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Skin Cancer and PCBs
Skin Cancer Studies and PCBs
This is not a complete list of all skin cancer research involving
PCB exposures. For more melanoma studies, visit the TOXNET
database operated by the National Library of Medicine (the source of these
abstracts.) Keep in mind that these skin cancer 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 melanoma studies 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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melanoma research found an association between PCB exposure in an occupational
environment and mortality from malignant melanoma
NIOSH conducted a retrospective cohort study of workers manufacturing electrical
capacitors with known exposure to polychlorinated biphenyls (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. Aroclor-1242 was used through 1970
and Aroclor-1016 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 #2
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more deaths were observed than expected for malignant melanoma (8 observed,
but less than 2 expected)
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all skin cancer deaths were due to malignant melanoma
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excess mortality applied to both sexes
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all 8 melanoma deaths occurred 5 or more years after initial employment
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risk of malignant melanoma was not related to cumulative PCB exposure.
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an association between employment at this factory and malignant melanoma
seems to be evident
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. The study cohort consisted of
2742 men and 846 women (total 3588) who had worked at the factory for at
least 1 day between January 1957 and March 1977. Personnel records and
data were obtained from the company's files. Vital status was determined
through the Social Security Administration. A proportional hazards model
was used to determine whether a dose response relationship existed between
PCB exposure and mortality from malignant melanoma or brain cancer. 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). All skin cancer deaths were due to malignant melanoma.All
eight melanoma deaths and five brain cancer deaths occurred 5 or
more years after initial employment. This excess mortality applied
to both sexes. The proportional hazards analysis showed that on average,
brain cancer cases had more than twice the estimated cumulative PCB dose
than the comparison group, and had worked in close proximity to the impregnation
ovens. 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. The
authors conclude that an association between employment at this factory
and malignant melanoma and brain cancer seems to be evident.
(Sinks
et al, 1992)
Study #3
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mortality rates from malignant melanoma were increased among men with any
experience in potentially PCB exposed jobs
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the data suggest that PCBs cause cancer, with malignant melanoma being
of particular concern in the electrical industry
Cancer mortality among a cohort of 139,000 US electric utility workers
was analyzed to determine the potential for carcinogenicity of long term
exposure to polychlorinated biphenyls (PCBs). The period of follow up included
2.66 million person/years of experience, during which there were 20,733
deaths. The favorable standardized mortality ratio of 0.77 for all causes
of death was largely attributable to low mortality from cardiovascular
diseases and cancer. Total cancer mortality was not related to the total
duration of employment in jobs with potential exposure to dielectric fluids
containing PCBs, or to employment as an electrician, laborer, and material
handler. SMRs of 1.2 to 1.3 were found among men with long term employment
as mechanics, linemen, or cable splicers. There was little evidence of
excess liver cancer among men who had worked jobs with potential PCB exposure.
Mortality
rates from malignant melanoma were increased among men with any experience
in potentially exposed jobs. Mortality from brain cancer was increased
among men with 2,000 to 10,000 hours of exposure to PCB insulating fluids,
but there were no deaths among workers exposed for more than 10,000 hours.
The authors note that this study was larger and provides more detailed
information on exposure than past investigations of workers exposed to
PCBs. They conclude that the data suggest that PCBs cause cancer, with
malignant melanoma being of particular concern in the electrical industry.
(Loomis et al, 1997)
Study #4
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an elevated number of melanoma cases occurred among 72 people studied
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there are biologic reasons for assuming a connection between exposure to
PCBs and melanomas such as the occurrence of chloracne
The possible carcinogenicity of Arochlor-1254 (11097691), a commercial
polychlorinated-biphenyl (1336363) (PCB), is reported. The material was
used for 9 years by a northeastern petrochemical plant. Preliminary analysis
of information supplied by the medical director of the plant shows that
of all 31 men who were thought to have had heavy exposure to the material,
two malignant melanomas are known. By contrast, a rate of only 0.04
malignant melanomas per 1,000 population would be expected according to
the Third National Cancer Survey. In addition, a third case of malignant
melanoma among 41 employees having less exposure to the compound is
known. Although the data are based on a very small number of subjects,
there
are biologic reasons for assuming a connection between exposure to PCBs
and melanomas such as the occurrence of chloracne resulting from industrial
exposure to PCBs and acneform eruptions among Japanese women who accidentally
ingested rice oil containing PCBs. Since PCBs exist for a long time in
the environment, further study of the possibility of the carcinogenicity
of PCBs is urged. (Bahn et al, 1976)
Study #5
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medical conditions which have arisen among the PCB exposed population include
malignant melanoma of the skin
An incident was described involving the overheating of an electrical panel
and subsequent overheating of a nearby electrical transformer, resulting
in leakage of fuel containing polychlorinated biphenyls (PCBs) and causing
widespread contamination of a New York State Office building in Binghamton.
Usual circuit breakers and other safety devices designed to prevent such
overheating failed, and contaminated smoke was vented throughout the 22
story building through air shafts from the transformer room. Chemical analysis
of air and soot samples revealed high concentrations of PCBs and pyrolytic
products of PCBs. The building was subsequently closed and remained closed
at the time of this report. Data on the medical consequences of those individuals
exposed were incomplete, and will not be fully realized for some time.
Medical
conditions which have arisen among the exposed population include malignant
melanoma of the skin, transient erythema of the face, fetal damage
and wastage, and serious psychiatric disorders, including one serious suicide
attempt. The author concludes that electrical incidents involving transformers
containing PCBs constitute a previously unrecognized health hazard. The
author recommends preventive measures for exposure to PCBs, such as enclosing
PCB transformers to prevent contamination of buildings, installing adequate
fire and temperature safety devices, and replacing PCB containing electrical
devices. The author also identifies the need for intense multispecialty
research into all aspects of such accidents. (Schecter, 1983)
Study #6
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medical surveillance indicated that PCB exposed workers showed signs of
chloracne, transient skin rashes, and skin cancer
A case study concerning a transformer leak of 180 to 200 gallons of Pyranol
(52673628) in an office building was examined. An electrical transformer
containing polychlorinated biphenyls (PCBs) and tetrachlorinated benzene
exploded, and started a fire. Because of the unusual system of air shafts,
the entire building and adjacent garage became contaminated with toxic
chemicals. Polychlorinated dioxins, furans, and biphenylenes were formed
as pyrolitic byproducts. Over 500 workers were exposed to the chemicals.
