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Immune Study Reviews 1-22
The following reviews indicate a strong link between PCB
exposure, infections and immunity.
Study Review #1
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there is no "safe" level of PCB exposure --- any PCB exposure
could carry risk, no matter how small the exposure
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the immune system is one of several targets for toxic effects
of PCBs
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to achieve human consumption levels close to zero-PCBs would
require prohibition of important foods, such as fish
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political judgements are made to balance public health protection
with the need to prevent "excessive losses of food" (ie: fish consumption
warnings are weaker than a pure public health warning would require)
Polychlorinated biphenyls (PCBs) were discovered before the
turn of the century and their usefulness for industry, because of their
physical properties, was recognized early. The PCBs have been used commercially,
since 1930, as dielectric and heat-exchange fluids and in a variety of
other applications. They have become widely distributed in the environment
throughout the world, and are persistent and accumulate in food webs. Human
exposure to PCBs has resulted largely from the consumption of contaminated
food, but also from inhalation and skin absorption in work environments.
PCBs accumulate in the fatty tissues of humans and other animals and have
caused toxic effects in both, particularly if repeated exposure occurs.
The skin and liver are the major sites of pathology, but the gastrointestinal
tract, the immune system, and the nervous system are also targets.
Polychlorinated dibenzofurans (PCDFs), which are contaminants in commercial
PCB mixtures, contribute significantly to their toxicity. The results of
studies on rodents suggest that some PCB congeners may be carcinogenic
and that they can promote the carcinogenicity of other chemicals. It is
clear from available data on polychlorinated biphenyls (PCBs) and polychlorinated
terphenyls (PCTs) that, in an ideal situation, it would be preferable
not to have these compounds in food at any level. However, it is equally
clear that the reduction of PCBs or PCTs exposure from food sources to
"zero" or to a level approaching zero, would mean the elimination (prohibition
of the consumption) of large amounts of important food items, such as fish,
but more importantly breast milk. National and international scientific
committees have to decide where the proper balance lies between providing
an adequate degree of public health protection and avoiding excessive losses
of food. No levels of PCBs or PCTs exposure that can provide an absolute
assurance of safety can be identified on the basis of the available data.
Environmental transport, distribution, and transformation: In the atmosphere,
PCBs exist primarily in the vapour phase; the tendency to adsorb on particulates
increases with the degree of chlorination. The virtually universal distribution
of PCBs suggests transport in air. At present, the major source of PCB
exposure in the general environment appears to be the redistribution of
PCBs, previously introduced into the environment. This redistribution involves
volatilization from soil and water into the atmosphere with subsequent
transport in air and removal from the atmosphere via wet/dry deposition
(of PCBs bound to particulates) and then re-volatilization. Concentrations
of PCBs in precipitation range from 0.001 to 0.25 ug/litre. Since
the volatilization and degradation rates of PCBs vary between congeners,
this redistribution leads to an alteration in the composition of PCB mixtures
in the environment. In water, PCBs are adsorbed on sediments and other
organic matter; experimental and monitoring data have shown that PCB concentrations
in sediment and suspended matter are higher than those in associated water
columns. Strong adsorption on sediment, especially in the case of the higher
chlorinated PCBs, decreases the rate of volatilization. On the basis of
their water solubilities and n-octanol-water partition coefficients, the
lower chlorinated PCB congeners will sorb less strongly than the higher
chlorinated isomers. Although adsorption can immobilize PCBs for relatively
long periods in the aquatic environment, desorption into the water column
has been shown to occur by both abiotic and biotic routes. The substantial
quantities of PCBs in aquatic sediments can therefore act as both an environmental
sink and a reservoir of PCBs for organisms. Most of the environmental load
of PCBs has been estimated to be in aquatic sediment. The low solubility
and the strong adsorption of PCBs on soil particles lirnits leaching in
soil; lower chlorinated PCBs will tend to leach more than the highly chlorinated
PCBs. Degradation of PCBs in the environment is dependent on the degree
