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PCB Studies Involving the Liver
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to PCBs and Liver Damage Table of Contents
The following is a sampling of research articles related
to PCB effects on liver function. For more examples, visit TOXNET,
an online database maintained by the National Library of Medicine, the
source of these abstracts.
Study #1
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PCBs induce microsomal liver enzymes
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such induction may lead to hepatogenic porphyria and increased
degradation of endogenous steroids in the liver
The effects of long-term exposure to low levels of chlorinated
hydrocarbons in birds and laboratory animals are reviewed, with particular
reference to their implications for man. In contrast to the results of
acute overexposure, these effects are difficult to recognize and combat
in time. The induction of microsomal liver enzymes by the chlorinated hydrocarbons
has sometimes been viewed as an advantageous adaptive process. However,
this interpretation is opposed by the observations of hepatogenic porphyria
and increased degradation of endogenous steroids in the liver noted
after such induction, particularly involving the mixed function oxidase
system. More detailed studies on the porphyrogenic properties of the polychlorinated
biphenyls revealed the presence of traces of polychlorobenzofurans in the
commercial preparations. The latter are undergoing continued investigation
in connection with their extreme persistence and suspected heptatoxicity.
(Dutch,1971)
Study #2
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PCBs are considered prototypes of workplace chemicals causing
liver toxicity
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liver sensitivity should warn physicians that other organs
may also be affected
The hepatotoxic effects of occupational exposure to
chemicals are reviewed. Workplace chemicals that have produced hepatic
effects in animals or humans are listed. The process of metabolism of chemicals
in the liver and the hepatic processes are described. Hepatic responses
range from fatty infiltration to cell death and necrosis; from metabolic
changes, such as proliferation of the smooth endoplasmic reticulum, to
porphyrias; from infiltration of granulomas to cirrhosis; from vascular
lesions of peliosis hepatitis to angiosarcoma; and from parenchymal cell
adaptation to neoplasia. Hepatic effects of carbon-tetrachloride (56235),
vinyl-chloride (75014), and polychlorinated biphenyls are presented
as the prototypes of a number of other compounds. Occupations are listed
in which workers may be exposed to xylene (1330207). Some important industrial
chemicals, their use in the workplace, and the hepatic responses in humans
are noted. The clinical sequence of acute carbon-tetrachloride poisoning
is illustrated over a 21 day period. The sequence begins with dizziness,
headache, and confusion. This is followed by gastrointestinal pain, nausea
and vomiting, and diarrhea; then, necrosis, jaundice, and coma occur, resulting
in hepatic death. After this, renal death, pulmonary edema and cardiac
failure occur. Exposure to vinyl-chloride is associated with multiple systemic
diseases, including acroosteolysis, thrombocytopenia, and liver damage.
The general molecular structure of polychlorinated biphenyls is illustrated,
and various chlorine substituents are represented. The author concludes
that hepatotoxicity may be only one facet of adverse effects. Liver
sensitivity should warn physicians that other organs may also be affected.
(Pond, 1982)
Study #3
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PCBs cause hepatomegaly (enlarged liver), liver hemorrhage,
porphyria and liver damage
Environmental contamination by polychlorinated biphenyls
(PCBs) was reviewed. Topics included fundamental terminology, production
and application, characterization of mixtures and related compounds, pollution
aspects, dose effects, and analytical methods. Emphasis was placed on environmental
pollution from the perspective of the analytical chemist. The distribution
of PCB congeners in environmental samples was discussed using the occurrence
of the components of aroclor-1260 (11096825) in human milk and birds eggs
as examples. Time trends of environmental PCB contamination were considered.
Laboratory animal studies indicated that PCBs cause: body weight loss,
chloracne, hepatomegaly, liver hemorrhage, porphyria,
and bile duct, gall bladder, urinary tract,
endocrine system, and reproductive system dysfunction, teratogenesis, and
carcinogenesis. Liver damage, dermal lesions, respiratory system
disorders, eye problems, immunodeficiency, and reproductive system dysfunction
were typical sequelae of human PCB poisoning. Chloracne was the most common
manifestation of occupational exposure. Definite evidence of human PCB
carcinogenicity was not presented. Diagnostic difficulties were associated
with contamination with polychlorinated dibenzo-p-dioxins and dibenzofurans.