Air and soot PCB concentrations were measured, and employees underwent
medical surveillance. PCBs in air ranged from 80 micrograms per cubic meter
(microg/m3) the first week to 2 to 3microg/m3 1 month later. Soot PCB concentrations
ranged from 2,100,000 parts per billion (ppb) to 50,000ppb. Medical
surveillance indicated that exposed workers showed signs of chloracne,
transient skin rashes, skin cancer, liver pathology, nervousness,
irritability, insomnia, impotence, fatigue, elevated serum cholesterol
and triglyceride, hypertension, and psychoneurotic illness. Over 22 million
dollars were spent for cleaning procedures, which included: removal of
walls, floors, ceilings, and light fixtures; discarding furniture; rewiring
and plumbing repairs; and partial clearing of air ducts, shafts, and hidden
spaces. Over 1 billion dollars in lawsuit damages have been filed. The
authors conclude that prevention of similar incidents will be of increasing
importance in the future. (Schecter et al, 1985)
Study #7
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several cases of skin cancer, including one malignant melanoma, were found
in PCB exposed workers.
An incident involving release of polychlorinated biphenyl and chlorinated
benzene compounds was described, including various follow up studies. On
February 5, 1981, an electrical malfunction in the Binghamton State Office
Building (BSOB) led to overheating of a transformer and leakage of between
180 and 200 US gallons of transformer fluid from the overheated transformer
in a basement of the building, in the first reported incident of this kind.
Polychlorinated-biphenyl (1336363) (PCB) content in the soot from the fire
was 5 percent. Soot samples also contained 2,168,000 parts per billion
(ppb) of polychlorinated dibenzofurans (PCDFs), 20,000ppb of polychlorinated
dibenzo-p-dioxins (PCDDs), as well as 50,000ppb of chlorinated biphenylenes.
Guinea-pig bioassays indicated that the BSOB soot did not inactivate the
chemicals. Toxicity appeared to be largely due to the level of 2,3,7,8
substituted penta and hexa chlorinated dibenzofurans. Soot produced malformations
in chick embryos as well as decreased viability. Elevated serum PCB levels
in exposed persons returned to normal levels within 1 to 2 years in some
cases. Some exposed persons had elevated PCDF levels. Serum liver enzyme
elevations were usually transient, but were prolonged in three cases. Changes
were observed in mitochondria. Several cases of skin cancer, including
one malignant melanoma, were found in exposed workers. Risk assessment
calculations for reentry into the building, and "acceptable daily intakes"
of PCDDs and PCDFs were calculated. Calculations were derived from animal
studies. After several years of cleanup, usually by repeated washing with
steam or water and detergent rather than by removing and replacing walls,
floors, and lighting fixtures, results were uneven, even after 4 years
and 30 million dollars of cleanup effort. (Schecter, 1986)
Study #8
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an increase in the standardized incidence ratio was detected for malignant
melanoma
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the 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.
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 #9
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PCBs are halogenated aromatic compounds which cause chloracne
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skin lesions can develop into skin cancer
Different types of acne can be produced by three different groups of chemicals.
The first group contains petroleum, and its derivatives, particularly all
compounds found in crude oils, and these cause oil acne. Blisters appear
in areas where oil exposure is heavy. Areas of the body covered with oil
soaked clothing may also develop oil acne. Persons with this condition
should see a physician as the skin lesions can develop into skin cancer.
The second group contains certain coal-tar (8007452) products which cause
coal-tar acne. The oily substance and keratin form the black plugs that
mark this condition. These are typically found around the eyes. The condition
usually clears rapidly. This condition may result in skin cancer if not
treated appropriately and promptly. The third group contains halogenated
aromatic compounds such as polychlorinated-biphenyls (1336363) which cause
chloracne. The oily substance and keratin form yellow cysts and gray
plugs. The skin lesions are usually on the face, but may involve the shoulders
and chest, back and abdomen. Chloracne may develop 3 to 4 weeks after exposure
and may last up to 15 years even if exposure stops. Complications include
liver disease, bronchitis, nausea, vomiting, and diarrhea. The nervous
system can also be poisoned causing symptoms such as headache, fatigue,
irritability, palm sweating and numbness of the legs. Simple measures such
as good personal hygiene, engineering controls and use of protective equipment
can help prevent a person from developing occupational acne. (Bertolini,
1989)
Study #10
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melanoma and fluorescent lighting (with PCB-containing ballasts) may be
associated
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the cluster of melanoma cases among workers in high energy research laboratories
may be an example
The general scope and etiology of skin cancer and the kinds of chemical
and physical agents known to produce occupational skin cancer were reviewed.
Incidence rates per 100,000 population in men and women for the three most
common types of skin cancer were given as: basal cell carcinoma, 218.0
and 121.0; squamous cell carcinoma, 61.0 and 23.0, and melanoma, 5.9 and
5.3. Of the three types, only melanoma has a significant mortality (1.6
per 100,000 population in white males). Cutaneous carcinogenesis was discussed
in terms of three phases of cancer development, initiation and the conversion
and propagation stages of promotion. The principal agents associated with
occupational skin cancer were discussed. These included ultraviolet radiation,
ionizing radiation, polycyclic aromatic hydrocarbons and arsenic (7440382).
Chemicals
positive in rodent bioassays for cutaneous carcinogenesis were discussed
briefly: cisplatinum coordination complexes, quinolenes and azarenes,
carbamates, phorbol esters, nitrogen-mustard (51752), bis(chloromethyl)-ether
(542881), propiolactone (57578), alkyl nitrosoureas and polycyclic arylamines.
Chloroprene (126998), tarry biproducts during manufacture of 4,4'bipyridyl
(553264) and polychlorinated biphenyls (1336363) which have been
implicated
in epidemiological studies were also discussed. The possible association
of melanoma and fluorescent lighting, the cluster of cases of melanoma
among workers in high energy research laboratories, and small numbers
of cases of mycosis fungoides among machinists were discussed as examples
of possible occupational skin cancer. The author concludes that
the skin is a responsive organ for the development of cancer under experimental
conditions and a documented realistic model in an occupational setting,
and that the possibilities are expansive that other agents besides those
now documented may be positive in experimental models or significant epidemiologically.
