. Under the Toxic Substances Control Act, Congress banned
further manufacture and limited distribution beyond 1979. Discussion
of the absorption, metabolism and excretion of PCBs included the role of
the cytochrome-P450 enzymes in the liver, lung, and small
intestine of animals and humans, excretion products, serum levels in occupationally
exposed persons, and the half lives of various isomers. Health effects
in animals and humans including tumorigenicity (especially hepatocellular
carcinomas), tumor promoter effects, chloracne, serum lipid alterations,
reproductive effects in women, and epidemiologic studies were discussed.
PCBs were not mutagenic. Polybrominated biphenyls (PBBs) are similar to
PCBs, but have not been widespread environmental contaminants. Although
various health effects including neurobehavioral alterations were reported,
no human clinical illnesses were causally linked with PBB with certainty.
The information available on the health effects and pharmacokinetics of
chlorinated benzenes (CBs) was limited to isolated case reports. While
some connection between CBs and liver and kidney carcinomas, and adrenal
and parathyroid adenomas was evident in laboratory animals, no epidemiologic
association with cancer was established for humans. The major known human
health effect was the development of porphyria cutanea tarda. (Shields
et al, 1992)
Study #11
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the lung enzyme, cytochrome P450 1A1, was significantly increased
by PCBs
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cytochrome P450 IIB1 was significantly elevated
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total PCB lung content decreased with half lives of 17 and
9 weeks
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lower chlorinated PCBs cleared more rapidly that highly chlorinated
compounds
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regulation of lung enzymes following PCBs involves interactions
between specific PCB congeners
The effects of aroclor-1254 (11097691) on pulmonary cytochrome-P-450IA1
(P450IA1) and cytochrome-P450IIB1 (P450IIB1) were studied in mice. Male
Swiss-mice were injected intraperitoneally with 100 or 500mg/kg aroclor-1254.
Selected mice were killed 48 or 96 hours or 1, 4, 12, or 30 weeks after
dosing and the lungs were removed. The lungs were analyzed for P450IA1
and P450IIB1 by determining ethoxyresorufin-O-deethylase and benzyloxyresorufin-O-dealkylase
activity, respectively, using a Western immunoblotting technique. The total
aroclor-1254 concentration and the concentrations of individual polychlorinated
biphenyl (PCB) congeners in the lung and carcass (less the liver) were
determined at these times by gas chromatography. Pulmonary P450IA1 content
was significantly increased by both aroclor-1254 doses for the entire 30
week period. Maximum induction by 100 and 500mg/kg aroclor-1254 occurred
at 4 weeks and 96 hours, respectively. P450IIB1 was significantly elevated
by the 100mg/kg dose only at the 30 minute sampling point. The 500mg/kg
dose significantly induced P450IIB1 between 48 hours and 12 weeks, after
which the concentration returned to the control value. The total PCB
content of the lung decreased with half lives of approximately 17 and 9
weeks after the 100 and 500mg/kg doses, respectively. Clearance of
PCBs from the carcass was similar after both doses, characterized by halflives
of 11 to 16 weeks. The less highly chlorinated congeners were cleared
more rapidly than the more highly chlorinated compounds. The changes
in lung PCB content were not correlated with induction of P450IA1 and P450IIB1.
The authors conclude that aroclor-1254 causes induction and inhibition
of cytochrome-P450 isozymes in the mouse lung. The changes in isozyme
activity do not correlate with the profile of elimination of PCB congeners.
This suggests that regulation of steady state cytochrome-P450 isozymes
following PCB exposure involves interactions between specific PCB congeners.
(Beebe et al, 1992)
Study #12
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the Ah receptor is not involved in PCB suppression of the
lung enzyme, cytochrome CYP2B
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regulation of the lung enzyme, cytochrome CYP1A1, does appear
to involve the Ah receptor
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PCBs decreased the cytochrome P4502B by about 50-60% in both
strains of mice
The effects of Aroclor-1254 (11097691) on cytochrome-P450
isozymes were studied in Ah receptor responsive and nonresponsive mice.