The biochemical effects of PCBs were discussed with respect to coplanar
and noncoplanar PCBs. Benefits and drawbacks of chromatographic and spectrometric
analyses were considered. Other procedures were also discussed. (Lang,
1992)
Study #4
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the liver is the major target organ for PCBs
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PCBs produce porphyria
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the liver is the primary target of PCB carcinogenicity
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occupational PCB exposure is associated with subclinical
alterations in serum enzymes suggestive of liver enzyme induction and possible
hepatocellular damage
Aroclors appear to have a low order of acute lethality. Data
for non- Aroclor PCB mixtures and specific PCB isomers suggest that mice
and guinea pigs are more sensitive than rats. Aroclors are lethal at much
lower total doses when administered subchronically or chronically than
acutely, indicating that PCBs bioaccumulate to concentrations that are
toxic. Animal studies have shown that the liver and cutaneous tissues
are the major target organs for Aroclors. Aroclors have also been
shown to produce stomach and thyroid alterations, immunosuppressive effects,
and porphyria in animals. Animals are sensitive to repeated exposures
to Aroclors as a result of rapid bioaccumulation to toxic levels. Monkeys
are particularly sensitive to the toxic effects of Aroclors. Toxic effects
have not been documented in humans who were exposed to Aroclors via the
environment. Occupational exposure to Aroclors has been associated with
reversible skin lesions and subclinical alterations in serum enzymes
that are suggestive of liver enzyme induction and possible hepatocellular
damage. More serious health effects were observed in humans who consumed
rice oil that had been contaminated with Kaneclors in Japan ("Yusho" incident)
and Taiwan ("Yu Cheng" incident). Aroclors appear to be fetotoxic but not
teratogenic in various species of animals, including rats, mice, rabbits,
and monkeys, but the possibility that contaminants (e.g. PCDFs) may be
responsible for the effects should be recognized. Slight decreases in birth
weight, gestational age, and/or neonatal behavioral performance have been
reported in infants born to mothers who had environmental or occupational
exposure to PCBs. These effects are inconclusive and not definitely attributable
to PCBs. Oral exposure to Aroclors produced deleterious effects on reproduction
in monkeys, mink, and, at higher doses, rodents. PCBs have produced generally
negative results in vitro and in vivo mutagenic assays. Feeding studies
in laboratory animals demonstrated the carcinogenicity of several PCB mixtures,
but it is not clear which components of the mixture or metabolites are
actually carcinogenic. The liver is the primary target of PCB carcinogenicity.
(Shortened) (ATSDR, 1989)
Study #5
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PCBs have been responsible for porphyria outbreaks in Turkey
and Japan
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PCBs stimulate drug metabolism and heme synthesis within
1 week of treatment
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PCBs cause hepatic porphyria, weight loss, tremor, liver
damage and increased mortality
Species differences in experimental porphyria caused by polyhalogenated
aromatic compounds are discussed. Some of the compounds that cause porphyria
are considered to be environmental contaminants. Hexachlorobenzene (118741)
and polychlorinated-biphenyls (1336363) (PCBs) have been responsible
for outbreaks of porphyria in Turkey and Japan. Stimulation of drug
metabolism and heme synthesis has occurred in different species within
1 week of treatment by PCBs. Exposures longer than 1 week cause hepatic
porphyria in mammals such as man, rats, and rabbits. This porphyria is
characterized by porphyrinic compounds accumulating in the liver, kidney,
and other organs. Mammals suffer loss of weight, liver damage and increased
mortality. Human porphyria is also known in cases of alcoholism. Intoxication
by hexachlorobenzene, PCBs, and hexabromobenzene (87821) has caused porphyria,
loss of weight, tremor, and increased mortality in Japanese-quail and chicken.
In the case of birds and mammals, porphyria development due to PCB intoxication
is correlated with loss of weight. The porphyria develops as a consequence
of liver damage. Species differences in experimental porphyria caused by
polyhalogenated aromatic compounds are attributed to differences within
and between species, the physiological state of the animal, route of administration,
age, and feeding schedule. (Strik, 1973)
Study #6
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PCBs cause increased accumulation of porphyrins, which causes
hepatic porphyria in different species
The porphyrinogenic action of polyhalogenated aromatic compounds
was investigated with special reference to porphyria and environmental
concerns. Various polyhalogenated aromatic compounds and polyhalogenated
aliphatic compounds which have been involved in human poisons are listed,
including polychlorinated biphenyls, polybrominated biphenyls, chlorodibenzodioxins,
vinyl chloride, hexachlorobenzene, and octachlorostyrene. A brief list
is given of the effects of chronic exposure to various compounds. Such
exposure to polyhalogenated aromatic compounds causes hepatic porphyria
in different species. Increased accumulation of porphyrins caused by
polyhalogenated aromatics compounds causes hepatic porphyria in different
species. Increased accumulation of porphyrins caused by polyhalogenated
aromatics is not related to an increase in delta-aminolevulinic acid synthetase
in the liver. Results of various studies on the effects of exposure to
such compounds on the appearance of hepatic porphyria are briefly listed.