of chlorination of the biphenyl. In general, persistence of PCB congeners
increases as the degree of chlorination increases. In the atmosphere, the
vapour phase reaction of PCBs with hydroxyl radicals (which are photochemically
formed by sunlight) may be the dominant transformation process. Estimated
half-lives for this reaction in the atmosphere range from about 10 days
for a monochlorobiphenyl to 1.5 years for a heptachlorobiphenyl. In
the aquatic environment, hydrolysis and oxidation do not significantly
degrade PCBs. Photolysis appears to be the only viable abiotic degradation
process in water; however, available experimental data are not sufficient
to determine its rate or importance in the environment. Microorganisms
degrade mono-, di-, and trichlorinated biphenyls relatively rapidly and
tetrachlorobiphenyls slowly, whilst higher chlorinated biphenyls are resistant
to biodegradation. Chlorine substitution positions on the biphenyl ring
appear to be important in determining the biodegradation rate. PCBs containing
chlorine atoms in the para positions are preferentially biodegraded. Higher
chlorinated congeners are biotransformed anaerobically, by a reductive
dechlorination, to lower chlorinated PCBs, which may then be biodegradable
by aerobic processes. Several factors determine the degree of bioaccumulation
in adipose tissues: the duration and level of exposure, the chemical structure
of the compound, and the position and pattern of substitution. In general,
the higher chlorinated congeners are accumulated more readily. Experimentally
determined bioconcentration factors of various PCBs in aquatic species
(fish, shrimp, oyster) range from 200 up to 70 000 or more. In the
open ocean, there is bioaccumulation of PCBs in higher trophic levels with
an increased proportion of higher chlorinated biphenyls in higher ranking
predators. Transfer of PCBs from soil to vegetation takes place mainly
by adsorption on the external surfaces of terrestrial plants; little translocation
takes place. Effects on organisms in the environment: Laboratory studies
Effects of PCB mixtures on microorganisms are highly variable with some
species adversely affected by a level of 0.1 mg/litre and others unaffected
by 100 mg/litre; effects on different species do not vary consistently
with the degree of chlorination of the mixtures. Almost all of the studies
of the effects of PCBs on aquatic organisms have been concerned with Aroclor
mixtures. Results have been extremely variable with no consistent relationship
between percentage chlori nation or environmental conditions and toxicity,
even with closely-related organisms. Over 96 h, under static conditions,
LC50 values have ranged between 12 mg/litre and > 10 mg/litre for various
aquatic invertebrate species and different Aroclor mixtures. Flow-through
conditions increased the toxicity of the PCBs. Generally, the most toxic
mixtures were Aroclors in the mid-range of chlorination; low and high percentage
chlorination mixtures were less toxic. This was also true for sub-lethal
effects, such as reproduction effects in Daphnia. Crustaceans seem to be
more susceptible to PCBs during moult. In model populations, the community
structure of estuarine species changed on exposure to Aroclor 1254, with
the numbers of amphipods, bryozoans, crabs, and molluscs decreasing
and those of annelids, brachyopods, coelenterates, echinoderms, an (incomplete
abstract) [WHO (World Health Organization) working group, 1993]
Study Review #2
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dioxin is the common name for a series of 75 dibenzodioxins,
135 dibenzofurans and 209 PCBs.
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they suppress the immune system
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dioxins and dioxin-like chemicals are present in the environment,
food chain and body tissues at doses at or near levels supposed to cause
harm to public health
Dioxin is the common name for a series of 75 dibenzodioxins,
135 dibenzofurans and 209 PCBs. Among these chemicals, less than 30
prove to be toxic. Those molecules can act as hormone disrupters, suppress
the immune system, alter the physiology of the sebaceus follicle and
participate in the carcinogenesis of sarcomas, lymphomas and some carcinomas.
They may be responsible for some birth defects. In some regions of the
world, dioxins and dioxin-like chemicals are present in the environment,
the food chain and body tissues at doses at or near at the level supposed
to cause harm to public health. (Pierard et al, 1999)
Study Review #3
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extensive evidence has accumulated over 20 years showing
immune systems of several species are a target for toxicity
The U.S. Environmental Protection Agency (EPA) is conducting
a scientific reassessment of the risks of exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin
(TCDD) and chemically similar compounds collectively known as dioxin.