Male C57BL/6Nr-mice (C57) and DBA/2NCr-mice (DBA) were injected intraperitoneally
with 250mg/kg Aroclor-1254. C57-mice were Ah responsive and DBA-mice were
Ah nonresponsive. Selected mice were killed 48 hours or 1, 4, or 12 weeks
after Aroclor-1254 and the liver, lungs, kidneys, and small intestine were
removed. The tissues were homogenized and assayed for ethoxyresorufin-O-dealkylase
(EROD), methoxyresorufin-O-dealkylase (MROD), and benzyloxyresorufin-O-dealkylase
(BROD) activities as markers for cytochrome-P4501A1 (CYP1A1), cytochrome-P4501A2
(CYP1A2), and cytochrome-P4502B (CYP2B), respectively. Microsomes were
prepared and analyzed directly for CYP1A1, CYP1A2, and CYP2B using immunoblotting
techniques. Hepatic CYP2B was significantly increased in both mouse strains
by Aroclor-1254. The maximum increase in C57-mice, 15 times the control
value, occurred after 1 week. The maximum increase in DBA-mice, five times
the control value, occurred after 48 hours. Lung P4502B was decreased
by about 50 to 60% in both strains. The decreases persisted longer in DBA-mice.
Intestinal CYP2B was significantly increased at 48 hours and 4 weeks in
both strains. CYP1A1 was significantly increased by Aroclor-1254 in
all tissues in C57-mice, but not DBA-mice. CYP1A2 was not detected
in the lung or intestine of either strain. Hepatic CYP1A2 was significantly
increased in both mouse strains. The increase was greater in C57-mice.
Renal CYP1A2 was slightly increased in C57-mice, but not in DBA-mice. The
observed changes in P450 isozymes detected by immunoblotting generally
correlated with the changes in EROD, MEROD, and BROD activity. The authors
conclude that the Ah receptor is not involved in the suppression of
pulmonary CYP2B by Aroclor-1254. Regulation of CYP1A1 and CYP1A2
in the examined tissues appears to involve the Ah receptor. (Beebe,
1995a)
Study #13
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kidneys are more sensitive than lungs to PCB enzyme induction,
but the effect is more persistent in lungs
In this report, we have investigated the effect of dietary
exposure to Aroclor 1254 (1-100 ppm) given chronically or discontinuously
over an 84-day time interval to the female F344 rat. Cytochrome P4501A
was quantified in lung and kidney by measuring the dealkylation of ethoxyresorufin
substrate and by Western immunoblotting. P4501A displayed a dose- and
time-dependent increase in both extrahepatic organs. The kidney appeared
to be more responsive to induction than lung at all doses (maximum of 500-fold
induction following 84 days exposure to 100 ppm). Further, there was evidence
by enzymatic activity, immunoblotting and Northern analysis of total RNA
for the presence of 1A2 in the most highly induced kidneys. The decline
in 1A induction observed following discontinuous exposure was more prominent
in the kidney than in the lung. These data demonstrate the sensitivity
of kidney to P4501A induction capacity as compared to lung, although the
persistence of the induction response was evident in lung and not kidney.
(Beebe, 1995b)
Study #14
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PCB Aroclor 1254 was a potent enzyme inducing agent in the
lungs
The metabolism of 3-methylcholanthrene (56495) (3-MC) in
liver
and lungs and the effects of enzyme induction on the metabolic profile
were investigated in Sprague-Dawley-rats. Animals were pretreated for 3
consecutive days with 40 milligrams per kilogram (mg/kg) 3-MC or 75mg/kg
phenobarbital (50066) (PB), then were killed on day 4. Some rats were also
treated
with 500mg/kg Aroclor-1254 (11097691) 5 days before killing. Liver
and lung microsomes were isolated, and protein concentrations were measured.
Microsomal proteins were incubated with radiolabeled 3-MC, and metabolites
were extracted and analyzed using high performance liquid chromatography.
There was little qualitative difference in the metabolism of 3-MC by microsomes
from different sources. Arochlor-1254 and 3-MC were the most
potent inducing agents. Metabolism of 3-MC by lung microsomes was similar
to that of liver microsomes, but lung microsomes were less efficient at
metabolizing 3-MC. When PB induced microsomes were used, total metabolism
was less than that of untreated controls. None of the eluted peaks could
be induced unless microsomes induced by Aroclor-1254 or 3-MC were
used. A general increase in the contribution of early eluting peaks
to total metabolism after induction was seen in both liver and lung. The
authors conclude that the bay region theory of carcinogenesis suggests
that 3-MC is metabolized to a 9,10-dihydrodiol and then to a bay region
diol-epoxide. The exact chemical nature of the ultimate carcinogenic form
of 3-MC is still unknown. (Gangarosa et al, 1983)
Study #15
-
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
Mutational activation of the K-ras oncogene often occurs
in human and mouse lung adenocarcinomas. Since K-ras p21 functions
in trans-membrane signaling, we have investigated whether the amount of
this protein in lung cell membranes is a variable that could influence
lung tumorigenesis, either due to genetic differences or in response to
tumor promoters. The six mouse strains assessed showed little difference
in the total lung K-ras p21 after immunoprecipitation and immunoblotting.