(Strik, 1978)
Study #7
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PCBs cause chronic hepatic porphyria
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qualitative changes in urinary porphyrins such as increases
in uroporphyrin and heptacarboxylic-porphyrin, have been noted in PCB exposed
workers
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urinary excretion of porphyrins can be one indicator of PCB
exposure
Urinary excretion of porphyrins as an indicator of exposure
to chlorinated hydrocarbons was discussed. Topics included the uses and
toxicological properties of chlorinated hydrocarbons, chemical porphyria,
and urinary excretion of porphyrins. Chronic hepatic porphyria in
humans is a disorder of hepatic porphyrin metabolism that can be inherited
as a congenital anomaly or be caused by exposure to chemicals such as vinyl-chloride
(75014), hexachlorobenzene (118741), polybrominated biphenyls (PBBs), polychlorinated-biphenyls
(1336363) (PCBs), 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) (TCDD),
chlorinated naphthalenes, and some organophosphorus and organochlorine
pesticides. The mechanism of chemical induced porphyria involves inhibiting
uroporphyrinogen-decarboxylase, an enzyme in the heme biosynthetic pathway.
This results in an excess of uroporphyrin and heptacarboxylic-porphyrin
accumulating and being excreted in the urine. Studies in PBB, PCB, and
TCDD exposed workers have not shown any excess excretion of urinary porphyrins.
The normal excretion of total porphyrin appears to be 200 micrograms per
liter. Qualitative changes in urinary porphyrins such as increases in
uroporphyrin and heptacarboxylic-porphyrin, however, have been noted in
workers exposed to PCBs and TCDD. The author concludes that qualitative
changes in the pattern of porphyrin excretion may reflect early changes
in heme synthesis and may be useful in evaluating exposure to porphyrinogenic
chemicals. (Strik, 1987)
Study #8
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PCB caused porphyria, characterized by delayed development,
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PCBs caused increased excretion of urinary uroporphyrins
and accumulation of carboxyporphyrins in the liver
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PCBs increased drug-metabolizing capacity of the liver.
Aroclor 1254, which consists of a mixture of polychlorinated
biphenyls (PCBs) containing 54% chlorine, produced an experimental hepatic
porphyria in rats resembling hexachlorobenzene poisoning and human porphyria
cutanea tarda. The PCB-induced porphyria is characterized by delayed development,
increased excretion of urinary uroporphyrins, accumulation of 8- and 7-carboxyporphyrins
in the liver and increased drug-metabolizing capacity of the liver. Cytochrome
P-450 and microsomal heme were increased maximally at 1 wk, in the absence
of an increase in the rate-limited enzyme in heme synthesis, -aminolevulinic
acid (ALA) synthetase. Induction of ALA synthetase and porphyria occurred
later, after 2-7 mo. exposure to PCB. No induction of ALA synthetase could
be demonstrated prior to the onset of porphyria. Market induction of ALA
synthetase occurred 5 h after large single doses of Aroclor 1254; however,
the doses required were larger than those used to produce porphyria when
administered chronically, and induction appeared to be related to the marked
increased in cytochrome P-450 seen 24 h after administration of the drug.
(Goldstein et al, 1974)
Study #9
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PCBs caused increased liver weight and porphyria
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PCBs increased all drug metabolizing pathways tested
Aroclor 1242 and Aroclor 1016 are polychlorinated biphenyl
(PCB) mixtures with similar chlorine content (42 vs. 41%), but Aroclor
1242 contains 9% biphenyl homologs with 5 or more chlorines while Aroclor
1016 contains only 1%. The effects of Aroclor 1242 and Aroclor 1016 on
induction of hepatic porphyria and drug metabolizing enzymes were compared
in female rats fed 100 ppm or 500 ppm of each. At 1 week Aroclor 1242 markedly
increased
liver weight and all drug metabolizing pathways tested including
cytochrome P-450, N-demethylase, nitroreductase, aniline hydroxylase and
glucuronyl transferase, while Aroclor 1016 produced only very minimal effects.
