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Brain Cancer Studies
Studies that indicate links between chemical exposure and increased risk of brain cancer and brain tumors
Study
#1 - PCB Exposure
· mortality from brain cancer was modestly increased
among men with up to 10,000 hours PCB exposure
· no deaths from brain cancer occurred among the most
highly PCB exposed men
· a five-year lag time increased the brain cancer rate
OBJECTIVES: To assess whether excess mortality from cancer,
malignant melanoma of the skin, and cancers of the brain and
liver in particular, is associated with long term occupational
exposure to polychlorinated biphenyls (PCBs).
METHODS: An epidemiological study of mortality was conducted
among 138,905 men employed for at least six months between
1950 and 1986 at five electrical power companies in the United
States. Exposures were assessed by panels composed of workers,
hygienists, and managers at each company, who considered tasks
performed by workers in 28 job categories and estimated weekly
exposures in hours for each job. Poisson regression was used
to examine mortality in relation to exposure to electrical
insulating fluids containing PCBs, controlling for demographic
and occupational factors.
RESULTS: Neither all cause nor total cancer mortality was
related to cumulative exposure to PCB insulating fluids. Mortality
from malignant melanoma increased with exposure; rate ratios
(RRs) relative to unexposed men for melanoma were 1.23 (95%
confidence interval (95% CI) 0.56 to 2.52), 1.71 (0.68 to
4.28) and 1.93 (0.52 to 7.14) for men with < 2000, >
2000-10,000, and > 10,000 hours of cumulative exposure
to PCB insulating fluids, respectively, without consideration
of latency. Lagging exposure by 20 years yielded RRs of 1.29
(0.76 to 2.18), 2.56 (1.09 to 5.97), and 4.81 (1.49 to 15.50)
for the same exposure levels.
Mortality from brain cancer was modestly increased among men
with < 2000 hours (RR 1.61, 95% CI 0.86 to 3.01) and >
2000-10,000 hours exposure (RR 1.79, 95% CI 0.81 to 3.95),
but there were no deaths from brain cancer among the most
highly exposed men. A lag of five years yielded slightly increased
RRs. Mortality from liver cancer was not associated with exposure
to PCB insulating fluids.
CONCLUSIONS: This study was larger and provided more detailed
information on exposure than past investigations of workers
exposed to PCBs. The results suggest that PCBs cause cancer,
with malignant melanoma being of particular concern in this
industry. (Loomis
et al, 1997)
Study #2 Electrical Workers
· More deaths were observed than expected for cancer
of the brain and nervous system
· The average estimated cumulative dose for the cases
of brain cancer was greater than for other workers
On the basis of evidence from animal studies, polychlorinated
biphenyls (PCBs) are considered potentially carcinogenic to
humans. However, the results of studies in human populations
exposed to PCBs have been inconsistent. The authors conducted
a retrospective cohort analysis (1957-1986) comparing the
mortality of 3,588 electrical capacitor manufacturing workers
with known exposure to PCBs with age-, sex-, and calendar
time-specific mortality rates for all whites in the United
States. Proportional hazards modeling was also performed to
examine the association between cumulative PCB exposure and
site-specific cancer mortality.
All-cause mortality (192 deaths observed, 283.3 expected)
and total cancer mortality (54 deaths observed, 63.7 expected)
were lower than expected. More deaths were observed than expected
for malignant melanoma (8 observed, less than 2.0 expected)
and cancer of the brain and nervous system (5 observed, 2.8
expected). The average estimated cumulative dose for the cases
of brain cancer (22.9 units) was greater than for other workers
(12.9 units), but the 95% confidence intervals around this
difference were broad.
The risk of malignant melanoma was not related to cumulative
PCB exposure. These results provide some evidence of an association
between employment at this plant and malignant melanoma and
cancer of the brain. The possibility that the results are
due to chance, bias, or confounding cannot be
excluded. (Sinks et al, 1992)
Study #3 PCB Exposed Worker
· PCBs are known to deposit preferentially in nervous
tissue
· Study examined two PCB-exposed workers with brain
cancer
· Researchers urge more studies of link between PCBs
and brain cancer
Polychlorinated biphenyls have been shown to be carcinogens
in animal studies. Because of lipid solubility and lack of
biodegradation, they are known to deposit preferentially in
fat and nervous tissue. In this report, we describe a 31-year-old
male with prolonged polychlorinated biphenyls exposure who
developed glioblastoma multiforme [brain cancer]. Fat biopsy
documented the presence of markedly elevated PCB levels.
