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Human Studies of PCBs and Lung Cancer
This may not be a complete list of all lung cancer research
involving PCB exposures. For more lung cancer 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 were 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.
Study #1
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PCBs were linked to a statistically significant increase
in lung cancer deaths
A PCB-exposed group in Japan had a statistically significant
increase in lung cancer deaths. This was a case involving rice oil contaminated
with PCBs and furans. [Some scientists argue that the cancers were due
to the furans, not the PCBs; however, commercial mixtures of PCBs generally
came contaminated with furans from the manufacturer. The Fox River is contaminated
with both PCBs and furans as a result, and both chemicals are picked up
and accumulated in fish.] (Kuratsune et al, 1987)
Study #2
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PCBs were linked to an increase in lung cancer deaths
This study followed employees who had worked at Monsanto's
PCB production plant. The researchers found that the incidence of lung
cancer deaths among these workers was somewhat higher than would ordinarily
be expected. The increase, however, was not considered statistically significant.
(Zack et al, 1979)
Study #3
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PCBs may be associated with an increased incidence for all
cancers combined, including lung cancer, in 5,088 men studied
Calculated cumulative exposures to electromagnetic (EM) fields
during the production and distribution of hydroelectric power and the incidence
of cancer were compared. The study cohort included 5,088 men employed in
eight large Norwegian hydroelectric power companies. They had been employed
for at least 1 year between 1920 and 1985. During the follow up period
from 1951 through 1991, 486 new cases of cancer were observed. Stomach
cancer showed an excess risk among workers with more than 30 years on the
job. An increase in the standardized incidence ratio was detected for malignant
melanoma as well. An analysis by duration of employment indicated an
increased incidence ratio for all cancers combined, cancer of the pancreas,
lung,
and kidney, malignant melanoma, nonmelanoma, and lymphoma. Of the three
cases of leukemia, two were among workers who had been employed for less
than 20 years. An excess risk was noted for malignant melanoma at cumulative
exposures above 35 microtesla years. The evaluation of risk for malignant
melanoma and combined exposures to magnetic fields and possible exposure
to electric discharges or to oils contaminated with polychlorinated
biphenyls showed a tendency toward an effect. The authors conclude
that no association was observed between the occurrence of leukemia or
brain tumors and exposure to electric or magnetic fields in hydroelectric
power companies. (Tynes et al, 1994)
Study #4
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lung cancer deaths were elevated, but not considered statistically
significant
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small number of deaths limits interpretation
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results support the possibility of PCBs posing a carcinogenic
risk to humans
A study of mortality in electrical capacitor manufacturing
workers was conducted. The cohort consisted of 2100 workers, 1556 females,
employed for at least 1 week at a capacitor manufacturing facility at Milan,
Italy, between 1946 and 1978. The facility used polychlorinated-biphenyls
(1336363) (PCBs) as the dielectric fluid until 1980. Vital status of the
cohort at the end of 1982 was determined. Death certificates for all decedents
were reviewed. Standardized mortality ratios (SMRs) were computed, based
on national and local mortality rates. Overall mortality among male workers,
30 deaths, was similar to that expected. There were 14 deaths due to
cancer, which was significantly more than expected, based on either
local or national rates. Deaths due to cancer of the gastrointestinal tract
were significantly elevated. Deaths due to lung cancer and hematologic
neoplasms were nonsignificantly elevated. Female workers showed
an overall mortality, 34 deaths, that was significantly increased above
that expected. Twelve cancer deaths were observed, against 5.3 expected
using the local population for comparison. Deaths due to hematologic neoplasms
were significantly increased above that expected, 4 observed versus 1.1
expected based on local mortality rates. There was a significant deficit
of deaths due to cardiovascular disease. Accidental deaths were significantly
elevated, with a SMR of 225. The authors note that the small number
of deaths limits interpretation of the results. The results, however,
agree with those of previous studies and support the possibility of PCBs
posing a carcinogenic risk to humans. (Bertazzi et al, 1987)
Study #5
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16 of 58 employees (27.6 percent) had lung cancer and were
probably exposed to PCBs
In response to a request from OSHA, possible hazardous working
conditions at the McGraw-Edison (SIC-3612) facility located in Canonsburg,
Pennsylvania were investigated. The company produced large power transformers
plus various sizes of power circuit breakers. Exposures to welding fumes,
high voltage electricity, paint solvent vapors, noise, and transformer
oils were possible. Past exposures to oils containing polychlorinated-biphenyls
(1336363), and asbestos (1332214) were possible. A group of 58 employees
was examined in an attempt to verify possible clustering of cancer cases.