At 6 mo. 500 ppm of either Aroclor markedly increased drug metabolism,
while at the lower dose, Aroclor 1016 was much less effective than Aroclor
1242. Both doses of Aroclor 1242 produced porphyria, but only the higher
dose of Aroclor 1016 was porphyrogenic. The porphyria occurred after a
lag of 1-6 mo. and was characterized by excretion and hepatic storage of
uroporphyrins. Aroclor tissue concentrations were similar in rats fed equal
doses of 2 mixtures. The marked differences in the biological effects of
Aroclor 1016 and Aroclor 1242 cannot be explained by differences in absorption,
metabolism or excretion. (Goldstein, et al, 1975)
Study #10
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liver enlargement is observed that may progress to liver
damage
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neoplastic liver nodules and hepatocellular carcinomas (liver
cancer)
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porphyria, immunosuppression, and interference with steroid
metabolism, which may be due to increases in microsomal enzyme activity
associated with liver enlargement
Excerpt: Experimental studies on the effects of PCBs and
PCTs: Most of the studies on the toxicity of PCBs have been performed with
the commercial mixtures. The PCBs are of low acute toxicity but the effects
are cumulative with prolonged administration; in mammals, liver enlargement
is observed that may progress to liver damage. Non-metastasizing neoplastic
liver nodules have been produced in rats and mice, some of which were
classified as hepatocellular carcinomas on the basis of histological
criteria in one study in rats and one study in mice. The monkey is much
more sensitive to PCBs than the rat, showing effects similar to those seen
in human Yusho patients (See section 8, p 65) with a similar order of exposure.
Low dose effects on fertility have been seen in both the monkey and the
mink, a species that is also relatively sensitive to PCBs. Other effects
of PCBs include porphyria, immunosuppression, and interference with
steroid metabolism; some of these may be attributable to the increase inmicrosomal
enzyme activity associated with liver enlargement. Some of the toxic
effects can be attributed to impurities in the commercial products. The
acute oral toxicity of Arochlors 1242 and 1254 is low for the mallard-
duck, LD50s > 2 g/kg body weight. The toxicity of PCBs to fish is not high
by comparison with that of some pesticides, but some aquatic invertebrates
are more sensitive. The 96-h LC50 for adult fish was 1.17 mg/l for Arochlor
1221 and 60 mg/l for Arochlor 1260. Young fish appear to be more sensitive,
96-h LC50s was 15 and 8 ug/l respectively for Arochlors 1242 and 1254.
The threshold for survival and reproduction of Daphnia magna exposed to
Arochlor 1248 was 5 ug/l. There is little information on the toxicity of
the PCTs. Clinical studies of the effects of PCBs in man: Information on
the effects of PCBs in man has been obtained from a large-scale incident
in Japan (Yusho), in which over 1000 individuals showed signs of poisoning
from the ingestion of rice oil contaminated with PCBs from a heat exchanger
liquid. The most striking effects were hypersecretion in the eyes, pigmentation
and acneiform eruptions of the skin, and disturbances of the respiratory
system. Babies born to Yusho mothers were of less than normal size and
initially showed skin pigmentation. Over a six-year period, the effects
on the skin diminished very gradually, but the nonspecific symptoms tended
to become somewhat more prominent. The smallest dose of PCBs calculated
to produce an effect was approximately 0.5 g over about 120 days, but as
the rice oil contained chlorinated dibenzofurans at a concentration of
5 mg/kg of rice oil in addition to PCBs at 2000 3000 mg/kg it is not certain
that the symptoms were due solely to PCBs. Dose-effect relationships: Experimental
studies on the dose effect relationship have shown that no effects on growth,
and reproduction are seen in rats receiving PCB levels of I mg/kg body
weight per day; there may be liver enlargement and a reversible induction
of microsome enzyme activity at a level of I mg/kg/day but not at 0.1
mg/kg/day. Effects on reproduction are seen in the monkey with PCB levels
of about 0.12 mg/kg/day. Symptoms were reported in some Yusho patients
ingesting less than 0.1 mg/kg/day. (WHO working group, 1976)
Study #11
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porphyrinogenic PCBs may increase ALA-synthetase by inhibiting
UROD and therefore depleting heme
Studies on the mechanism of induction of porphyria and Yusho
disease by polychlorinated-biphenyls (1336363) (PCBs) were described. The
structural requirement of synthetic PCBs for inducing porphyria was studied
in cultured chick embryo liver cells. The inhibitory effect of PCB isomers
on uroporphyrinogen-decarboxylase (UROD) was investigated by using cultured
chick liver cells supplemented with exogenous delta-aminolevulinic-acid
(ALA) and chicken erythrocyte enzyme. The time course of induction of ALA-synthetase,
cytochrome-P450, and mixed function oxidases, and the inhibition of UROD
in the livers of two strains of mice fed PCBs were assessed. The most active
PCB isomers were found to have chlorine atoms substituted at the para and
meta positions, and to have highly conjugated and nearly coplanar conformations.