However, amount of ras p21 in the membrane fraction showed significant
differences, with C57BL/6 and BALB/c having 3-5-fold more than NIH Swiss,
AKR and DBA mice. Interestingly, a congenic AKR strain having the Ahrb-1
Ah receptor allele from C57BL/6 mice (designated AKR.B6Ah) had high lung
membrane K-ras p21 similar to that of C57BL/6. To test for possible
changes related to lung tumor promotion, mice were treated with a promotional
dose of TCDD (5 nmol/kg). After 48 h C57BL/6 lungs showed an increase
in p21 in both total and membrane fractions. BALB/c, DBA and Swiss mice
showed an increase only in membranes. There was no change in the AKR and
AKR.B6Ah. Aroclor 1254 (250 mg/kg) caused an increase in membrane/cytosol
ratio in Swiss mice. Thus the membrane:cytosol K-ras p21 ratio may
be influenced by the Ahr phenotype, and TCDD and PCBs can induce p21
or increase its membrane level in certain strains, but these properties
are not fully dependent on Ahr receptor type. In confirmation of the
relevance of these findings for the tumor target cell type, the immortalized
alveolar type 2 E10 cell line presented K-ras p21 in membrane, and this
was increased 4-fold by treatment with 10 nM TCDD. (RAMAKRISHNA
et al, 1998)
Study #16
-
HPOP and BOP (two tobacco carcinogens) required the presence
of lung enzymes induced by PCBs in order to show positive mutagenic activity
The mutagenic activities of (carcinogen) N-nitrosobis(2-hydroxypropyl)amine
(BHP) and its related compounds were studied in Salmonella typhimurium
TA100 and TA98 strains by Ames's liquid incubation assay in the presence
or absence of lung and liver S9 of rats treated with polychlorinated
biphenyl (PCB). BHP and its related compounds, N-nitroso-(2-hydroxypropyl)(2-oxopropyl)amine
(HPOP), N-nitrosobis(2-oxopropyl)amine (BOP), N-nitrosobis(2-acetoxypropyl)amine
(BAP) and N-nitroso-2,6-dimethylmorpholine (NDMM) showed negative mutagenicity
in the absence of lung and liver S9 in TA100 and TA98 strains while those
compounds showed positive in the presence of liver S9 in TA100 strain.
HPOP
and BOP showed positive mutagenic activity in the presence of lung S9
in TA100 strain. HPOP showed the strongest mutagenic activity in the presence
of lung and liver S9. (Mori et al, 1983)
Study #17
-
lung abscesses and pneumonia have been observed in mammalian
species exposed to PCBs
The status of the toxicologic, carcinogenic, teratogenic,
and mutagenic aspects of the PCBs of greatest relevance to man is
reviewed. Summaries of oral and dermal toxicity of Aroclors to rats and
rabbits indicate that they are of low acute toxicity. Lethal affects appear
to be cumulative. Summaries of PCB-induced pathologic changes show liver
alterations and skin lesions to be the most striking change in mammals,
whereas fluid in the pericardial sac, kidney damage, and reduced spleen
are found in birds. The toxic nature of contaminating polychlorodibenzofurans
is pointed out. Effects of low level feeding show reduced rate of weight
gain, increased kidney and liver weights, and elevated serum alkaline phosphatase.
Morphological and ultrastructural changes in livers of treated rats are
described. Acute and chnroic feeding studies resulted in fewer and smaller
offspring, decreased weanling survival, and lowered mating indices in rats;
and body weight loss, eggshell thinning, and poor egg hatchability in chickens.