Of the original 58, no records were found for three, and 18 individuals
had died but had never had cancer. The remaining 37 were all confirmed
cancer cases covering 13 different types. An apparent clustering of cancer
in recent years was demonstrated. All but one case occurred in white males
between the ages of 43 and 69 years. Lung cancer was the most common
type, 16 of the 37 cases. The authors conclude that, compared with
the general population, lung cancer was occurring probably at no greater
rate among these employees than in the general population. No evidence
was found to associate causally the number of cancer cases among the workers
and any occupational exposures they may have been experiencing at this
facility. The authors recommend that a thorough industrial hygiene survey
be made at this facility. (Sanderson et al, 1988)
Study #6
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tumors in patients who inadvertently consumed PCBs in 1968
included lung cancer
The general toxic effects and the carcinogenic potential
of the polychlorinated biphenyls (1336363) (PCBs) were reviewed. Low level
exposure of primates to PCBs has caused widespread deleterious effects
that persist indefinitely. General effects of the PCBs in man and in nonhuman
primate experimental animals were discussed. In man, the effects have included
fatigue, headaches, digestive disorders, menstrual disturbances, and hyperpigmentation
in infants born to mothers exposed to PCBs. In experimental animals, the
most consistent tissue modification has been a marked hypertrophy of the
liver. Biochemical implications of the PCBs as possible carcinogens were
discussed in terms of several metabolites and their association with cellular
macromolecules. Morphological changes and tumor development associated
with chronic feeding of PCBs to rodents and monkeys were described, including
neoplastic liver nodules, liver adenofibrosis, hepatocellular carcinomas,
and hyperplastic and metaplastic alterations of the stomach. Preliminary
observations on the association of PCBs and tumor development in man were
reviewed. Tumors in patients who inadvertently consumed PCBs in 1968
have included one or more occurrences of stomach, liver, lung,
and breast cancers, malignant melanomas, and a malignant lymphoma.
The author concludes that although there is only suggestive evidence that
persons exposed to PCBs have a higher incidence of cancer, the data that
have been obtained in lower animals warrant concern in man, and that until
a better understanding of the potential danger of low level, long term
exposure is established, it appears that any level of exposure may be injurious
to human health. (Allen et al, 1977)
Study #7
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two workers out of 19 developed lung cancer, but the study
was too small to calculate significance
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the results do not exclude the possibility of a cancer risk
from PCBs
Mortality and cancer incidence of a cohort of 142 Swedish
male workers engaged in the manufacturing of capacitors, who were exposed
to polychlorinated-biphenyls (PCBs) for at least 6 months between 1965
and 1978, were investigated. Mean exposure time was 6.5 years. Previous
sampling and analysis of airborne PCBs showed a level of 0.1mg/m3. Expected
numbers, standardized for sex, age and calendar year, were calculated from
national statistics. Twenty-two deaths were reported between 1965 and 1982,
and seven cancers were reported between 1965 and 1980; both figures were
in good agreement with those expected. Latency time ranged from 4 to 22
years (median of 13 years). The separate analysis of 19 workers with a
higher exposure (capacitor fillers and repairmen) did not show increased
trends of mortality or cancer incidence. Two workers had lung cancer,
and one developed a slow growing mesenchymal tumor and a malignant lymphoma,
both occurring after 10 years of exposure. Although the size of the
cohort was small and the follow up time short, the authors conclude
that the results obtained do not indicate any excess mortality or cancer
incidence at the facility studied, however, they do not exclude the possibility
of a carcinogenic risk from PCB exposure. (Gustavsson et al, 1986)
Study #8
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two of 12 autopsies found lung cancer in PCB poisoning victims
Autopsy findings of 12 patients with yusho including 2 stillborn
babies are reported. Characteristic pathological changes were acne-like
eruptions and cutaneous pigmentation with histological features of follicular
hyperkeratosis, dilated hair follicles, and an increase of melanin pigment
of the epidermis. In addition to the skin lesions, multiplication of the
duct epithelium of the esophageal gland was found in 6 patients. Unusual
multiple small foci of myocardial necrosis and fibrosis with basophilic
myofibrillar degeneration were found in one patient, suggesting a relation
to PCB exposure. Five cases with carcinomas (two involving the liver,
two
the lung, and one the esophagus) were also found, but their causal
relationship with PCB was not certain. Nine cases showed the characteristic
gas chromatographic pattern of yusho, but two cases had the same one as
that of healthy controls. (Kikuchi, 1984)
Study #9
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firefighters are often exposed to PCBs
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firefighters have a higher incidence of lung cancer
The long term health hazards of fire fighting are reviewed.