(Shmunes, 1987)
Study #11
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studies indicate PCBs may be involved in development of malignant melanoma
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the increasing incidence of malignant melanoma may be due to the interrelation
of exposure to sunlight with chemical pollution of the environment
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a possible cause of malignant melanoma may be artificial stimulation of
melanocytes with xenobiotic substrates or an excess of natural substrate
A hypothesis that the increasing incidence of malignant melanoma is
due to the interrelation of exposure to sunlight with chemical pollution
of the environment was proposed. Three epidemiological studies of chemical
industry workers, two among Du Pont Company workers and one among employees
of the Lawrence Livermore National Laboratory, were discussed. All three
studies found a significant increase in the incidence of malignant melanoma.
The authors assert that a possible explanation for the increase in malignant
melanoma incidence is occupational exposure to chemicals. The standardized
incidence rates for melanoma in the Du Pont studies are too high to be
attributed solely to sunlight exposure. The excess melanoma incidence in
the Lawrence Livermore Laboratory subjects does not seem to be due to radiation
exposure, as no cases of acute lymphocytic or chronic myelocytic leukemia
(the types of cancer most often associated with radiation exposure) were
found. Other studies have indicated that polychlorinated-biphenyls (1336363)
(PCBs) and L-dopamine may be involved in the development of malignant
melanoma. The authors conclude that a possible cause of malignant
melanoma may be the artificial stimulation of the melanocytes with xenobiotic
substrates or an excess of a natural substrate. (Morpurgo et al, 1987)
Study #12
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excess risk for melanoma found in electrical engineers (3 deaths vs. 0.9
expected) --- [electrical equipment has frequently contained PCBs]
A survey of mortality among electrical engineers was conducted. The cohort
consisted of 1254 males who graduated from the Royal Institute of Technology
in Stockholm, Sweden, from 1930 to 1959 with a master of science degree
in electrical engineering. The cohort was followed until the end of 1979.
Death certificates were reviewed. Standardized mortality ratios (SMR) were
computed. The mortality in the cohort was compared with the expected mortality
calculated from age specific and year specific mortality rates of the general
Swedish male population. Of the 1254 subjects, 11 could not be traced.
A total of 108 subjects died during the study period. The mortality of
the electrical engineers was lower than expected. The SMR for overall mortality
was 0.9. SMR for cause specific mortality ranged from 0.2 to 1.0, except
for melanoma. The SMR for melanoma was 3.2, 3 deaths versus 0.9 expected.
The authors conclude that the low SMR for mortality in electrical engineers
is probably due in part to the healthy worker effect and is partly the
result of a less hazardous work environment and life style. Although
there were only three deaths due to melanoma, this probably represents
an excess risk. (Olin et al, 1985)
Study #13
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electrical occupations were associated with a nonsignificant increased
melanoma risk [electrical equipment has frequently contained PCBs]
A study of occupational risk factors for cutaneous melanoma among Swedish
males was conducted. The records of the Swedish Cancer Environment Registry
(CER), a registry that linked incidence data from the National Swedish
Cancer Registry for the period 1961 to 1979 with occupational data from
the 1960 national census, were searched to identify all cases of cutaneous
melanoma. Standardized cumulative incidence ratios (SIRs) were calculated
for the identified melanoma cases for employment in all major industrial
and occupational categories. There were 3,850 cutaneous melanoma cases
identified in the CER database; 49.1% of the melanomas occurred on the
trunk, 16.0% on the face, neck, or scalp, 13.1% on the legs, 9.6% on the
arms, and 12.2% occurred at multiple or unspecified sites. The risks for
melanoma for all sites combined were significantly decreased for the industrial
and occupational categories of farming, forestry, hunting, and fishing.
Small,
but significantly elevated risks were seen for workers employed in general
manufacturing industries. Moderately increased risks were observed
for employment in the beverage and tobacco industries, SIRs on the order
of 1.6. SIRs ranging up to 3.0 were observed for persons employed as chemists,
geologists, meteorologists, physicians, dentists, veterinarians, pharmacists,
teachers, lawyers, editors, chemical production workers, and in the shoe
manufacturing industry. Employment in electrical and electronics industries
and occupations, of interest because of previous associations with melanoma,
was associated with a nonsignificant increased melanoma risk. The authors
conclude that this analysis has confirmed previous associations and indicated
new associations such as employment in breweries and shoe production. (Linet
et al, 1995)
Study #14
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suggestive evidence of an increased risk of malignant melanoma due to proximity
with electrical equipment [which has frequently contained PCBs]
Health effects of living near or working with electrical generation and
transmission equipment were reviewed. Epidemiological studies of the occurrence
of cancer in individuals living near electrical transmission facilities
were reviewed. These have yielded inconsistent results. Some studies found
nonsignificant increases in leukemia mortality while others found no excess
risk. Studies of the risk of suicide in persons living near installations
transmitting electricity were discussed. Studies of the association between
leukemia and employment in the electrical power industry were reviewed.
Combining the results of 11 epidemiological studies yielded an overall
relative risk for leukemia of 1.18; however, not all studies reported a
relative risk greater than 1.0 and in only two studies was the relative
risk significant at the 5 percent level. The association was strongest
for acute myeloid leukemia. No consistent association with a given occupation
within the electrical industry was found. Studies of other cancers and
employment in the electrical industry were discussed. No consistent
results were obtained for neoplasms other than leukemia except for suggestive
evidence of an increased risk of malignant melanoma. Studies of the
effects of exposure to electrical fields on pregnancy outcome were discussed.
A Swedish study of offspring whose fathers worked in switchyards found
an excess incidence of adverse pregnancy outcomes due to an increased incidence
of congenital malformations; however, there was no consistent pattern in
the types of malformations reported. The authors conclude that the weak
association found between leukemia and employment in the electrical industry
may not necessarily reflect exposure to electromagnetic fields as the workers
are exposed to other chemical and physical agents. (Coleman et al, 1988)
Study #15
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four studies indicated elevated risks for malignant melanoma for electronics/electrical
workers and electrical engineers [electrical equipment has frequently contained
PCBs]
Epidemiologic evidence for a link between exposure to extremely low frequency
electromagnetic (ELF) fields and cancer was reviewed. Techniques for measuring
ELF fields and their limitations were described. Studies of the cancer
risk of residential ELF field exposures were reviewed. Five studies of
the relationship between childhood cancer and ELF field exposure and seven
of the relationship between adult cancer and ELF field exposure showed
strong associations for childhood brain and central nervous system (CNS)
cancer, odds ratios (ORs) above 2, and weaker associations for childhood
and adult leukemia. Wire codes were more strongly associated with an increased
cancer risk in children than direct field measurements. The association
with wire codes was dose related. Studies of occupational exposures were
reviewed. These included 12 studies examining the risk of leukemia, seven
examining the risk of brain cancer, and eight examining the risk of all
cancer types. Eleven studies examining leukemia risks found an elevated
risk in at least one electrical occupation. All studies focussed specifically
on brain or CNS cancers found a significant correlation with at least some
electrical occupations. Electronics workers, electrical engineers, and
unspecified electrical workers in four studies had ORs for gliomas, astrocytomas,
and unspecified brain tumors of 3.94 to 10.3. Three studies examining the
risk of all cancers found nonsignificant increased risks for leukemia.