A co-worker also developed a malignant astrocytoma [brain
cancer]. The nature of PCBs and their role in human carcinogenesis
are discussed. The possibility of an etiologic link between
PCBs and brain tumors should be further investigated. (Petruska
et al, 1991)
Study #4 Electrical Capacitor Worker (NIOSH Study)
· increased incidence of brain cancer among workers
who had more than twice the estimated cumulative PCB dose
than the comparison group
NIOSH conducted a retrospective cohort study of workers manufacturing
electrical capacitors with known exposure to polychlorinated
biphenyls (1336363) (PCBs) in an effort to further evaluate
the carcinogenicity of PCBs. The study cohort manufactured
electric capacitors in the midwest United States beginning
in 1957. PCBs were used as a dielectric fluid until late in
1977 when they were replaced with isopropyl-biphenyl (25640782).
Aroclor-1242 (53469219) was used through 1970 and Aroclor-1016
(12674112) was used afterwards. Included in the analysis were
3588 men and women employed for at least one day between January
1, 1957 and March 31, 1977.
The results provided some evidence for an association between
PCB exposure in an occupational environment and mortality
from malignant melanoma. There was an increased incidence
of brain cancer among workers who had more than twice the
estimated cumulative PCB dose than the comparison group. The
authors conclude that this brain cancer observation suggests
that this outcome be carefully observed in further followup
of this cohort. (Sinks et al, 1991)
Study #5 Westinghouse Electric PCB Study
· PCB-exposed workers experienced excess in the number
of deaths resulting from brain cancer
A study was undertaken of the mortality experience of 3588
male and female workers at the Westinghouse Electric Corporation
located in Bloomington, Indiana from 1957 to 1977. There was
possible exposure to polychlorinated biphenyls (PCBs). The
mortality was less than had been expected; however, there
was an excess in the number of deaths resulting from brain
cancer and from malignant melanomas. Investigators were not
able to demonstrate statistically significant relations between
excess mortality and PCB exposure. A notification letter was
mailed to 3189 individuals.
Anecdotal information provided by some cohort members indicated
that the potential for both dermal and airborne PCB exposure
during capacitor manufacture was great. The authors conclude
that the decision to communicate risk information to members
of a cohort should be handled separately from, and after completion
of review of the scientific merits of the study. The vital
status of the cohort should be updated as close to the notification
date as possible. (Mazzuckelli et al, 1993)
Study #6 Electrical Worker - PCBs.
· elevated risks of brain cancer have been noted in
electrical workers, who tend to be exposed to PCBs
A summary was provided of past research into residential and
occupational exposures to electromagnetic fields and the possible
relationship between exposure and the incidence of cancer.
Information was presented concerning exposure assessment,
potential cofounders, and biological mechanisms. Sources of
electric and magnetic fields included household appliances,
electric power lines, electric blankets, and various types
of office equipment.
One of the major criticisms of previous investigations on
the incidence of cancer in electrical workers had been that
they were based on job titles and did not therefore assessed
individual exposures to electromagnetic fields. However, elevated
risks of leukemia and brain cancer have been noted in electrical
workers. The use of personal dosimetry data will make the
case more convincing. Potential cofounders which were significant
in occupational exposure investigations included life style
factors such as smoking, diet, social class and others not
attributed to a specific job.
Other cofactors included exposures on the job to solvents,
polychlorinated biphenyls, ionizing radiation and welding
fumes, some of which may be very closely correlated with exposure
to electromagnetic fields in a particular industry. Future
investigations of cancer among electrical workers should attempt
to examine all possible work related causes of leukemia and
brain cancer to narrow the list of candidates. Possible mechanisms
of action and the time span between exposure and diagnosis
of disease were reviewed. (Savitz et al, 1989)
Study #7
· Brain cancer was significantly increased in females
exposed to dioxin
A study of mortality was conducted in persons involved in
the Seveso accident in which an accidental explosion at a
Hoffmana Roche chemical factory at Meda, Italy in 1976 contaminated
a wide area with 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016)
(TCDD). The cohort consisted of 556 persons who lived in an
area with average soil TCDD concentrations of 15.5 to 580.4
micrograms per square meter (microg/m2) (zone-A), 3920 persons
living in an area having average soil TCDD concentrations
below 50 microg/m2 (zone-B), and 26,227 persons who lived
in an area having soil TCDD concentrations generally below
5microg/m2 (zone-R).
The comparisons consisted of 167,391 persons living in surrounding
areas who did not experience any TCDD fallout from the explosion.