Although the physical dangers of the occupations are obvious, dangers from
inhaling toxic gases, some carcinogenic, in heated air and fumes are not
so readily apparent. Liver and kidney problems, the incidence of birth
defects among offspring, and increased susceptibility to infectious disease
are all cited as problems needing investigation. Available data suggests
that fire fighters have a higher incidence of cancer of the mouth
and throat, lungs and lymph system, and intestines and rectum. It
is suggested that due to the increased use of plastics, risks from smoke
inhalation have greatly increased for fire fighters. Some of the toxic
components of certain plastics whose primary function is to suppress smoke
and retard flame make the smoke more toxic when these materials get hot
enough to burn. Lung hazards produced by acrylonitrile (107131), asbestos
(1332214), cadmium (7440439), carbon-tetrachloride (56235), chromium (7440473),
creosote (8021394), benzene (71432), and polychlorinated biphenyls
are considered. It is recommended that fire departments clear their facilities
of deteriorating asbestos gloves, uniforms, or blankets. Legislation and
regulation are also recommended to direct use of alternative materials
which would be less toxic when they burn. (Polakoff, 1984)
Study #10
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abnormal serum oncogene proteins in workers with known exposure
to carcinogens (such as PCBs) may represent an early marker of neoplastic
disease (cancer)
A new technique for detecting serum oncogene proteins was
described and tested in municipal workers exposed to polychlorinated-biphenyls
(1336363) (PCBs). The study group was selected from a group of 24 municipal
employees exposed to the PCBs in transformer oil during the removal and
cleaning of old transformers. A total of 16 workers submitted to a complete
evaluation including a medical and occupational history, possible sources
of other PCB exposures, exposures to other hazardous materials, complete
physical and dermatological examination, and laboratory tests for serum
triglycerides, serum PCB levels, liver function tests, and the presence
of oncogene related proteins in the serum. The assay for serum oncogene
proteins was based on a modification of the urine immunoblot method. The
average age of the 16 workers was 42 years, and all reported some skin
contact with the transformer oil during the clean up and removal operations.
Two workers reported prior exposure to PCBs, and seven reported exposure
to other carcinogenic materials. Twelve of the sixteen workers were current
or recent cigarette smokers. Serum PCB levels were negligible in 11 of
the 16 workers and ranged from 0.6 to 10.6 parts per billion in the other
five workers. Eight workers showed abnormal serum oncogenes not found in
normal unexposed individuals. Six workers with positive smoking histories
showed abnormal oncogenes of the fes variety; fes type proteins were not
observed in any nonsmokers. The ras related oncogenes were detected in
three workers, and one worker showed abnormal banding patterns for sis
oncogene related proteins. The authors conclude that the abnormal serum
oncogene proteins in these workers with known exposure to carcinogens may
represent an early marker of neoplastic disease. (Brandt-Rauf et al,
1988)
Study #11
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half of PCB poisoning victims showed respiratory damage
Studies were conducted on respiratory involvement of 197
patients with Yusho disease. Observations included: signs of chronic bronchitis
or pneumonia were found in one-half the patients; signs of secondary infection
found in the sputum; and a slight level of occlusion in the terminal airways
and a reduction in arterial blood partial oxygen pressure were noted in
lung function tests. Effects of giving polychlorinated biphenyls orally
with oil to rats and mice were studied. Morphological changes in the lungs
of experimental animals were marked in the type II alveolar cells. No morphological
changes were noted in the lung surfactants. The alveolar phagocytes showed
a picture of consuming lipids containing polychlorinated biphenyls. (Shigematsu
et al, 1974)
Study #12
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The incidence and severity of respiratory symptoms correlated
well with the concentration of PCB in the blood and sputa
Clinical, laboratory and pathological findings on respiratory
involvement in polychlorinated biphenyl (PCB) poisoning were studied in
401 patients and their pathological changes were produced in rats given
PCB orally. Respiratory symptoms included expectoration in 40% of the 289
nonsmoking patients with PCB poisoning and mild wheezing in 2%. The
incidence and severity of the respiratory symptoms correlated well with
the concentration of PCB in the blood and sputa. Chest roentgenographic
findings, pulmonary function tests and pathological findings revealed bronchiolitis
in many, and pneumonia or atelectasis in about 1/10 of the patients with
reticulo-linear shadows. Peribronchiolar changes may be primarily due to
either PCB poisoning or associated infection. Respiratory distress was
often exacerbated by viral or bacterial infection persisting for more than
a half year in about half of the patients examined. The Ig(immunoglobulin)A
and IgM levels in the serum decreased considerably within 2 yr after the
onset of the disease and definite decreases in IgA levels may correlate
well with the bacterial infection. PCB found in sputa may have been present
in association with lipid in type II cells of the lung (or with excretion
from bronchial cells) and may have been phagocytosed in alveolar macrophages
and may change their phagocytic function. (Shigematsu et al, 1978)
Study #13
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for 5 years after PCB poisoning, respiratory symptoms persisted
in most patients; in patients with high blood PCB levels, signs of chronically
infected airways were observed
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pathologic changes in lungs and thymus were observed in rats,
including necrosis of Clara cells, mild pulmonary edema
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respiratory problems were mainly in small airways and were
due primarily to furans [PCBs are usually contaminated with furans]
Respiratory involvement and immune status was studied and
followed up for 14 years in 401 patients with polychlorinated-biphenyl
(1336363) (PCB) poisoning caused by ingestion of contaminated edible rice-bran-oil.