Bladder cancers, heptaomas, lung abscesses, pneumonia, spleen atrophy,
intracranial abscesses, hyperplasia and dysplasia of gastric mucosa, fetotoxicity,
abortions, maternal deaths, and stillbirths have been observed in mammalian
species. A high incidence of chromosomal aberrations has been reported
in ring doves, but none was observed in human lymphocyte cultures, rat
bone marrow or spermatogonia. Suppressed immunological responses have been
observed in ducks, guinea pigs, rabbits, and chickens. An outbreak of PCB
poisoning in Japan in 1968 resulted in 1081 patients being affected by
chloracne, blindness, gastrointestional symptoms, skin discoloration in
infants of poisoned mothers, decreased birth weights, increased urinary
17-ketosteriods, respiratory distress, a hematological picture suggesting
inflammation, and elevated blood-serum triglycerides. (Fishbein, 1974)
Study #18
-
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
Intracellular receptors involved in mediating toxic responses
to certain chemical agents were discussed. Several soluble intracellular
receptors which have been implicated in binding toxic agents, including
the glucocorticoid receptor, the peroxisome proliferator activated receptor,
and the dioxin receptor, were described. Stress related responses such
as neuronal degeneration and lymphocytic apoptosis have been reported to
involve the glucocorticoid receptor. The peroxisome proliferator activated
receptor has been reported to be activated by the binding of fatty acid
ligands and to be involved in hepatocarcinogenesis in rodents. The dioxin
receptor, when activated, has been reported to initiate a cascade of genes
including those involved in metabolic activation of promutagens such as
cytochrome-P450s. Activation of the dioxin receptor to its DNA binding
state by several heterocyclic amines formed during frying of foods as well
as by methyl substituted indolocarbazoles has been reported. A uteroglobin
lung protein has also been identified which, although not a receptor, has
served to specifically concentrate methylsulfone metabolites of polychlorinated
biphenyls in lung Clara cells. (Gustafsson, 1995)
Study #19
-
enzymes induced by PCBs increase the mutagenicity of nitrosamines
For optimum mutagenesis in Chinese hamster V79 lung
cells, the amount of liver postmitochondrial fraction in the assay
was of critical importance, depending on the chemicals being tested.
Benzo(a)pyrene (BP) required lower (1-5%) concentrations of the liver 15,000
from methylcholanthrene pretreated rats for a maximum induction of cytotoxicity
and mutagenicity, as determined by 8-azaguanine- and ouabain-resistance.
A sharp peak of mutagenicity and cytotoxicity was induced by 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene
(7,8-diol BP) at a concentration of 1% of the S15 fraction. Little or no
response was induced by these compounds with the S15 concentrations of
> 10%. Similarly, aflatoxin B1 induced a sharp peak of mutagenicity and
cytotoxicity at a concentration of 2% of the liver S15 fraction from
Aroclor-pretreated rats. Under the same condition, non-carcinogenic
aflatoxin G2 did not induce cytotoxicity and mutagenicity. Analaysis of
BP metabolites by high-pressure liquid chromatography indicates that with
the 30% S15 fraction, 80% of BP was metabolized during the 1st 15 min,
while with the 2% S15 fraction, 7,8-diol BP increased continuously throughout
the 120-min incubation period, suggesting a strong metabolic competition
to rapidly remove BP and 7,8-diol BP with a high concentration of the S15.
N-nitrosodimethylamine induced mutagenicity and cytotoxicity which increased
linearly in proportion to the increasing amount of the S15 fraction from
phenobarbitone- and Aroclor-pretreated rats. Various nitrosamines with
different lipophilicity were examined at a high (30%) and low (2%) concentration
of the S15 fraction from Aroclor-pretreated rats, in which ratios of mutation
frequencies at 30 and 2% correlated inversely with lipophilicity of the
compound. The lipid solubility of test compounds may be a factor which
determines the concentration of post-mitochondrial supernatant for optimum
mutagenesis. (Kuroki et al, 1979)
Study #20
-
PCBs and dioxin together increased the incidence of lung
and palate/nasal turbinates or tongue cancer in both sexes
Trace amounts of 2,3,7,8- tetrachlorodibenzo-p-dioxin
(TCDD), other chlorinated dioxins, chlorinated phenols, polybrominated
biphenyls, and polychlorinated biphenyl were present in samples
of fish taken from the lower Tittabawassee River in Michigan. Fact sheets
containing results of toxicity studies indicate dietary doses of 0.001
ug/kg/day of TCDD for 2 years induces "some few" swollen liver cells in
females, but causes no adverse effects in male rats, does not effect fertility,
nor neonatal growth or survival. A similar regimen of 0.01 ug/kg/day is
not lethal but leads to decreased litter size, while a diet 0.1 ug/kg/day
for 2 years leads to increased incidence of liver cancer in females,
lung and palate/nasal turbinates or tongue cancer in both sexes, and
a marked decrease in reproductive capacity. The no-effect dose was 0.01
ug/kg/day when administered orally 5 days/week for 90 days, and 0.1 ug/kg/day
caused toxic effects (not described). Acute oral LD50 values are: 22 ug/kg
for male rats and 45 ug/kg for female rats; 0.6 ug/kg for male guinea pigs
(21 ug/kg in another study); 115 ug/kg for rabbits; >300 ug/kg for dogs
and monkeys. (Dow Chemical Company letter)
Study #21
-
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.