All subjects were 20 to 74 years old. Vital status of the
cohort as of December 31, 1986 was determined. Death certificates
of all decedents were examined. Mortality from cardiovascular
diseases was significantly elevated in subjects living in
zone-A. In zone-B residents, significant excess mortality
from total cancer, Hodgkin's disease, melanoma, and leukemia
occurred among males although the number of cases was small.
Single deaths occurred among females from gall bladder and
biliary tract cancer, soft tumor sarcomas, and thyroid cancer.
In zone-R, slight deficits in mortality from total cancer
in both males and females and lung cancer in males and significant
decreases in breast cancer in females occurred. Mortality
from soft tissue sarcoma was significantly increased in males.
Mortality from uterine and brain cancer was significantly
increased in females.
Mortality from cardiovascular disease was increased. The authors
conclude that the mortality pattern of individuals exposed
to TCDD differs from that of the population in the surrounding
territory. While no definite conclusions can be drawn, the
data suggest that TCDD can cause delayed health effects. (Bertazzi
et al, 1989
Study #8
· A statistically significant higher concentration
of PCB was found in extracted lipids of adipose tissue samples
from terminal brain cancer patients
A statistically significant correlation was demonstrated between
the content of PCB and DDE in lipids extracted from subcutaneous
abdominal tissue of terminal patients and their age. A higher
concentration of PCB and DDE was found in extracted lipids
of adipose tissue samples from terminal cancer patients (malignant
lymphoma, retroperitoneal carcinoma, glioblastoma, adenocarcinoma,
cancer of the breast, mesothelioma, carcinoma of the cervix,
pulmonary carcinoma, cancer of the rectum, cancer of the colon,
lymphosarcoma, etc.) than in the adipose tissue of patients
who died of other diseases. This difference was statistically
significant.
The results are discussed and the need for further investigations
of a possible cause-effect relationship between exposure to
organochlorine compounds and neoplasias is stressed. (Unger
et al, 1980)
Study #9
· Nerve Growth Factor (NGF) was more potent in the
presence of PCBs
· PCBs have the potential to influence the NGF neurotrophic
system
The effects of Aroclor 1254, a mixture of polychlorinated
biphenyls (PCBs), on nerve growth factor (NGF) receptors and
neurite outgrowth in PC12 cells were examined. Aroclor 1254
enhanced the NGF-stimulated neurite elongation and decreased
the Kd value for binding of 125I-labeled NGF to the high-affinity
NGF receptors. The NGF dose-response curve for neurite outgrowth
was also shifted to the left in cells pretreated with Aroclor
1254, suggesting that NGF was more potent in the presence
of PCBs.
Thus, one mechanism by which PCBs may enhance NGF-stimulated
neurotrophic effects is in increasing the affinity of binding
of NGF to the high-affinity NGF receptors, which are believed
to mediate the neurotrophic effects of NGF. The data suggest
that PCBs have the potential to influence the NGF neurotrophic
system. (Angus et al, 1995)
Study #10
· children of fathers exposed to dioxin experienced
increased rates of brain cancer
BACKGROUND: A case-control study was conducted with 183 histologically
confirmed neuroblastoma cases aged 0-14 years diagnosed among
residents of New York State, excluding New York City, between
1976 and 1987. Three hundred seventy-two controls were selected
from the New York State live birth certificate registry and
were matched to cases on year of birth.
METHODS: Parental occupational exposures at the time of each
child's birth were obtained from maternal telephone interviews,
successfully completed for 85% of cases and 87% of controls.
RESULTS: Odds ratios were significantly elevated for maternal
occupation in the service (OR = 2.0, 95% CI = 1.0 4.1) and
retail (OR = 2.0, 95% CI = 1.1-3.7) industries and paternal
occupation in materials handling (OR = 3.8, 95% CI = 1.1-14.6).
Odds ratios were also significantly elevated for maternal
report of occupational exposure to acetone (OR = 3.1, 95%
CI = 1.7-5.6), insecticides (OR = 2.3, 95% CI = 1.4-3.7),
lead (OR = 4.7, 95% CI = 1.3-18.2) and petroleum (OR = 3.0,
95% CI = 1.5-6.1) and paternal exposure to creosote (OR =
2.1, 95% CI = 1.1-4.3), dioxin (OR = 6.9, 95% CI = 1.3-68.4),
lead (OR = 2.4, 95% CI = 1.2-4.8), and petroleum (OR = 1.8,
95% CI = 1.1-2.8).
CONCLUSIONS: Due to the uncertainty of the biologic plausibility
of these associations and the possibility of alternative explanations,
these results should be interpreted cautiously. (Kerr et al,
2000)
Study #11
· there is suggestive evidence that brain tumors are
associated with parental exposures to chemicals.