Four of these found elevated risks for brain or CNS cancer. Four studies
also indicated elevated risks for malignant melanoma. The author concludes
that there is strong, but not conclusive, evidence that ELF radiation is
carcinogenic. The most consistent epidemiologic findings are increased
risks of leukemia and brain cancer among workers in electrical occupations
and increases in brain cancer in children. The evidence for an increased
brain cancer risk is the most convincing. The studies have generally used
imprecise surrogates to assess exposure. (Bates, 1991)
Study #16
Schwartzbaum JA, Setzer RW, Kupper LL. An Exploratory Analysis of the
Occupational Correlates of Large Pigmented Nevi at Lawrence Livermore National
Laboratory. Journal of Occupational Medicine, Vol. 32, No. 7, pages 605-611,
39 references, 1990
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occurrence of cutaneous malignant melanoma was 3 times the expected figure
among workers
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skin cancers were associated with engineering and electrical engineering
duties [possibly exposed to PCB contaminated machinery & electrical
equipment]
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skin cancers associated with building constructed in 1969 [with PCB paints,
caulk or sealants?]
An earlier investigation had indicated that the occurrence of cutaneous
malignant melanoma (CMM) was three times the expected figure among workers
at the Lawrence Livermore National Laboratory (LLNL). This current investigation
was the first step in determining whether the elevated CMM at LLNL resulted
from occupational induction of pigmented nevi. Data consisted of an analysis
of data collected on 110 subjects, initially designated as referents, in
a case control investigation of CMM among employees of LLNL. A total of
38 employees reported having at least one large pigmented nevus and 72
reported none. Associations with the reported presence of pigmented nevi
were demonstrated between four occupational factors: hired before 1962,
engineering duties, electrical engineering duties, and skin exposed
to rare earth metals. A weak association was also demonstrated between
working in a building constructed in 1969 and the presence of pigmented
nevi. (Schwartzbaum et al, 1990)
Study #17
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an apparent excess of malignant melanoma has been reported in workers exposed
to Aroclor 1254
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epidemiological data provide suggestive evidence of a relationship between
exposure to PCBs and the development of malignant melanoma
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case reports and epidemiological studies indicate malignant tumors occurring
after PCB exposure, including malignant melanomas
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PCBs should be regarded as carcinogenic to humans.
The carcinogenic risk to humans of polychlorinated biphenyls (PCBs) is
reviewed. Synonyms, tradenames, structures, and weights of PCBs are summarized.
Chemical and physical properties are described. Uses of PCBs are discussed,
including capacitors, transformers, hydraulic equipment, heat transfer
systems, vacuum pumps, lubricants, plasticizers, and inks. A variety of
studies of PCB occurrences and concentrations are summarized, including
occupational exposure, in air, water and sediments, food, animals, human
tissues and secretions, milk, and blood. Methods of analysis for PCBs are
described. Studies in animals show that male dd-mice, male BALB/cJ-mice,
Sherman rats, Donryu-rats, male Wistar-rats, and female Sherman-rats fed
PCBs had benign or malignant liver tumors. Other animal studies are discussed,
including toxicity studies in chickens, rats, and rabbits; immune effects
in guinea-pigs; endocrine effects in rats; distribution and secretion of
PCBs; and embryotoxicity, reproductive, and teratogenicity tests in a variety
of animals. The metabolism of PCB isomers in a variety of animals is appended.
Toxic effects of PCBs in humans are reviewed. Studies of in-utero effects
of PCB contaminated oil ingestion in humans show pigmentation of the skin
and gingiva of infants; another study indicates malformations of infants.
Five polychlorinated biphenyl mixtures have been tested in mice and/or
rats only by oral administration. Kanechlor 500 and Aroclor 1254 are carcinogenic
in mice, and Aroclor 1260 is carcinogenic in rats; all induced benign and
malignant liver-cell tumours. In an experiment in rats of only one year's
duration, Kanechlor 500, 400 and 300 induced liver lesions described as
multiple hyperplastic nodules. Human exposure to small amounts of polychlorinated
biphenyls is widespread as a result of environmental contamination and
the high stability of these compounds. They are commonly found in human
tissues. Unusually high levels of exposure to polychlorinated biphenyls
have occurred among workers manufacturing or using them and in Japanese
who consumed rice oil accidentally contaminated with Kanechlor 400. The
latter showed acute and chronic toxic effects. An apparent excess of
malignant melanoma has been reported in workers exposed to Aroclor 1254.
No melanomas were reported in 9 persons who died from cancer among the
1200 Japanese heavily exposed to Kanechlor 400, but these deaths all occurred
within 5 1/2 years of first exposure. Neither the workers exposed occupationally
nor the Japanese were exposed solely to polychlorinated biphenyls. There
is experimental evidence of a carcinogenic effect of some polychlorinated
biphenyls in rodents. The epidemiological data provide suggestive evidence
of a relationship between exposure to polychlorinated biphenyls and the
development of malignant melanoma. Efforts should be made to obtain
both confirmatory experimental and epidemiological evidence; in particular,
continuing follow-up of survivors of the Yusho episode is necessary. In
the meantime, for practical purposes, polychlorinated biphenyls should
be regarded as if they were carcinogenic to humans. Almost without exception,
polychlorinated biphenyls contain various levels of polychlorinated dibenzofurans
as contaminants, and the polychlorinated biphenyls responsible for the
Yusho episode in Japan were found to contain an unusually high level of
polychlorinated dibenzofurans. It is not known if and to what extent polychlorinated
dibenzofurans play a role in the observed carcinogenic effects of polychlorinated
biphenyls. Case reports and epidemiological studies indicate malignant
tumors occurring after PCB exposure, including malignant melanomas,
malignant neoplasms, and malignant lymphomas. The authors conclude that
polychlorinated
biphenyls should be regarded as carcinogenic to humans. (IARC, 1978)
Study #18
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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.