Respiratory tract biotransformation of many xenobiotics
found in inhaled environmental pollutants is generally considered essential
for the mutagenic, carcinogenic, and/or toxic response of lung tissue to
these xenobiotics. Typical environmental pollutants contain known carcinogens
adsorbed onto particles which can deposit in the nasal pharyngeal region
of the respiratory tract. The purpose of this study was to characterize
the metabolic capacity of rat nasal tissue. Both oxidative and nonoxidative
enzyme activities were investigated which included aryl hydrocarbon hydroxylase
(AHH), epoxide hydrolase (EH), uridine 5'-diphosphate-glucuronyltransferase
(UDPGT), and glutathione transferase. Specific enzyme activities of AHH,
EH, UDPGT, and glutathione transferase were 0.023, 6.4, 20.4, and 24.8
nmol product/mg protein per min, respectively. Benzo(a)pyrene was metabolized
by AHH to dihydrodiols, quinones, and phenols in quantities which were
ê 10 times greater than those reported for rat lung microsomes. Small,
but detectable, quantities of benzo(a)pyrene tetrols were also measured
in reaction flasks in which rat nasal tissue was incubated with benzo(a)pyrene.
Attempts to increase the microsomal enzyme activities of AHH, EH, and UDPGT
by pretreating rats with inducing agents by both i.p. injection (phenobarbital,
3-methylcholanthrene, Aroclor 1254, and 2,3,7,8-tetrachlorodibenzo-p-dioxine)
and inhalation exposure (BaP) resulted in rat nasal monooxygenases only
being induced (2-fold) after pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Phenobarbital increased enzyme activities of EH and UDPGT by ê 50%.
Rat nasal tissue may contain multiple forms of cytochrome P-450 and of
EH and UDPGT. Nasal tissue may be important in determining the metabolic
fate of inhaled xenobiotics. (Bond, 1983)
Study #22
-
mouse lung tissue enzymes induced by PCBs were used to test
metabolic behavior of several toxic compounds
Hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine,
phenylhydrazine, procarbazine, isoniazid, isocarboxazid, nialamide, 2,4-dinitrophenylhydrazine,
phenelzine, hydralazine, dihydralazine, carbamylhydrazine, mebanazine,
iproniazid and 1-carbamyl-2-phenylhydrazine were tested for DNA-damaging
activity by the alkaline elution technique and for mutagenic activity in
the Salmonella microsome (Ames) test. The first 9 compounds listed (56%)
induced a significant DNA fragmentation in the liver and/or lung of i.p.-treated
male Swiss mice. The DNA damaging potency varied over anteen of the first
14 compounds listed (81% of the total), isocarboxazid being inactive, were
positive in the Ames test, with a broad range of activity towards the 5
bacterial strains of S. typhimurium used (TA1535, TA100, TA1537, TA1538
and TA98) and of metabolic behavior in the presence of S-9 mix containing
rat
liver, mouse liver or mouse lung postmitochondrial preparations from
Aroclor-treated animals. The mutagenic potency varied over an almost
7000-fold range. For 11 of the 16 hydrazine derivatives tested, homogeneous
carcinogenicity data (induction of pulmonary tumors in mice chronically
treated p.o. (orally)) were available from literature. Carcinogenic potency
varied over an 1900-fold range. The 5 most potent carcinogens were all
positive in the DNA damage test. Their carcinogenic potency varied over
a 130-fold range and their DNA-damaging potency seemed to vary on a more
compressed scale, but regression analysis indicated the existence of a
strong positive correlation between in vivo DNA-damaging and carcinogenic
potencies, while a lack of correlation was found between mutagenic
and carcinogenic potencies. There was correlation between DNA-damaging
and mutagenic potencies. (Parodi et al, 1981)
Study #23
-
PCB induced enzymes help promote mutations induced by cigarette
smoke condensate
We used colony probe hybridization and polymerase chain reaction/DNA
sequence analysis to determine the mutations in approximately 1600 revertants
of Salmonella induced by cigarette smoke condensate (CSC) in the presence
of S9. CSC induced approximately 80% GC-- > TA transversions and approximately
20% GC-- > AT transitions at the base-substitution allele (hisG46) in strain
TA100. This spectrum was similar to those of the polycyclic aromatic hydrocarbon
(PAH) benzo[alpha]pyrene and various aromatic amines such as 4-aminobiphenyl
and Glu-P-1, all of which are present in CSC. This spectrum was also similar
to that produced by PAHs in other bacteria, mammalian cells, and rodents
as well as to that of the p53 gene in lung tumors from smokers. The results
in Salmonella are consistent with a role for the PAH component of cigarette