Respiratory symptoms correlated with PCB levels in blood and were often
exacerbated by viral or bacterial infection. Symptoms improved gradually
but remained after 14 years. Study and follow up included assessment of
subjective symptoms, chest x-rays, pulmonary function tests, sputum microbiology,
and measurement of immunoglobulin and PCB levels in serum and sputum. Pulmonary
function and immunological status observed in February and March of 1983
(11 year follow up) were reported. Approximately 1 year after onset of
disease, half of the patients complained of expectoration; these patients
had high blood PCB concentrations. In some patients, wheezes without radiological,
physiological, or immunological evidence of bronchial asthma or pulmonary
emphysema were observed. For 5 years after onset, respiratory symptoms
persisted in most patients; in patients with high blood PCB levels, signs
of chronically infected airways were observed. PCB levels in blood
changed little during the observation period. Pulmonary function was tested
in 12 nonsmoking patients; in eight, inspiratory and expiratory rhonchi
were audible at all times in 1970 and 1974 (2 to 6 years after disease
onset). In 1983, slight improvement was observed and no audible rhonchi
were noted. Immunoglobulin-A and immunoglobulin-M levels were decreased,
while immunoglobulin-G level was increased in 1970. In 1972, these immunoglobulins
were normal except in three patients. In Sprague-Dawley-rats fed polychlorinated
dibenzofurans (PCDFs) (0.25 milligrams three times per week for 1 or 2
weeks), pathologic changes in lungs and thymus were observed, including
necrosis
of Clara cells, mild pulmonary edema, and thymic atrophy, with similar
but milder effects noted for PCBs. The authors conclude that
respiratory
involvement in patients with PCB and PCDF poisoning is located mainly in
small airways and is due primarily to PCDFs. (Nakanishi et al, 1985)
Study #14
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dioxins are known to cause squamous carcinomas of the oropharynx
and lungs (certain PCBs are dioxin-like)
Studies involving polychlorinated biphenyls (PCBs) are reviewed.
PCBs
are a class of halogenated aromatic compounds, including halogenated biphenyls,
naphthalenes, dibenzodioxides, and dibenzofurans. PCBs persist in the
environment and are retained in tissue because they are lipid soluble.
They affect reproduction, suppress the immune system, cause tumors in laboratory
rodents, cause hepatic porphyria, and cause chick edema in chickens. Cell
mediated immunity is impaired by PCB, although the degree of impairment
is determined by the type of isomers present. PCBs are not teratogenic,
but they are fetotoxic, producing cleft palates, subcutaneous edema, and
hemorrhage. PCBs are passed to mammalian offspring in the milk. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin
(1746016) (TCDD) is known to cause hepatocellular carcinomas and squamous
carcinomas of the oropharynx and lungs. Subcutaneous sarcomas and tumors
of the thyroid are also noted. The primary source of PCB exposure to the
general United States population is fish from contaminated water. Serum
cholesterol levels in humans are directly proportional to PCB levels. The
concentration of PCB in human milk is particularly high. There is no clear
evidence of harm to humans from PCB, but research is inconclusive. The
author concludes that PCB may be a cancer promoter, but additional
studies on exposed human cohorts, such as fishermen, must be done before
any conclusions about the effects of PCB on humans can be reached. (Kimbrough,
1985)
Study #15
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PCB induces enzymes which helps promote mutations caused
by oil vapors
The genotoxic effects of oil vapors associated with wok cooking
in China were studied in-vitro. Condensates were collected from filters
mounted above woks in which the oils were heated to 270 degrees-C. Positive
results in a mutation assay with Salmonella-typhimurium strain (TA-98)
and Aroclor-1254 induced rat liver S9 were seen using unrefined
rapeseed oils (URSO), refined rapeseed oils, and soybean oils. The addition
of 0.1% or more butylated-hydroxyanisole (BHA) to the URSO prior to heating
inhibited its mutagenic effects. Hydrogenation of rapeseed oil also eliminated
its mutagenic effect. URSO condensates were determined to be mutagenic
in the SV50 forward mutation assay as well and these oils induced increased
numbers of sister chromatid exchanges in V79-Chinese-hamster cells compared
with controls. The addition of BHA or oil hydrogenation resulted in a decrease
in the number of sister chromatid exchanges. A dose dependent increase
in the number of polychromatic erythrocytes with micronuclei was seen in
mice injected with URSO condensates; this increase was inhibited with the
use of URSO condensates. The authors conclude that the high incidence
of lung cancer seen in females in China may be due to exposure to cooking
oil emissions. (Qu et al, 1992)
Study #16
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several epidemiologic studies on the carcinogenicity of PCBs
in both occupational exposure and accidental intoxication suggest that
PCBs might be a potent carcinogen in the lung.