UROD was inhibited in-vitro by the most active porphyrin inducers with
purified enzyme. The effects of PCB poisoning from contaminated food in
Japan and Taiwan were discussed, and uroporphyrin and coproporphyrin levels
were determined in the urine of 20 patients, 2 years after poisoning. There
was a slight elevation in urinary uroporphyrin levels in three of the 20
patients. The authors conclude that porphyrinogenic PCBs may increase
ALA-synthetase by inhibiting UROD and therefore depleting heme. (Seki
et al, 1987)
Study #12
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hepatic porphyria due to PCBs is the best understood of the
biological effects of this class of compounds
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PCBs cause enzyme induction and inhibition, changes in liver
morphology, hepatic porphyria, and production of liver tumors
Mechanisms of biological action of polychlorinated biphenyls
(PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated
dibenzofurans (PCDFs) in experimental animals are discussed. PCBs cause
a wide variety of biological effects in laboratory animals including enzyme
induction and inhibition, decreased reproductive efficiency, changes
in liver morphology, changes in plasma lipid concentration, hepatic
porphyria, decreased immunocompetence, and production of tumors
in the livers of rodents. The mechanism by which PCBs cause hepatic
porphyria is the best understood of the biological effects of this class
of compounds. The biological event that results in hepatic porphyria
appears to be inhibition of uroporphyrinogen-decarboxylase, the enzyme
responsible for the stepwise decarboxylation of uroporphyrinogen to coproporphyrinogen.
Various PCDDs and PCDFs cause such effects as enzyme induction, lethality,
lymphoid involution, liver damage, chloracne, teratogenic effects, and
increased tumorigenesis in various organs of rats and mice. The concentrations
of PCDDs and PCDFs necessary to cause these effects are many orders of
magnitude lower than the concentration of commercial PCBs required to cause
the same or similar biological effects. Among the biological effects of
PCDDs and PCDFs, the mechanism of induction of enzyme activity is the most
understood. The increase in enzyme activity apparently results from binding
of the compound to a receptor protein in the cell and translocation of
the compound/receptor complex into the nucleus. The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD) is discussed. The acute toxic effects of TCDD are probably
due to the compound itself rather than its metabolites, although a role
for TCDD metabolites in biological effects other than acute toxicity cannot
be ruled out. (Neal, 1985)
Study #13
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PCBs cause hepatic porphyria
Studies involving polychlorinated biphenyls (PCBs) are reviewed.
PCBs are a class of halogenated aromatic compounds, including halogenated
biphenyls, naphthalenes, dibenzodioxides, and dibenzofurans. PCBs persist
in the environment and are retained in tissue because they are lipid soluble.
They affect reproduction, suppress the immune system, cause tumors in laboratory
rodents, cause hepatic porphyria, and cause chick edema in chickens.
Cell mediated immunity is impaired by PCB, although the degree of impairment
is determined by the type of isomers present. PCBs are not teratogenic,
but they are fetotoxic, producing cleft palates, subcutaneous edema, and
hemorrhage. PCBs are passed to mammalian offspring in the milk. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin
(1746016) (TCDD) is known to cause hepatocellular carcinomas and
squamous carcinomas of the oropharynx and lungs. Subcutaneous sarcomas
and tumors of the thyroid are also noted. The primary source of PCB exposure
to the general United States population is fish from contaminated water.