smoke in the base-substitution specificity found in the p53 gene of smoking-associated
lung tumors. At the frameshift allele in strains TA1538 and TA98, CSC
induced only a hotspot 2-base deletion, which is a mutation spectrum that
is identical to that induced by the heterocyclic amine pyrolysate products
of amino acids, such as Glu-P-1. This is consistent with bioassay-directed
fractionation studies showing that aromatic amines account for most of
the frameshift specificity of CSC in Salmonella. Rodent and human studies
indicate that aromatic amines are responsible for smoking-associated bladder
cancer. Repeated freezing and thawing of the CSC samples changed the chemical
composition of the mixtures as evidenced by the production of an altered
mutation spectrum. This emphasizes the necessity of proper storage and
handling of labile complex mixtures. This study (i) confirms our previous
studies showing that the mutation spectrum of a complex mixture reflects
the dominance of one or a few classes of chemical mutagens within the mixture,
and (ii) illustrates the potential of bioassay-directed molecular analysis
for identifying the chemical classes in a complex mixture that are responsible
for specific classes of mutation and tumor types produced by the mixture.
(DeMarini et al, 1995)
Study #24
-
metabolic activation is required before NNK (a tobacco chemical)
will induce lung tumors
-
PCBs induce the enzyme (cytochrome P450) which metabolically
activates NNK
The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) induces tumor formation in the liver, lung, nasal cavity,
and pancreas of rats. Metabolic activation is required for the tumorigenicity
of this compound. The involvement of cytochrome P450 enzymes in
NNK bioactivation was investigated in rats by studies with chemical
inducers and antibodies against P450s. Liver microsomal enzymes catalyzed
the formation of 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde), 4-hydroxy-1-(3-pyridyl)-1-butanone
(keto alcohol), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone
(NNK-N-oxide), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)
from NNK. When the activity was expressed on a per nanomole P450 basis,
treatments of rats with 3-methylcholanthrene (MC), phenobarbital (PB),
pregnenolone 16-alpha-carbonitrile (PCN), Aroclor 1254 (AR), safrole
(SA), and isosafrole (ISA) increased the keto aldehyde formation in
liver microsomes 2.0-, 2.4-, 3.8 (Guo et al, 1992)
Study #25
-
PCBs were used to stimulate lung enzymes used to test whether
a class of chemicals caused mutations
Homogeneous mutagenicity data, available for 16 hydrazine
derivatives (potential carcinogens) assayed in the Salmonella/microsome
test, were tentatively associated with their chemical structure. Some possible
relationships were detected between chemical features and the following
parameters in vitro: mutagenic potency, expressed as revertants/micromole
compound, which varied over a 3200-fold range without S-9 mix and a 7000-fold
range with S-9 mix; reversion mechanism, as inferred from the selective
sensitivity of 5 S. typhimurium tester strains; and metabolic behavior
in the presence of S-9 mix containing rat liver, mouse liver or
mouse lung S-9 fractions from animals treated with Aroclor-1254. (DE
FLORA et al, 1981)
Study #26
-
PCBs strongly stimulated the activity of the NADPH-requiring
enzymes responsible for ICR deactivation, which may relate to lung cancer.
The mutagenicity patterns and the metabolic behaviour of
4 structurally related ICR compounds were investigated using the Salmonella/microsome
test. ICR 191 and ICR 170 reverted 4 his- strains (TA1537 greater than
TA100 greater than TA98 and TA1538), while ICR 191-OH and ICR 170-OH reverted
TA1537 only, with a narrow range of mutagenic activity. Although all the
products tested were shown to contain a common mutagenic impurity, analysis
of chemicals fractionated by h.p.l.c. provided evidence that pure ICR 191-OH
and ICR 170-OH also induce frameshift errors. The mutagenic activity of
all the 4 ICR compounds, as well as of their common impurity, was decreased
in the presence of S-9 mix containing rat liver S-9 fractions, a trend
confirmed by h.p.l.c. of ICR/S-9 mixtures. Despite the greater mutagenic
potency in the absence of metabolic systems, ICR 191 was deactivated far
more efficiently and rapidly than ICR 170 by a variety of mouse (liver
greater than lung) and rat (liver greater than testis greater than
kidney greater than lung greater than striated muscle greater than
spleen) S-9 fractions. Mouse preparations were more effective than the
corresponding rat preparations. Aroclor 1254 strongly stimulated the
activity of the NADPH-requiring enzymes responsible for ICR deactivation.