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PCBs have been reported to promote lung tumors
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certain types of PCBs associated with cancer also increase
cytochrome P-450-dependent monooxygenases, which are abundant in bronchiolar
(lung) Clara cells
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PCBs may promote tumors by inhibiting intercellular communication
and/or by stimulating cell proliferation
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furans induce necrosis (cell death) and epoxide formation
to their target cells, which might result in lung cancer [PCBs are usually
contaminated with furans]
PCBs are compounds whose physical/chemical properties led
to their wide spread commercial use. The persistence and stability of PCBs
have resulted in a worldwide distribution. PCDFs, ones of PCB derivatives,
are primary causal agents of mass food poisoning, called Yusho in Japan
and Yu-Cheng in Taiwan. Several epidemiologic studies on the carcinogenicity
of PCBs in both occupational exposure and accidental intoxication suggest
that PCBs might be a potent carcinogen in liver and lung.
Many investigators reported that PCBs induced hepatocellular carcinoma
in rat and mice. Although either mutagenic or genotoxic effects of PCBs
are not definite, their tumor promoting effects have been repeatedly demonstrated
in the liver. The effects of PCBs as tumor promoter in the lung have
also been reported. PCB congeners that efficaciously promote carcinogenesis
increase cytochrome P-450-dependent monooxygenases, which are abundant
both in bronchiolar Clara cells and in hepatocytes. PCB congeners which
are inducers of P-450 may be active as tumor promoters by inhibiting intercellular
communication and/or by stimulating cell proliferation. Furan derivatives
like PCDFs have high affinity to bronchiolar Clara cells and hepatocytes.
PCDFs
induce necrosis and epoxide formation to their target cells, which might
result in carcinogenesis of liver and lung. (NAKANISHI et al,
1991)
Study #17
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PCBs stimulate production of lung macrophages
Samples of human epithelial lining fluid and a variety of
pulmonary alveolar macrophage (PAM) preparations were tested for their
ability to reduce hexavalent chromium (7440473) (Cr-VI), and were compared
with preparations of other human or adult Sprague-Dawley rat cells. The
patterns of this reaction and other biochemical parameters were examined
and related to smoking habits; its inducibility by Aroclor-1254
(11097691) was evaluated in rat pulmonary alveolar macrophages. Preparations
of PAM obtained from 47 subjects were shown to reduce Cr-VI and decrease
its mutagenicity; specific activity was significantly higher than in preparations
of mixed cell populations from human peripheral lung parenchyma or bronchial
tree, or from rat lung or liver. In smokers, at equivalent numbers of pulmonary
alveolar macrophages, Cr-VI reduction, total protein and oxidoreductase
activities were significantly reduced; there were no significant variations
between lung cancer and noncancer patients. In rats, the Cr-VI reducing
activity of pulmonary macrophage preparations was generally induced by
Aroclor-1254. The epithelial lining fluid also displayed some Cr-VI
reduction. The authors conclude that alveolar macrophages represent an
important aspecific defense mechanism and in some cases also possess metabolic
systems capable of the intracellular detoxification of direct-acting chemicals.