Extensive evidence has accumulated over the past 20 years to demonstrate
that the immune systems of several species are a target for toxicity
of TCDD and structurally related halogenated aromatic hydrocarbons, including
the chlorinated dibenzofurans, polychlorinated biphenyls, and polybrominated
biphenyls. Review draft. See also Volume 3, PB93-222677 and Volume 5, PB93-222693.
Prepared in cooperation with Oregon State Univ., Corvallis. Coll. of Veterinary
Medicine. Sponsored by Environmental Protection Agency, Washington, DC.
Office of Health and Environmental Assessment. (Kerkvliet, 1993)
Study Review #4
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PCBs are one of the 12 worst Persistent Organic Pollutants
(POPs) identified by the United Nations Environment Program as requiring
urgent regulatory attention
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POPs are known to play a role in immune system dysfunction
and greater susceptibility to disease
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All of the POPs are closely related Chlorinated Organic Compounds
Persistent organic pollutants (POPs) can travel thousands
of miles, accumulate in the food chain, and persist in the environment,
taking as long as centuries to degrade. POPs are known to play a role in
birth defects, cancer, immune system dysfunction, and reproductive
problems in wildlife. While the effects of POPs on human health are unclear,
many researchers believe that long-term exposure contributes to increasing
rates of birth defects, fertility problems, greater susceptibility to
disease, diminished intelligence, and certain cancers. Twelve POPs
have been identified by the United Nations Environment Programme as requiring
urgent regulatory attention. They include the pesticides aldrin, chlordane,
DDT, dieldrin, endrin, heptachlor, hexachlorobenzene, mirex, and toxaphene.
Of the remaining three POPs, polychlorinated biphenyls are industrial
products (used in electrical transformers), and dioxins and furans
are unintentional by-products of industrial processes. (Fisher, 1999)
Study Review #5
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immune system changes occur at dioxin doses one-tenth to
one-hundredth of the cancer-causing dose (certain PCBs are dioxin-like)
Human cancer risks associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD) were assessed. Studies have indicated that the oral median
lethal dose of TCDD in animals varies from 0.6 to 130 micrograms/kilogram
(microg/kg). Cancer has been induced in rats and mice given TCDD at levels
of 0.1 microg/kg/day. Decreased immune responsiveness has been observed
at dose levels one tenth to one hundredth of the carcinogenic dose.
Reproductive and teratogenic effects in animals have been seen at similar
exposure levels. Some studies have suggested that TCDD promotes tumor formation
through a process that does not involve damage to DNA, while other evidence
supports the view that TCDD is a mutagen and clastogen. The elements in
the no threshold approach to risk assessment are dose response data in
animal experiments, an estimate of TCDD exposure in people, and a mathematical
procedure to extrapolate the animal data to human exposure levels. Bioassays
in Sprague-Dawley-rats indicated an increase in tumor rate from zero to
20 percent in male and from 19 to 72 percent in female rats following exposure
to TCDD at zero and 0.1 microg/kg/day. Mathematical models have predicted
a wide range of risks. The probit model generates a risk of 500 excess
cases per million population, while the multistage model predicts a much
smaller risk. Human susceptibility to cancer may be determined by a wide
range of genetic, environmental, and lifestyle factors, all of which must
interact in a precise fashion for the disease to occur. Estimation of cancer
risk from animal exposure extrapolation has proved to be inadequate possibly
because TCDD does not perceptively increase cancer risk in humans or because
the carcinogenic action of TCDD is inconsistent with the assumptions of
the mathematical models. (Wood, 1986)
Study Review #5
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the immune system can provide significant deterrants to cancer
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some chemicals promote tumors indirectly by altering the
functions of the immune system
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PCBs promote tumors by this method
The immunotoxicity of carcinogenic pesticides and related
chemicals was reviewed. Immune surveillance theory and its role in carcinogenesis
were discussed. Current experimental data have indicated that the immune
system is capable of providing a significant deterrent to spontaneous or
exogenously induced tumors. This is accomplished by various effector
cell populations recognizing and lyzing or inhibiting the growth of tumor
cells. The authors note that enhancing the relevant effector mechanisms
will result in reducing the incidence of tumors, tumor growth, or metastases.