· causes of endocrine-related cancers or susceptibility
to cancer may be a result of developmental exposures rather
than exposures existing at or near the time of tumor detection
Developing organisms have increased susceptibility to cancer
if they are exposed to environmental toxicants during rapid
growth and differentiation. Human studies have demonstrated
clear increases in cancer after prenatal exposure to ionizing
radiation, and there is suggestive evidence that brain tumors
and leukemia are associated with parental exposures to chemicals.
Animal experiments have demonstrated increased tumor formation
induced by prenatal or neonatal exposure to a variety of chemicals,
including direct-acting carcinogens and drugs. Recently, natural
estrogens have been classified as known human carcinogens.
Prenatal exposure to natural and synthetic estrogens is associated
with increases in breast and vaginal tumors in humans as well
as uterine tumors in animals. Synthetic halogenated chemicals
increase liver tumors after early life-stage exposure.
Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin,
has been shown to be a developmental toxicant of the mammary
gland in rodents. Dioxin alters multiple endocrine systems,
and its effects on the developing breast involve delayed proliferation
and differentiation of the mammary gland, as well as an elongation
of the window of sensitivity to potential carcinogens. Implications
of these new findings suggest that causes of endocrine-related
cancers or susceptibility to cancer may be a result of developmental
exposures rather than exposures existing at or near the time
of tumor detection. (Birnbaum et al, 2003)
Study #12
· A glioma case [brain cancer] was associated with
dioxin exposure
The vital status of 61 employees of a chemical company who
were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
(1746016) was reviewed. Job classifications were categorized
into high and low potential exposure to facilitate epidemiologic
research. Production employees working in the area of highest
TCDD contamination and those engaged in sampling operations
as well as maintenance personnel assigned to production equipment
were categorized as high potential. Production personnel working
away from areas of highest contamination and those maintenance
employees not directly involved with production equipment
were considered low exposure. Sixty one employees, age ranging
from 20 to 64 years were chosen and vital statistics for all
were determined through December 31, 1978. Expected numbers
of deaths were calculated from cause specific/age specific
mortality rates for the U.S. white male population. Severity
of acne like lesions observed among 49 of the 61 patients
ranged from questionable to severe.
Acnegenic responses were observed in 30 of 34 persons in the
high exposure group and 14 of 16 in the low exposure group.
Four deaths, one due to cardiovascular disease and three due
to malignant neoplasms, were observed compared to the 7.8
expected. The neoplasms included an adenocarcinoma, a fibrosarcoma,
and a glioma [brain cancer]. The authors conclude that although
TCDD exposure may be sufficient to produce chloracne it does
not increase overall mortality or cardiovascular death. Because
no single type of tumor was predominant, dioxin cannot be
considered a potent human carcinogen with organ or tissue
specificity. [Note: this is a very small sample size.] (Cook
et al, 1980)
Study #13
· alteration of cellular redox balance may mediate
the TCDD-induced inhibition of proliferation in human neuronal
cells.
Oxidative
stress has been known to be involved in the mechanism of toxic
effects of various agents on many cellular systems. In this
study we investigated the role of reactive oxygen species
(ROS) in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced
neuronal cell toxicity using SK-N-SH human neuroblastoma cells.
TCDD inhibited proliferation of the cells in a dose-dependent
manner, which was revealed by MTT staining, counting of cells
stained with trypan blue and [3H]thymidine uptake assay. TCDD
also suppressed the basal generation of ROS in a time- and
concentration-dependent manner assessed by 2',7'-dichlorofluorescein
fluorescence.
In addition, TCDD induced a dose-dependent inhibition of lipid
peroxidation, a biomarker of oxidative stress, whereas it
significantly increased the level of glutathione (GSH), an
intracellular free radical scavenger in the cells. Moreover,
TCDD altered the activities of major antioxidant enzymes;
increase in superoxide dismutase (SOD) and catalase, but decrease
in glutathione peroxidase (GSH-Px) and glutathione reductase
(GSH-Red). Pretreatment with L-buthionine-S,R-sulfoximine
(BSO, 50 microM), an inhibitor of GSH synthesis, significantly
prevented the TCDD-induced reduction in lipid peroxidation
and cell proliferation. Interestingly, exogenous application
of an oxidant, H2O2 (50 microM) markedly restored the inhibited
cell proliferation induced by TCDD. Taken together, these
results suggest that alteration of cellular redox balance
may mediate the TCDD-induced inhibition of proliferation in
human neuronal cells. (Lee et al, 2002)
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