Serum cholesterol levels in humans are directly proportional to PCB levels.
The concentration of PCB in human milk is particularly high. There is no
clear evidence of harm to humans from PCB, but research is inconclusive.
The author concludes that PCB may be a cancer promoter, but additional
studies on exposed human cohorts, such as fishermen, must be done before
any conclusions about the effects of PCB on humans can be reached. (Kimbrough,
1985)
Study #14
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biotransformation in the liver via hydroxylation and conjugation
with glucuronic-acid, and varying degrees of metabolism and excretion according
to specific molecular structures.
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abnormal findings on liver function tests have been found
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stimulation of enzyme production and porphyria
The toxicology of polychlorinated biphenyls (PCBs) is reviewed.
PCBs are defined as belonging to the class of halogenated aromatic hydrocarbons,
and are a family of chemicals with varying numbers and positions of chlorine
(7782505) atoms attached to a biphenyl nucleus. The degree of chlorination
and the isomeric structure affect biological variables, including the rate
of metabolism and excretion. Contamination of PCBs with polychlorinated
dibenzofurans is noted, and is of particular concern because of their greater
toxicity and their similarity to dibenzodioxins. Molecular structures of
PCBs, dibenzofurans, and chlorinated dibenzodioxins are illustrated. The
uses of PCBs in industry are cited. They include heat exchange and dielectric
fluids in transformers and capacitors, hydraulic and lubricating fluids,
diffusion pump oils, plasticizers for plastics and coatings, ingredients
in caulking compounds, printing inks, paints, adhesives, carbon free paper,
flame retardants, and extenders for pesticides. The risks of environmental
contamination are assessed; PCBs are chemically inert and resistant to
metabolic transformation. The general pharmacokinetics of PCBs is outlined:
absorption by all routes, distribution primarily into fat, biotransformation
in the liver via hydroxylation and conjugation with glucuronic-acid, and
varying degrees of metabolism and excretion according to specific molecular
structures. There is essentially no pharmacokinetic data available
for humans. Epidemiologic studies of health effects are summarized. PCBs
have a low potential for producing acute oral effects. They are associated
with chloracne. Abnormal findings on liver function tests have been
found; and there is a potential for reproductive and fetotoxic effects
in humans. Biochemical effects of PCBs are described: stimulation of
enzyme production, porphyria, and immunosuppressive and endocrine effects.
Potential carcinogenicity is not known for humans. The complexity of medical
surveillance of PCB exposure is stressed. The author concludes that PCBs
have unpredictable long term health effects. There is no question of the
necessity of keeping human exposures as low as possible. (Letz, 1983)
Study #15
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PCBs were potent inducers of hepatic porphyria
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Furans had only a slight effect, if any
Induction of hepatic porphyria by polychlorinated dibenzofurans
and chlorinated biphenyls was compared in male SD rats. The polychlorinated-biphenyl
mixture (Kanechlor-500) was a potent inducer of hepatic porphyria, while
the mixture of polychlorinated dibenzofurans had only a slight effect,
if any, at the levels which it proved possible to administer. (Oishi,
et al, 1978)
Study #16
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hypobilirubinemia in PCB poisoning seems to be caused through
either inhibition of heme catabolism or augmentation of bilirubin elimination
-
PCB induces hepatic microsomal enzymes
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PCB induced hypobilirubinemia seems due mainly to accelerated
bilirubin disposal from the blood
Serum bilirubin analyses in 121 adult outpatients with polychlorinated-biphenyl
(1336363) (PCB) poisoning and 257 healthy adult controls were performed
to investigate the lowering effect of hepatic microsomal indices, such
as PCB, on some body constituents. Bilirubin is a nonpolar organic anion
product of heme catabolism. Under physiologic conditions, the formed bilirubin
is selectively transferred from the blood into the liver and excreted into
the bile. The hypobilirubinemia in PCB poisoning seems to be caused
through either inhibition of heme catabolism or augmentation of bilirubin
elimination. Like DDT (50293), PCB induces hepatic microsomal enzymes.