H.p.l.c. analyses ruled out interconversion among the 4 ICR compounds in
the presence of liver S-9 fractions, while revealing the appearance of
new distinct peaks for ICR 191, ICR 170 and ICR 170-OH. The selective metabolic
deactivation of ICR compounds may be related to the findings of previous
carcinogenicity studies (1-3) which showed the induction of lung adenomas
following i.v. but not i.p. administration of ICR 170. Conversely, ICR
191 and ICR 191-OH showed no activity even when administered i.v. Since
intercalation of ICR compounds into DNA is the molecular basis for both
mutagenic and antitumor activities (4), their distinctive metabolic reactivity
may be also responsible for the differential efficacy in pharmacological
assays. (DE FLORA et al, 1982)
Study #27
-
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
The polychlorinated biphenyls (PCBs) mixture, Aroclor 1254,
is a weak inducer of aryl hydrocarbon hydroxylase (AHH) activity in
rabbit lung. In contrast, 2,3,4,7,8-pentachlorodibenzofuran (PCDF),
like 3-methylcholanthrene (3-MC), caused a 3-fold increase in pulmonary
AHH activity. An important finding of the present studies was that
AHH activity, whether assayed by the flourometric or HPLC methods, was
dependent on the buffer used in the incubation mixture. The metabolism
of benzo(a) pyrene (BP) to its oxidative metabolites, as assayed by HPLC,
revealed that PCBS, PCDF and 3-MC pretreatments caused greater
than 15-fold and about 3- to 4-fold increase in the formation of
the tumorigenic metabolites 9,10- and 7,8-dihydrodiols, respectively.
In contrast to 3-MC and PCDF, PCBs caused a 75% decrease in the formation
of the K-region metabolite, BP-4, 5-dihydrodiol. These studies strongly
suggest that the catalysis of BP metabolism is mediated by more than one
isoform of cytoch (Veng et al, 1993)
Study #28
-
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
The cytotoxicity, genotoxicity and transforming activity
of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were studied by
the assays of colony-forming efficiency (CFE), micronucleus formation (MN),
and cell transformation in rat tracheal epithelial (RTE) cells both in
vitro and in vivo. Liver S9, primary hepatocytes and RTE cells from normal
and Aroclor-1254 induced rats were compared for bioactivation of NNK using
Salmonella mutagenesis as the endpoint. Results from the in vitro experiments
indicated that low concentrations of NNK (0.01-25 micrograms/ml) caused
from 15% to greater than 100% increases in CFE of RTE cells. At high concentrations
(100-200 micrograms/ml), NNK was significantly toxic to RTE cells. NNK
treatment in vitro (50-200 micrograms/ml) increased MN frequency as much
as 3-fold above background and significantly increased the transformation
frequency (TF) in 4/5 (50 micrograms/ml) and 6/8 (100 micrograms/ml) experiments.
The in vivo exposure of rats to NNK (150-450 mg/kg, given i.p.) resulted
in a 60-85% reduction in CFE and a 3-5-fold increase in MN formation in
RTE cells. In vivo treatment with cumulative doses of 150 and 300 mg/kg
of NNK produced significant increases in TF of tracheal cells from 3/3
and 2/3 rats, respectively. Without activation, NNK was not mutagenic
in Salmonella TA1535. The bioactivation of NNK to a mutagenic metabolite
was achieved by incubation of NNK with liver S9 fraction from Aroclor-1254
induced rats or primary hepatocytes from both untreated and Aroclor-1254
pretreated rats. RTE cells did not produce sufficient quantities of
mutagenic NNK metabolites to be detected by the Salmonella assay. (Zhu
et al, 1991)
Study #29
-
PCBs combined with main-stream and side-stream cigarette
smoke condensates to induce AHH activity in the lung
Aryl hydrocarbon hydroxylase (AHH) and dimethylnitrosamine
demethylase (DMND) activities in pulmonary and hepatic tissues of
male Sprague-Dawley rats were assayed following pretreatment with known
inducers (benzo[a]pyrene, 3-methylcholanthrene, Aroclor 1254,
phenobarbital) and with main-stream (MS) and side-stream (SS) cigarette
smoke condensates and their related fractions. Biochemical assays by spectrophotofluorimetry
(AHH activity) and spectrophotometry (DMND activity) and by a biological
assay (Ames test) were performed to detect AHH and DMND induction. Ames
test proved to be much less sensitive than the spectrophotofluorimetric
analysis for AHH determination. Both main-stream and side-stream cigarette
smoke condensates and some fractions, containing water-soluble bases, water-insoluble
bases, and polycyclic aromatic hydrocarbons, were found to induce AHH
activity in lung and liver, the lung being induced to the greatest
extent. The highest levels of AHH inducibility were found for the SS-smoke
condensate and related fractions. In particular, the insoluble bases fractions
gave the highest induction. On the contrary, pulmonary DMND activity was
not affected by pretreatment with the same materials, while hepatic DMND
response was only minimally induced by Aroclor and phenobarbital treatment.