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several early studies showed a significant excess of all cancers
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,
1987)
Study #19
-
indoors PCB exposure may be linked to malignant melanoma, through exposure
to PCB-containing fluorescent light ballasts and other electrical appliances
PCBs are used as a dielectric fluid in "closed" electric components such
as the small capacitors used in fluorescent light installations and other
electric apparatus in offices. High PCB concentrations have been detected
close to data screen terminals, and in kitchens and laboratories. PCBs
may escape from electrical systems, especially if the temperature is high.
Indoors
PCB exposure may be linked to malignant melanoma. (Jensen, 1982)
Study #20
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Several studies of human mortality following PCB exposure were discussed
in which cancer mortality rates for exposed workers were significantly
elevated for skin melanoma
A review of human morbidity and mortality studies on the effects of polychlorinated
biphenyls (PCBs), as well as experimental animal studies, was presented.
Since PCB exposure was rarely limited to a single congener, the review
dealt with the effects of complex mixtures of PCBs, possibly containing
polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans
(PCDFs). Abnormal dermatological symptoms, such as chloracne, were considered
clinical signs of occupational exposure to PCBs. Other commonly reported
symptoms, including burning sensations in the eyes or skin and rashes,
were concurrent with exposure while chloracne persisted for years. Findings
of elevation of the liver enzymes gamma-glutamyltranspeptidase (GGTP) and
serum glutamic-oxaloacetic transaminase (SGOT), and serum triglycerides
and cholesterol levels were cited. The elevation of diastolic blood pressure
with increased serum PCB levels in the general population was discussed.
Studies of infants born to PCB exposed mothers showed lower birth weights,
psychomotor development and poorer short term memory. Chronic animal studies
using PCBs uncontaminated with PCDFs were described, demonstrating the
production of precancerous lesions. The incidence of the lesions was directly
related to the degree of PCB chlorination. Studies in rats and mice found
hepatocellular carcinomas produced by exposure to Aroclor-1260 (11096825),
Aroclor-1254 (11097691) and Kanechlor-500 (37317412). Significant increases
in lymphomas and leukemias with PCB exposure were also reported. Based
on the presented evidence, PCBs were considered animal carcinogens, acting
as promoting agents. The ability of PCBs to alter the metabolism of other
carcinogens was discussed. Several studies of human mortality following
PCB exposure were discussed in which cancer mortality rates for exposed
workers were significantly elevated for cancers of the liver, biliary
tract and gallbladder, and for skin melanoma. (Nicholson et al,
1994)
Study #21
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workers heavily exposed to PCBs experience an excess of malignant melanomas
Health hazards associated with the production and industrial use of polychlorinated
biphenyls (PCB) are reviewed. Production techniques used in the preparation
of PCB mixtures and the sources of production are described. Main properties
of PCB that account for its widespread industrial use are identified. PCBs
are absorbed into worker metabolism primarily through cutaneous, respiratory,
or digestive exposures. PCB carcinogenicity is demonstrated in animal experiments.
Excess incidence of malignant tumors in Japanese accidently exposed during
consumption of rice oil contaminated with PCB during manufacture is discussed.
Workers
heavily exposed to PCBs experience an excess of malignant melanomas
and pancreas neoplasias. Exposed workers have relatively high PCB residue
concentrations ranging from several tens to several hundred parts per billion
(ppb). Workers involved with the assembly of capacitors and transformers
have PCB plasma concentrations ranging from 10 to 2,500ppb with concentration
increasing with longer duration of exposure. Plasma PCB concentrations
decrease relatively fast in workers exposed to short periods and very slowly
in workers exposed 10 years or longer and in those exposed to highly chlorinated
PCB mixtures. Digestive, upper respiratory, neurological, and other symptoms
of exposed workers are described. Safety and health protection methods
are discussed and inspection and monitoring techniques available to maintain
PCB concentrations within approved concentrations are described. A need
for periodic clinical examination of workers is stressed and specific medical
tests and treatments are discussed. (Wassermann et al, 1983)
Study #22
-
tumors in patients who inadvertently consumed PCBs in 1968 have included
one or more occurrences of malignant melanomas
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 #23
-
animal experiments and human studies have identified a wide variety of
chemicals which are associated with malignant melanoma, including PCBs
-
animal studies indicate that estrogens and estrogen progesterone combinations
cause an increase in melanocyte count and melanin content (which may increase
skin cancers) --- (certain PCBs are estrogen-mimics)
This review focuses on recognized nonsunlight risks for malignant melanoma
(MM) including occupational and environmental exposure to a variety of
chemical agents and physical conditions. Animal experiments and human
studies have identified a wide variety of chemicals which are associated
with MM. Specific chemicals include polycyclic aromatic hydrocarbons
(PAHs), cutting oils, vinyl-chloride (75014) monomers, polyvinyl-chloride
(9002862) (PVC), polychlorinated biphenyls (PCBs), hydrocarbon solvents,
asbestos (1332214), metals, and pharmaceuticals. Oil refinery workers are
frequently exposed to effluent streams rich in PAHs, including 7,12-dimethylbenz(a)anthracene
(57976). Machinists use cutting oils as a metal working cleanser, lubricant,
or coolant, many containing strongly carcinogenic PAHs such as benzo(a)pyrene
(50328). PVC is widely used to manufacture plastics and other synthetic
products. PCBs are present as contaminants in certain water supply
systems and are widely used in industry in the manufacture of capacitors,
transformers, fluid systems, fire retardants, plasticizers, adhesives,
electrical components, and food packaging materials. Occupational exposure
to asbestos occurs among asbestos miners and millers, textile production
workers, shipbuilders, insulators, and among automotive and petrochemical
workers. Chronic ingestion of arsenic (7440382) polluted water is a well
recognized cause of nonmelanoma skin cancer and may also contribute to
the development of MM. Animal studies have indicated that estrogens
and estrogen progesterone combinations cause an increase in melanocyte
count and melanin content. Strong evidence supports a relationship
between MM and exposure to ultraviolet radiation. Ultraviolet radiation
occurs not only from exposure to the sun but also from fluorescent lighting,
sunbeds/sunlamps, cinema projectors, insecticidal/germicidal lamps, welding
arcs, industrial printers/photocopiers, vacuum/discharge lamps, spotlighting,
and artillery photography. Various forms of trauma probably can also contribute
to the development of MM. Cases of MM originating in burn and cryocoagulation
scars have been reported. (Rockley et al, 1994)
Study #24
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PCBs are a suspected cause of malignant melanoma
This letter briefly reviews suspected causes of malignant melanoma.