Since the chlorine (7782505) content influences enzyme induction, the trace
amount of pentachlorinated-biphenyls and hexachlorinated-biphenyls still
remaining stimulates hepatic enzyme metabolism. Since PCB does not appear
to interfere with heme catabolism or induce hepatic porphyria, PCB induced
hypobilirubinemia seems due mainly to accelerated bilirubin disposal from
the blood. The mean serum bilirubin concentration was 0.48 plus or minus
0.26mg/100ml for the outpatients and 0.87 plus or minus 0.33mg/100ml in
the control group. This correlated inversely with the PCB blood levels
and serum triglyceride values which are characteristically increased by
the poisoning. Hyperbilirubinemia may be regarded as a nonspecific but
characteristic laboratory index for PCB poisoning, presumably for the enzyme
induction in man. (Hirayama et al, 1974)
Study #17
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liver enlargement, liver necrosis, and porphyria are some
of the health effects noted in PCB poisoned birds in Green Bay
Several species of colonial fish-eating birds nesting in
the Great Lakes basin, including herring gulls, common terns and double-crested
cormorants, have exhibited chronic impairment of reproduction. In addition
to eggshell thinning caused by high levels of DDT and metabolites, the
reproductive impairment is characterized by high embryonic and chick mortality,
edema, growth retardation, and deformities, hence the name Great Lakes
embryo mortality, edema, and deformities syndrome (GLEMEDS). The hypothesis
has been advanced that GLEMEDS in colonial fish-eating birds resembles
chick-edema disease of poultry and has been caused by exposure to chick-edema
active compounds that have a common mode of action through the cytochrome
P-448 system. Detailed evidence has been collected from the following three
groups of studies on herring gulls in the lower Great Lakes during the
early 1970s; Forster's terns in Green Bay, Wisconsin in 1983; and double-crested
cormorants and Caspian terns in various locations in the upper Great Lakes
from 1986 onwards. It has proved difficult to establish not only the onset
of the disease in the various species at various locations but also the
period in which chick-edema active compounds were released. Anecdotal evidence
suggested that serious egg mortality in Lake Ontario herring gulls first
occurred in 1966, through the signs of chick-edema disease were not looked
for until 1974. Only indirect evidence is available on the date of the
release of one of the presumed causal agents, 2,3,7,8-tetrachlorodibenzo-p-dioxin,
but highest levels may have occurred in the early to mid 1960s. More reliable
data show that the onset of the improvement of reproduction of Lake Ontario
herring gulls coincided with the declines in organochlorine compounds and
particularly 2,3,7,8-TCDD and PCB. Similarly, information on the onset
of the disease and exposures in the Forster's tern and double-crested cormorants
in Green Bay is uncertain but bird banders did not observe deformities
until the 1970s, which corresponds with the onset of high levels of
PCB. If the disappearance of the Caspian tern from Saginaw Bay in the
mid 1960s corresponds with the onset of GLEMEDS at that location, then
there is a close temporal relationship to the onset of high PCB levels.
Chick-edema disease is difficult to diagnose because there is no specific
lesion, but rather there is a suite of lesions. GLEMEDS is characterized
by an elevated incidence of embryonic and chick mortality, growth retardation,
and developmental abnormalities, including bill deformities, club feet,
missing eyes, and defective feathering, and there is also subcutaneous,
percardial, and peritoneal edema, liver enlargement, liver necrosis,
and porphyria. These signs conform to the known symptoms of chick-edema
disease. A variety of chick-edema active compounds, including non-ortho-substitued
PCBs and dibenzo-p-dioxins and furans substituted at the lateral positions,
produce chick-edema disease. The active compounds have specific conformational
requirements. In considering evidence on the strength of association, the
embryos and chicks of herring gulls from Lake Ontario and Forster's terns
from Green Bay had a significant increase in the incidence of the lesions
compared to the reference colonies. Similarly, the incidence of bill abnormalities
was significantly elevated in Great Lakes colonies of double-crested cormorants
particularly for Green Bay, Wisconsin. There was a significant dose-response
relationship between the incidence of embryonic mortality in cormorant
eggs and the presence of chick-edema active compounds expressed in 2,3,7,8-TCDD
equivalents. There is a high degree of consistency on replication. The
disease has been found in a variety of species in a variety of locations,
by different observers using different study designs. Outbreaks of the
disease have occurred at different times and seem only to be related to
exposures of developing embryos to high levels of chick-edema active compounds.
The new facts, that embryos and chicks of colonial, fish-eating birds can
exhibit signs resembling chick-edema disease when exposed to chick-edema
active compounds, cohere with existing biological theory, experience, and
experimentation. There are plausible routes of exposure and sources of
these compounds to the Great Lakes, and statistically significant dose-response
relationships have been demonstrated. (Gilbertson et al, 1991)
Study #18
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liver morphological changes due to PCBs have been studied
extensively.