(Pasquini et al, 1987)
Study #30
-
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
We have analyzed the effect of polychlorinated biphenyls
(PCB, Kanechlor-400) on 1-nitropyrene (1-NP) induced lung tumor. Male A/J
mice (6 weeks old) were used for the experiment. A total of 2.5 mg/kg PCB
was administered intraperitoneally (PCB group), a total of 0.38 mmol/kg
1-NP was administered intraperitoneally for 17 times (1-NP group), PCB
was administered followed by i.p. injection of 1-NP (PCB + 1-NP group),
and only vehicle was administered (control group). The lung lesions induced
were examined 18 weeks after the final treatment with 1-NP or vehicle.
In control group, no neoplastic lesion in the lung was induced. In PCB
group, only one lesion with adenoma was induced. In 1-NP group, various
kinds of lung neoplastic lesions including hyperplasia, adenoma and adenocarcinoma
were induced. In PCB + 1-NP group, both the number and size of tumors
induced were significantly more than those in 1-NP group. In addition,
the number of adenocarcinoma formed was more in PCB + 1-NP group than in
1-NP group. Each lesion was microdissected to collect and analyze DNA of
the targeted tissue. K-ras gene mutation was detected in part of adenoma
lesions and all the carcinoma lesions. The mutation was found in either
1-NP or PCB + 1-NP group, but not in control and PCB group. The
pattern of K-ras mutation was CAA to CGA in codon 61 or GGT to GAT in codon
12. There was no difference in the pattern of K-ras mutation despite of
the pretreatment with PCB. Although the present data are from small sample
size, it was suggested that PCB may promote (but not initiate) 1-NP
induced lung tumorigenesis, and may not induce K-ras mutation directly
in the experimental system. (Nakanishi et al, 1999)
Study #31
-
thymidine incorporation into lung DNA was significantly increased
by PCB injection
-
PCBs reduced DNA I-compounds, which may correlate with lung
cancer
The effects of a tumor promoting polychlorinated biphenyl
mixture, Arocolor 1254, on I-compounds (tissue, species and sex dependent
DNA modifications that increase with age in untreated rodents) were studied
by 32P-postlabeling in male Sprague-Dawley rat liver, kidney, and lung
DNA. Aroclor 1254 was dissolved in corn oil and intraperitoneally (i.p.)
injected (2ts. Control rats were given corn oil. Groups of 3 animals were
sacrificed at 2 and 6 weeks after the second injection of corn oil or Aroclor
1254. At both time points Aroclor 1254-treated rats had significantly lower
body weights and higher liver weights while kidney and lung weights
were unaffected. Thymidine incorporation into liver and lungDNA
was significantly increased at both time points, while kidney DNA showed
a small decrease at 2 weeks. Treatment resulted in significant reductions
(ranging from 29 to 100%) of each of nine liver I-spots at 2 and 6 weeks.
In treated rats there was no decrease in kidney I-spots at 2 weeks, while
the levels of only two out of ten kidney spots were reduced by 42-91% at
6 weeks. At 2 weeks three out of seven and at 6 weeks four out of seven
lung I-spots were lowered by 51-100% in the Aroclor 1254-treated rats.
Thus the effects decreased in the order liver > lung > kidney. Since
Aroclor 1254 has been reported to be a tumor promoter in liver and lung
but not kidney, these results suggest a correlation between organ specific
promotion of carcinogenesis by Aroclor 1254 and the reduction of DNA I-compounds.
(Nath
et al, 1991)
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