(Petrilli et al, 1986)
Study #18
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several chemicals (including tobacco constituents) were mutagenic
or more mutagenic in the presence of lung enzymes induced by PCBs
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enzymes may increase the lung cancer risk from these chemicals
The mutagenicity of N-nitrosopropylamines was investigated
in-vitro. The mutagenic potential of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine
(61499283) (HPOP), N-nitrosobis(2-oxopropyl)amine (6059934) (BOP), N-nitrosomethyl(2-oxopropyl)amine
(55984515) (MOP), N-nitrosomethyl(2-hydroxypropyl)amine (75411835) (MHP),
N-nitrosobis(2-hydroxypropyl)amine (53609646) (BHP), N-nitrosobis(2-acetoxypropyl)amine
(6041481) (BAP), and N-nitroso-2,6-dimethylmorpholine (1456286) (NDMM)
were evaluated in the Amesalmonella assay using strain TA-100 in the
presence or absence of lung and pancreas 9,000 times the force of gravity
(9,000G) S9 fractions from rats, hamsters, mice, rabbits, monkeys, and
humans. The S9 fractions were obtained from untreated or polychlorinated
biphenyl (PCB) induced animals. HPOP, MOP, and BOP showed positive
responses in the presence of lung S9 from all species. HPOP, MOP, BOP,
and MHP were mutagenic in the presence of lung S9 from PCB induced rats,
hamsters, and mice. In the presence of pancreas S9 from uninduced or
PCB treated animals, only HPOP and BOP were mutagenic. BHP, BAP, and NDMM
showed negative responses under all conditions. The mutagenicity of MHP,
BOP, and MOP was evaluated in the presence of lung S9 from PCB treated
rats, hamsters, and mice after preincubation in an atmosphere of carbon-monoxide
(630080) or after addition of cytochrome-c, metyrapone (54364), or 7,8-benzoflavone
(604591). Carbon-monoxide, cytochrome-c, and metyrapone completely inhibited
the mutagenic activity of MHP, but had no effect on that of MOP or BOP.
7,8-Benzoflavone had no effect on mutagenic activity of MOP, BOP, or MHP.
The authors conclude that only the methyl derivatives of N-nitrosopropylamines,
MHP and MOP, are activated by the lung from five animal species and humans.
The results provide the first evidence of activation of N-nitrosopropylamine
by human lung S9. Further studies are necessary to assess the cancer
risk to humans posed by these compounds. (Mori et al, 1986)
Study #19
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humans exposed to complex combustion mixtures will have higher
DNA adduct levels in lung cells
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adduct levels depend on the genotoxic and DNA adduct-forming
potency of the mixture
DNA adducts derived from complex mixtures of polycyclic aromatic
compounds emitted from tobacco smoke are compared to industrial pollution
sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and
urban air pollution. Exposures to coke oven emissions and smoky coal, both
potent rodent skin tumor initiators and lung carcinogens in humans, result
in high levels of DNA adducts compared to tobacco smoke in the in vitro
calf thymus DNA model system, in cultured lymphocytes, and in the mouse
skin assay. Using tobacco smoke as a model in human studies, we have compared
relative DNA adduct levels detected in blood lymphocytes, placental tissue,
bronchoalveolar lung lavage cells, sperm, and autopsy tissues of smokers
and nonsmokers. Adduct levels in DNA isolated from smokers were highest
in human heart and lung tissue with smaller but detectable differences
in placental tissue and lung lavage cells. Comparison of the DNA adduct
levels resulting from human exposure to different complex mixtures shows
that emissions from coke ovens, aluminum smelters, and smoky coal result
in higher DNA adduct levels than tobacco smoke exposure. These studies
suggest that humans exposed to complex combustion mixtures will have
higher DNA adduct levels in target cells (e.g., lung) as compared to
nontarget cells (e.g., lymphocytes) and that the adduct levels will
be dependent on the genotoxic and DNA adduct-forming potency of the mixture.
(Lewtas et al, 1993)
Study #20
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PCBs showed a significant excess of all cancers
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one study showed statistically significant increased human
mortality from all malignancies (33 observed, 15.5 expected), including
from lung cancer (8 observed, 2.5 expected).
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second study showed intragastric administration of PCBs to
mice increased the incidence of lung tumours induced by intraperitoneal
administration of N-nitrosodimethylamine (a tobacco chemical).