Industrial chemicals that have been suggested include arsenic, polychlorinated
biphenyls, alcohol and |-chloroacetophenone. Recent studies of an increased
incidence at plants producing polyvinyl chloride and asbestos products
are reported. The question of the mechanism of action is discussed: inhaled
vinyl chloride monomer migrates to the subcutaneous layers of the skin
after a short time. Transcutaneous penetration of asbestos fibres is a
possibility. (Hilt et al, 1983)
Study #25
-
studies of workers exposed to PCBs have reported excess mortality from
skin cancer (specifically malignant melanoma);
Epidemiologic evidence on the relationship between selected industries
and cancer is reviewed. This article will focus on several industries which
have not been covered elsewhere in this volume, briefly describe current
research on cancer in the agricultural and construction industries, and
discuss surveillance data on cancer mortality in relation to industry listed
on US death certificates. Employment in the rubber industry has been associated
with bladder cancer, leukemia, stomach, and lung cancer and is considered
by the International Agency for Research on Cancer (IARC) to have 'sufficient
evidence of carcinogenicity in humans.' Studies of workers exposed to
polychlorinated biphenyls (PCBs) have reported excess mortality from
gastrointestinal neoplasms, hematologic neoplasms, and skin cancer (specifically
malignant melanoma); IARC considers that the evidence for carcinogenicity
in humans is 'limited.' Employment in the boot and shoe industry has been
associated with nasal adenocarcinomas in England and Italy ('sufficient').
Hairdressers and barbers have been found to have excess bladder cancer
and less consistent evidence for several other sites ('limited'). Workers
exposed to wood dust have excess mortality from cancer of the nasal sinuses
and paranasal cavities; there is less consistent evidence for excess laryngeal
cancer ('sufficient'). Workers employed in the petroleum industry have
limited evidence for excess leukemia and other lymphatic and hematopoietic
neoplasms, and skin cancer (particularly malignant melanoma) ('limited').
(Ward et al, 1997)
Study #26
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primate studies may have included research on the relationship of PCBs
and melanoma
Research data from the 7 regional primate centers established under the
auspices of the National Institutes of Health (USA) are presented. Melanoma,
leukemia and borreliosis are studied. Behavioral and physiological effects
upon primates of such substances as tetrahydrocannibinol, corticosteroids
(triamcinolone) and polychlorinated biphenyl are examined. Other
studies concern primate response to vasectomy, cold and exposure to ozone.
External signs of maximum fertility in rhesus monkeys and function of fetal
steroid hormones in sexual differentiation are covered. Photographs, micrographs,
graphs, tables and index supplement the text. Papers in this book originally
appeared in Federation Proceedings 34(8): July 1975. (Goodwin et al, 1975)
Study #27
-
PCBs did not promote skin tumors in mice at the doses tested, using surface
skin application
The tumor promoting abilities of butylated-hydroxy-toluene (128370) (BHT),
butylated-hydroxy-anisole (25013165) (BHA), Aroclor-1254 (11097691)
(PCB), Firemaster-6 (59536651) (PBB), and 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD) were evaluated in a mouse skin tumorigenicity assay. Preshaven
female CD-1-mice were initiated with 0 or 200 nanomoles 7,12-dimethylbenz(a)anthracene
(DMBA). One week later 100 micrograms (microg) PCB, 1 milligram (mg) BHA,
1mg BHT, or 0.01microg TCDD were applied to the skin twice weekly for 30
weeks. 12-O-Tetradecanoylphorbol-13-acetate (TPA) applied at the rate of
2microg or weekly at 10microg was used as a positive control. TPA alone
increased the interfollicular epidermis from one to four layers. BHA, BHT,
PCB, and PBB had no effect. DMBA and TPA produced an average of 8.1 papillomas/mouse.
TPA alone produced only 0.03 papilloma/mouse. BHT produced 0.06 papilloma/mouse
after 30 weeks following DMBA initiation. None of the other compounds produced
any skin tumors either with or without DMBA initiation. TCDD produced skin
rashes. The authors conclude that BHA, BHT, PCB, PBB, and TCDD do
not promote skin tumors at the doses tested. Concentration may be an
important factor since several of the tested compounds are known to promote
tumors in other tissues. (Berry et al, 1978)
Study #28
-
evidence suggests that certain associated process streams in the production
of petroleum products produce skin cancer (PCBs are a petroleum product)
Lubricant base oils are petroleum products that are predominantly derived
from the vacuum distillation of crude oil. Various types of refinement
can be employed during the manufacturing process, and evidence suggests
that certain of the associated process streams produce skin cancer.
Polycyclic aromatic compounds (PACs), some of which are considered as the
causative agents, are removed, concentrated or chemically converted during
the refinement process. In order to understand the effects of various types
of refinement processes on carcinogenic potential, 94 oils were evaluated
in the mouse epidermal cancer bioassay. This Exxon database is unique,
because of the wide range of crude oils and processing histories represented.
Seven processing history classifications are described, and conclusions
concerning the impacts of each refinement process on dermal carcinogenicity
are discussed. This research also included an evaluation of selected biological
and chemical test methods for predicting carcinogenic potential. These
included a modified version of the Ames test for mutagenicity, as well
as analytical characterizations of the polycyclic aromatic structures
in the oils. For classification purposes, a sample was considered to be
carcinogenic if it resulted in the production of two or more tumor-bearing
animals (in test groups of either 40 or 50 animals). The modified Ames
test was considered to be positive if the mutagenicity index was > or =
2.0, and PAC analyses were similarly designated as positive or negative
according to proposed guidelines. All of the alternative test methods showed
similar agreement with dermal carcinogenicity bioassay data; concordance
values were > or = 80%. However, each test was incorrect in ca. 10%-20%
of the cases evaluated. (Incomplete abstract) (Chasey et al, 1994)
Study #29
-
the relationship between occupational exposure to PCBs and the occurrence
of chloracne was outlined, and the correlation between dermal availability
and the occurrence of epidermal tumors was described
The relationships between percutaneous absorption and toxicity were reviewed
with emphasis on the properties of the skin, principles of percutaneous
absorption, and chemicals frequently involved in dermatotoxicology and
their percutaneous absorption features. In both man and animals, percutaneous
absorption has been shown to depend on the anatomic site to which a given
agent was applied. It increased when the site of application was occluded.