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a widely studied effect is induction of hepatic microsomal
enzymes in mammals
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PCBs are associated with porphyria
PCBs are produced in the United States under the trade names
of Aroclor 1232, 1242, 1248, 1254, and 1260, and in Japan under the names
Kanechlor-200, -300, -400, -500, and -600. PCBs are transported in the
environment in several ways including dumping, vaporization, and leakage.
Residue levels in various species in Europe, North America, the Caribbean,
Japan, and the southern hemisphere are discussed; substrates include plankton;
fish; sea birds such as herring gulls and brown pelican; marine mammals
such as the ringed seal, harp seal, hooded seal, grey seal, bearded seal,
harbor seal, bottle-nosed dolphin, common dolphin, surinam dolphin, harbor
porpoise, sea lion, finback whale, and pilot whale; birds of prey; and
humans and human food. The physiological effects of PCBs are considered
mainly on a class-by-class basis. Acute toxicity is considered for mammals,
birds, fish, and insects. Liver morphological changes have been studied
extensively. A widely studied effect of organochlorine compounds is the
induction of hepatic microsomal enzymes in mammals. The effects of
these chemicals on mammalian reproduction are reviewed. Avian reproduction
is considered in the light of eggshell thickness, egg production and hatchability,
specific effects on the male of the species, and teratogenic effects. The
geometric similarity of DDT and PCBs to the synthetic estrogen, stilbestrol,
has led to examination of the possibility that chlorinated hydrocarbons
could act as synthetic estrogens. Current evidence has not suggested that
PCB exerts an important influence on thyroid function. DDT has caused an
increase in liver vitamin A levels, but comparable studies with PCBs are
not available. Carcinogenic studies are as yet very few. Some effects of
PCBs on immunosuppressive mechanisms have been reported. Hydropericardium
and generalized edema, porphyria, inhibition of adenosine triphosphatase,
physiological effects on microorganisms, and the effects on non-human primates
are also reviewed. (Peakall, 1975)
Study #19
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porphyrins were slightly elevated in children born to PCB-exposed
mothers
A study of urinary porphyrin excretion in children exposed
transplacentally to polyhalogenated aromatic compounds was conducted. The
cohort consisted of 75 children, mean age 45.4 months, born to mothers
who had been exposed to rice-oil contaminated with polychlorinated-biphenyls
(1336363), polychlorinated quaterphenyls, and polychlorinated dibenzofurans
in 1979 in Taiwan. The comparisons consisted of 74 children, mean age 39.8
months, who lived in the same neighborhoods but who had not been exposed
to the rice-oil. Twelve siblings, mean age 98.6 months, of the exposed
subjects were included and some were considered to have been directly exposed.
Spot urine samples were collected and analyzed for porphyrins, albumin,
and creatinine. Mean urinary albumin and creatinine concentrations did
not differ significantly between the groups. Mean concentrations of
coproporphyrins, pentaporphyrins, and hexaporphyrins were slightly elevated
in transplacentally exposed subjects. Eight exposed children and two
comparisons had total urinary porphyrin concentrations above 200 micrograms
per liter. Four subjects, two comparisons, and one sibling were diagnosed
as having type-B hepatic porphyria, based on uroporphyrin/coproporphyrin
ratios of greater than 1. No cases of porphyria cutanea tarda were seen.
The authors note that although the exposed children do not appear to have
symptoms directly related to the porphyria, a mild disturbance in porphyrin
metabolism that is apparently exposure related exists. Clinical followup
of the children is in progress. (Gladen et al, 1988)
Study #20
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PCBs may damage the cell membrane phospholipid structure
causing the symptoms of porphyria cutanea tarda
The effects of pesticides on porphyrin metabolism in rats
are reviewed. Results of studies with hexachlorocyclohexane (608731), hexachlorobenzene
(118741), polychlorinated-biphenyls (1336363), 2,4-dichlorophenoxyacetic-acid
(94757), and pentachlorphenol (87865) are summarized. The authors suggest
that chlorinated-hydrocarbons damage the cell membrane phospholipid
structure causing the symptoms of Porphyria cutanea tarda. (German).
(Simon et al, 1974)
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