A. Evidence for carcinogenicity to humans (limited) Information
on the possible carcinogenic risk of human exposure to polychlorinated
biphenyls (PCBs) comes from studies of occupational populations and of
populations exposed to the compounds accidentally. PCB mixtures may be
contaminated with polychlorinated dibenzofurans and polychlorinated dibenzodioxins
(see, e.g, p. 350). A slight increase in the incidence of cancer, particularly
melanoma of the skin, was reported in a small group of men exposed to Aroclor
1254, a mixture of PCBs. In a study of over 2500 US workers exposed to
a similar mixture of PCBs during the manufacture of electrical capacitors,
five deaths due to cancer of the liver and biliary passages were observed,
where as 1.9 would have been expected. This increase was sustained mainly
by female workers in one of the two plants in the study (four of the five
deaths), and all five workers had first been employed before the early
1950s. Another study of workers in a capacitor plant was conducted in Italy.
Exposure in the early years of production (until 1964) was to PCB mixtures
containing 54% chlorine (mainly Aroclor 1254 and Pyralene 1476), which
were later replaced by mixtures containing 42% chlorine (mainly Pyralene
3010 and 3011). Early results showed a significant excess of all cancers
among male workers, which was due mainly to cancers of the digestive system
and of the lymphatic and haematopoietic tissues. Among female workers,
a slight increase in mortality from cancer of the lymphatic and haematopoietic
tissues was reported. The study was later enlarged and extended to include
2100 workers and to cover the period 1946-1982. Both male and female workers
exhibited significantly increased cancer mortality in comparison with rates
for the local population (14 observed, 7.6 expected; and 12 and 5.3, respectively,
for men and women). Among male workers, cancers of the gastrointestinal
tract (two stomach, two pancreas, one liver and one biliary passages) taken
together were significantly increased (6 observed, 2.2 expected). Female
workers showed a significant increase in deaths from haematological neoplasms
(4 observed, 1.1 expected). In Sweden, among 142 male workers employed
between 1965 and 1978 in a capacitor manufacturing plant when PCB mixtures
containing up to 42% chlorine had been used, no significant excess of cancer
deaths was noted. Cancer incidence was also examined: the number of cases
observed corresponded well to that expected. One individual in a subgroup
with higher exposure developed two relatively rare tumours, both of which
occurred ten years after the start of exposure: a slow-growing mesenchymal
tumour (desmoid) and a malignant lymphoma. After contamination of cooking
oil with a mixture of PCBs (Kanechlor 400) in Japan in 1968, a large population
was intoxicated ('Yusho' disease). An early report on mortality from 1963-1983
showed a significantly increased risk of all cancers, and an almost five-fold
significantly elevated risk of primary liver cancer. The edible rice oil
had also been contaminated by polychlorinated quaterphenyls and polychlorinated
dibenzofurans. Dose response relationships were not clarified. A further
comprehensive study of 887 male 'Yusho' patients showed statistically
significantly increased mortality from all malignancies (33 observed,
15.5 expected), from liver cancer (9 observed, 1.6 expected) and from
lung cancer (8 observed, 2.5 expected). Use of local rather than national
rates in calculating expected number of deaths decreased the observed:expected
ratio for liver cancer from 5.6 to 3.9, which was still statistically significant.
A closer look at the geographical distribution of liver cancer cases did
not allow exclusion of factors other than PCB poisoning as a possible explanation
for this finding. For the 874 female patients examined, none of the noted
observed:expected ratios was significant. In a series of ten autopsies
of 'Yusho' patients, two adenocarcinomas of the liver were found, with
no indication of a direct association with exposure to PCBs. Ultrasonic
and tumour marker examination of two series of 79 and 125 patients with
'Yusho' disease in 1983 and 1984, respectively, did not reveal any case
of hepatic-cell carcinoma. Two studies of the PCB content of fat tissues
and cancer occurrence were available. An association was suggested between
PCB concentrations in subcutaneous abdominal adipose tissue and the occurrence
of cancers of the stomach, colon, pancreas, ovaries and prostate. No indication
emerged of a relationship between PCB content in extractable breast fat
tissue and the occurrence of breast cancer. The available studies suggest
an association between cancer and exposure to PCBs. The increased risk
from hepatobiliary cancer emerged consistently in different studies. Since,
however, the numbers were small, dose-response relationships could not
be evaluated, and the role of compounds other than PCBs could not be excluded,
the evidence was considered to be limited. B. Evidence for carcinogenicity
to animals (sufficient) Certain PCBs (particularly with greater than 50%
chlorination) produced benign and malignant liver neoplasms in mice and
rats after their oral administration. Oral administration of Aroclor 1254
to rats yielded hepatocellular adenomas and carcinomas as well as intestinal
metaplasia and a low, statistically nonsignificant incidence of stomach
adenocarcinomas. PCBs were inadequately tested in mice for induction of
skin tumours. In several studies, oral or intraperitoneal administration
of PCBs enhanced the incidences of preneoplastic lesions and of neoplasms
of the liver induced in rats by N-nitrosodiethylamine or 2-acetylaminofluorene.