Hydration of the skin increased the penetration of hydrosoluble nonpolar
products, but had little effect on the absorption of polar molecules. The
skin was found to metabolize topically applied agents before they became
systematically available, but unmetabolized products were also able to
penetrate the skin barrier; accordingly, some chemicals were more toxic
when applied topically than when taken orally. The cutaneous metabolic
production of carcinogens and the use of animal models of dermal toxicity
to make predictions of human health were reviewed and percutaneous absorption
in the newborn was examined. The relationship between occupational exposure
to polychlorinated-biphenyls (1336363) and the occurrence of chloracne
was outlined, and the correlation between dermal availability and the occurrence
of epidermal tumors was described. Finally, the potential toxicity
of cosmetic chemicals was evaluated. (Wester et al, 1985)
Study #30
-
study examined skin absorption of PCBs, toxicity and the relationship between
the dermal bioavailability of hydrocortisone and the incidence of epidermal
tumors (results not included)
The percutaneous absorption of industrial solvents was reviewed with regard
to the mechanisms, parameters, and clinical representation of percutaneous
absorption in humans. The advantages and limitations of determining absorption
by the in-vitro diffusion cell method and the in-vivo analysis of biologic
fluids and tissues were compared. The in-vitro method was preferred for
the comparison of the relative absorption of many compounds or the relative
absorption of one compound under varied conditions. In-vitro prediction
of in-vivo absorption was not demonstrated. In-vivo studies in humans were
determined most sensitive for assessing the specific absorption of an agent
in man. Comparative studies of percutaneous absorption using monkeys, rabbits,
rats, swine, and man indicated that percutaneous absorption rates in the
pig and rhesus-monkey were similar to man whereas the absorption rates
for rabbit and rat were significantly greater than man. The parameters
affecting percutaneous absorption were the dose concentration and the surface
area exposed, the skin location of application, occlusion, the skin condition,
the vehicle and the use of multiple doses, and metabolism. The analysis
of percutaneous absorption in determination of the toxicity of polychlorinated-biphenyls
and the relationship between the dermal bioavailability of hydrocortisone
and the incidence of epidermal tumors were included in the discussion.
Study #31
-
clear dose-dependent skin mutagenic activity was determined in the presence
of PCB-induced rat liver homogenates [PCB-induced enzymes converted wood
dust into a skin carcinogen]
A mutagenic fraction of beech wood was tested on the skin of young
female NMRI-mice in a lifetime carcinogenicity assay. Beech wood saw dust
fractions were prepared by extraction with methanol, and purification by
silica gel column chromatography to eliminated inhibitory compounds. A
clear dose dependent mutagenic activity was determined with the ethylacetate
phase of the extract in-vitro using Salmonella-typhimurium (TA-100) in
the presence of Aroclor induced rat liver homogenates. Mice were treated
twice a week with the extract on the shaved skin of the back for 3 months;
mice were observed until death. The mutagenic fraction dose dependently
induced
tumors on the site of application. The depth of penetration and the
induction of tumors and precancerous skin lesions by the test fraction
often involved both cutis and subcutis as well as the mammary glands just
beneath the skin. Tumors (56 percent malignant and 44 percent benign) were
of different types including squamous cell carcinoma, sebaceous gland adenoma,
squamous cell papilloma, adenocarcinoma of the mammary gland, keratoacanthoma,
papillary cystadenoma, hemangiosarcoma, neurofibrosarcoma, anaplastic carcinoma,
fibrosarcoma, lymphoma, and mixed tumors of the mammary gland. Of a total
of 34 tumors occurring among the treated animals, 21 were skin tumors,
12 originated from the mammary glands beneath the site of application and
one was a lymphoma. While no differences could be seen among the total
number of tumors at the three high doses, the difference between tumorigenic
activity of the lowest and next higher doses was statistically significant.
The authors conclude that since various types of tumors were formed, the
effects may be due to different carcinogenic substances, rather than to
a single compound, present in the wood dust extract. (Mohtashamipur et
al, 1989)
Study #32
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in Europe, cancers certified as occupational cancers are skin cancer caused
by occupational exposure to carcinogens [including PCBs]
The countries of central Europe, including Poland, the Czech Republic,
Slovakia, Hungary, Romania, and Bulgaria, suffer from environmental and
occupational health problems created during the political system in place
until the late 1980s. This situation is reflected by data on workplace
exposure to hazardous agents. Such data have been systematically collected
in Slovakia and the Czech Republic since 1977. The data presented describe
mainly the situation in the early 1990s. The number of workers employees;
2.2% were exposed to the suspected carcinogens [including PCBs].
The incidence of all certified occupational diseases in the Slovak Republic
was 53 per 100,000 insured employees in 1992. Cancers certified as occupational
cancers are skin cancer caused by occupational exposure to carcinogens,
lung cancer caused by ionizing radiation, and asbestosis together with
lung cancer. Specific information on occupational cancers from Romania
and Bulgaria was not available for this paper. It is difficult to predict
a trend for future incidences of occupational cancer. Improved control
technology, governmental regulatory activity to reduce exposure, surveillance
of diseases and risk factors, and vigilant use of preventive measures should,
however, ultimately reduce occupational cancer. (Fabianova et al, 1999)
Study #33
-
PCB commercial mixes, Aroclor 1016 and 1254, did not have any effect on
epidermal ODC activity and skin tumor development in mice, after skin application
-
Aroclor 1242 provided a small synergistic effect on the induction of epidermal
ODC activity
Aroclors are commercial preparations of polychlorinated biphenyls (PCBs)
which are potentially carcinogenic. Skin is a recognized target organ for
several effects of PCBs. In this investigation, the effect of Aroclor 1242,
1016, and 1254 on skin tumor development and epidermal ornithine decarboxylase
(ODC) activity was studied in mice. Aroclor 1242 treatment caused a slight
induction of epidermal ODC activity. Treatment with a suboptimal concentration
(2.5 nmole) of 12-0-tetradecanoyl phorbol-13-acetate (TPA) and Aroclor
1242 provided a small synergistic effect on the induction of epidermal
ODC activity. Aroclor 1242 did not cause skin tumor development in
7,12-dimethylbenz(a)anthracene-initiated mice. Aroclor 1242 treatment with
TPA resulted in a decrease in skin tumor development. Aroclor 1016 and
1254 do not have any effect on epidermal ODC activity and skin tumor development.
(Dwivedi et al, 1998)
Study #34
-
PCB increased aryl-hydrocarbon-hydroxylase (AHH) activity in mouse and
rat skin
-
PCB increased total BaP metabolite (a procarcinogen) formation in mouse
and rat skin
-
PCB increased total phenols in mouse and rat skin
-
different genetic strains of mice responded differently to PCBs
Benzo(a)pyrene (50328) (BaP) metabolism in skin microsomes were studied
in rodents differing in inducibility of cutaneous enzyme activity. The
backs of female C57BL/6N-mice responsive to aryl-hydrocarbon-hydroxylase
(AHH) induction, female DBA/2N-mice not AHH responsive, and tumor resistant
neonatal Sprague-Dawley-rats were painted with 100 milligrams per kilogram
of the polychlorinated biphenyl (PCB) Aroclor-1254 (11097691) or the polycyclic
aromatic hydrocarbon 3-methylcholanthrene (56495) (3-MC) in acetone or
acetone only. Animals were sacrificed after 24 hours, and skin microsomes
were obtained and incubated with BaP. AHH activity and formation of
BaP metabolites were determined. Compared to controls, PCB increased
AHH activity 16 to 18 times in C57-mice and rats, but only 2 times in DBA-mice,
while 3-MC increased activity 1.6 to 4 times in mice and 11 times in rats.
Total BaP metabolites in control DBA-mice were double those in other controls.
PCB
increased total BaP metabolite formation 10 to 12 times in C57-mice and
rats and 3 times in DBA-mice, while 3-MC increased total metabolites
4 to 8 times in C57-mice and rats but did not affect DBA-mice. In C57-mice
and rats, total phenols and the procarcinogen benzo(a)pyrene-7,8-diol
(57303998) were increased 11 to 20 and 10 to 12 times, respectively, by
PCB, and 7 to 8 and 4 to 7 times by 3-MC; values in DBA-mice ranged
from 0.8 to 2.5 times control. The authors conclude that enzyme activities
of skin microsomes and the quantity of BaP metabolites formed are not reliable
indicators of skin tumor susceptibility to BaP. (Bickers et al, 1983)
Study #35
-
PCB-induced liver enzymes metabolized certain PAH’s into more carcinogenic
chemicals
The tumor-initiating activity of several polymethylated phenanthrenes was
determined in mouse skin. Among the compounds assayed were 1,4-, 1,9-,
2,7-, 3,6-, 4,5-, 4,9- and 4,10-dimethylphenanthrene. Only the 1,4- and
4,10-dimethylphenanthrenes were active as tumor initiators. Initiating
doses of 300 mug and 1.0 mg of 1,4-dimethylphenanthrene after promotion
with tetradecanoylphorbol acetate induced 80 and 100% incidences of skin
tumors in mice, respectively. 4,10-Dimethylphenanthrene assayed under identical
conditions induced skin tumors in 35 and 55% of the mice. The in vitro
metabolism of 1,4-, 3,6-, 4,9- and 4,10-dimethylphenanthrene was studied
by incubation of the compounds with 9000 from livers of Aroclor-pretreated
rats. The major dihydrodiol metabolite of both 1,4- and 4,10-dimethylphenanthrene
was the 7,8-dihydrodiol, the requisite precursor for the formation of bay-region
dihydrodiol-epoxides. Dihydrodiols were not observed among the metabolites
of 4,9-dimethylphenanthrene. In the case of 3,6-dimethylphenanthrene, the
major diol metaboite formed in vitro was the 9,10-dihydrodiol. These
results support previously proposed structural requirements which favor
the carcinogenic activity of methylated polynuclear aromatic hydrocarbons.
These studies indicate that tumorigenic activity of methylated phenanthrenes
requires inhibition of dihydrodiol formation at the K-region (9,10-positions)
in addition to a bay-region methyl group and a free peri position, both
adjacent to an unsubstituted angular ring. (Lavoie et al, 1982)
Study #36
-
PCBs were used for enzyme activation, which was then blocked by curcumin
(which inhibited skin cancer)
Curcumin I (Cur 1) and curcumin III (Cur III) are the yellow coloring phenolic
compounds isolated from the spice turmeric. The effect of curcumins on
different stages of develop of cancer was studied. Cur I inhibited benzopyrene-
(BP) induced fore-stomach tumors in female swiss mice, and Cur III inhibited
Dimethylbenzanthracene-(DMBA) induced skin tumors in swiss bald mice. Cur
I also inhibited DMBA-initiated tetradeconyl phorbol acetate-promoted skin
tumors in female swiss mice. In vitro 3H-BP-DNA interaction studies, and
in
vivo carcinogen metabolizing enzyme studies revealed that curcumins exert
anti-carcinogenic activity by altering the activation and/or detoxification
process of carcinogen metabolism. Cur I and Cur III also exhibit in
vitro cytotoxicity against human chronic myeloid leukemia, which s dose
dependent. This study shows that curcumins inhibit cancer at initiation,
promotion and progression stages of development. [Aroclor 1254 PCBs
were used for enzyme activation, which was then blocked by curcumin.]
(Nagabhushan et al, 1992)
Study #37
-
certain PCBs did not induce skin tumors in mice after dermal application.
There is inadequate evidence that PCBs are carcinogenic to humans; PCBs
are carcinogenic to animals. Aroclor 1254 produced GGT-ase positive foci
in partially hepatectomized rats after i.p. application. TCB or TCBO
did not induce papillomas in mice after dermal application. Aroclor
1260 induced hepatocellular neoplasms in rats after oral application. This
group of compounds is well investigated, but the evidence of a carcinogenic
effect is insufficient to classify this group as probably carcinogenic
to humans. This group is classified as a suspect carcinogen group. (Dutch
Experts, 1995)
Study #38
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two fractions of white snakeroot were metabolically activated to toxic
agents by PCBs in skin cancer cell cultures
Components of white snakeroot, a plant toxic to livestock and human beings,
were activated by Aroclor 1254-induced rat liver microsomes. The toxic
products of microsomal activation were evaluated in murine melanoma
(B16F1) cell cultures. Toxic products in white snakeroot were inactive
in cell culture systems without microsomal activation. This activation
system revealed that at least 2 fractions of white snakeroot were metabolically
activated to cytotoxic agents. The autocatalytic inactivator of cytochrome
P-450, 1-aminobenzotriazole, inhibited activation of white snakeroot constituents
by rat liver microsomes. (Beier et al, 1987)
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