In
one study, intragastric administration of PCBs to mice increased the incidence
of lung tumours induced by intraperitoneal administration of N-nitrosodimethylamine.
C. Other relevant data No data were available on the genetic and related
effects of PCBs in humans. Dominant lethal effects were not induced in
rats administered PCBs orally, but were produced in rats nursed by females
that had received PCBs orally. PCBs did not induce chromosomal aberrations
in bone-marrow cells or spermatagonia of rats treated in vivo; micronuclei
were not induced in bone-marrow cells of mice in one study, while equivocal
results were obtained in a second study in which the PCBs were administered
in corn oil. They did not transform Syrian hamster embryo cells in vitro.
PCBs induced DNA strand breaks and unscheduled DNA synthesis in rat hepatocytes
in vitro. Neither chromosomal breakage nor aneuploidy was induced in Drosophila.
PCB mixtures did not induce SOS repair and were not mutagenic to bacteria.
2,2',5,5'-Tetrachlorobiphenyl induced DNA strand breaks in mouse cells
in vitro. 2,4,5,2',4',5'-Hexachlorobiphenyl but not 3,4,5,3',4',5'-hexachlorobiphenyl
inhibited intercellular communication in Chinese hamster V79 cells. Purified
2,4,2',4'-, 2,5,2',5'- and 3,4,3',4'-tetrachloro- and 2,4,6,2',4',6'-hexachlorobiphenyl
were not mutagenic to bacteria. (IARC - International Agency for the Research
of Cancer)
Study #21
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PCB induced enzymes may alter the metabolism and the pattern
of DNA adducts formed in human lung tissue as a result of certain carcinogenic
pollutants
It has previously been shown that 6-nitrochrysene can be
activated to electrophilic species capable of reacting with DNA through
metabolic pathways that form N-hydroxy-6-aminochrysene or trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene
as critical intermediates. Since the lung is a known target tissue for
the carcinogenic action of polycyclic nitroaromatic hydrocarbons, we
investigated the metabolism and DNA binding of [3H]6-nitrochrysene in 11
specimens of human bronchus. Analysis of medium from [3H]6-nitrochrysene-treated
explants indicated the presence of trans-9,10-dihydroxy-9,10-dihydro-6-nitrochrysene
(0.04-330 pmol/mg epithelial DNA), trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene
(12-1700 pmol/mg epithelial DNA), 6-aminochrysene (1.6-2200 pmol/mg epithelial
DNA), and trans-1,2-dihydroxy-1,2-dihydro-6-aminochyrsene (3.6-610 pmol/mg
epithelial DNA). Both the levels and the relative proportions of these
metabolites varied widely in explants from different individuals. The amount
of DNA recovered and the level of DNA modification were sufficient for
adduct analysis in eight of the 11 cases for which metabolite data were
obtained. Five additional bronchial specimens for which metabolite data
were not obtained were also analyzed for carcinogen-DNA adducts. The levels
of binding varied from 0.06 to 30.5 pmol [3H]6-nitrochrysene bound/mg DNA
(two adducts per 10(8) nucleotides-10 adducts per 10(6) nucleotides). HPLC
analyses of enzymatic hydrolysates of the explant DNA indicated that 11
of 13 cases contained adducts with retention times identical to those of
adducts derived from trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene or
N-hydroxy-6-aminochrysene. The adduct derived from trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene
was the major adduct detected in eight of 13 cases. The reasons for
the variation in metabolism and adduct formation observed in [3H]6-nitrochrysene-treated
explants of bronchus from different donors are not known but may reflect
differences in the activities of enzymes responsible for the metabolism
of this compound. The influence of induction of drug metabolizing enzymes
on the activation pathway of 6-nitrochrysene in an intact cell system was
tested using rat hepatocytes. 6-Nitrochrysene was incubated with freshly
isolated hepatocytes from rats that were either untreated or pretreated
with phenobarbital, 3-methylcholanthrene or Aroclor 1254. Although
the levels of adducts were similar in all cases, the pattern of DNA adducts
formed in these hepatocytes was dependent on the nature of the pretreatment
of the rats. As previously reported, hepatocytes from untreated rats
contained adducts derived from N-hydroxy-6-aminochrysene. (Delclos et al,
1989)
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Summary
of Animal Studies of Lung Cancer and PCBs
The
Animal Studies 1 - 31
The
Animal Studies 32 - 32
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