On the other hand, if the effector mechanisms are depressed tumor incidence,
latency, growth and metastasis will increase. Carcinogenic chemicals are
thought to exert their effects directly (genotoxicity) or indirectly
(epigenetically) by altering the functions of the immune system. Studies
on the immunotoxicity in animals and humans of organic carcinogenic pesticides
such as DDT (50293), dieldrin (60571), cyclodienes, and other organochlorine
insecticides, carbamates, inorganic carcinogenic pesticides that contain
lead (7439921) and arsenic (7440382), and halogenated aromatic hydrocarbons
such as polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins
were examined. (Exon et al, 1987)
Study Review #7
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PCBs and dioxins may affect primary antibody response
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background exposure levels of PCBs may change the T-cell
population
Polychlorinated biphenyls (PCBs), PCDDs and PCDFs (summarized
as dioxins) are potentially toxic compounds which occur widely in the environment.
They are presently a pollution problem because they are resistant to either
chemical or biologic degradation and they accumulate in the food chain.
Perinatal PCB/dioxin exposure may affect neurodevelopmental and behavioral
outcome in accidentally as well as in background prenatal exposed children,
suggesting that the developing human brain is particularly sensitive to
these compounds. Data regarding the potential immunotoxic effects
of PCBs and dioxins in human beings remain scarce. Adult humans are less
susceptible than perinatally exposed infants. Perinatal exposure to PCBs
and dioxins at a high level may affect primary antibody response.
Prenatal background exposure to PCBs and dioxins may result in changes
in the T-cell population without effect on the health status of the
infant nor on humoral immunity. In most studies a relation between PCB
exposure and birthweight have been found. PCBs and dioxins provide inter-
or intra-cellular signals that alter growth, differentiation and function
of cells in a tissue-, stage, or cell-specific manner. They have the potential
to disrupt the endocrine system of animals as well as humans. Perinatal
exposure to chemicals that mimics natural steroidal hormones can have a
profound impact on later development of the reproductive system. Elevated
levels of dioxins and PCB can also alter the human thyroid hormone status.
Relatively subtle thyroid hormone alterations have been observed in pregnant
mothers and their infants exposed to background levels of PCBs and dioxins.
Thyroid hormones are needed to stimulate neuronal and glial proliferation
and differentiation of the central nervous system. Androgens and estrogens
can also alter the development of the central nervous system. The brain-pituitary-reproductive
and thyroid Axis and the brain-thymus-lymphoid axis are linked by an array
of internal mechanisms of communication that use similar signals (neurotransmitters,
peptides, growth factors, hormones) acting on similar recognition targets.
The construction of the physiological systems of the pituitary/hypothalamic
region of the brain takes place in utero. At that time endocrine disruptors
may be the most threatening, leading to changes in the endocrine, immune,
and nervous systems and hypothalame function that do not respond to normal
hormonal and neurotransmitter messages in the usual manner throughout life.
In this presentation the key data concerning the effects of perinatal exposure
to PCBs and dioxins on the endocrine, reproductive, immune and central
nervous system in human infants and children will be described. The strengths
and weakness of our current understanding and conflicting study data about
the interaction between neural, immune and endocrine processes will
be discussed. (Weisglas-Kuperus, 1996)
Study Review #8
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alterations in lymphocyte subpopulations
Global contamination by a variety of anthropogenic persistent
organic chemicals, such as dioxins and PCBs, has resulted in human exposure
throughout all phases of development. Detectable concentrations of PCBs
and dioxins have been found in amniotic fluid, placenta and foetal tissue
samples while infants who are breast-fed can obtain blood levels greater
than those of their mother's. In two separate food poisoning episodes where
infants were exposed in utero to elevated levels of heat-degraded PCBs
(PCBs, PCQs, PCDFs), a variety of adverse mental and physical developmental
abnormalities have been observed. In additional human cohorts where exposure
could be considered as environmental or background, more subtle effects,
including lower birth weights, alterations in thyroid hormones and
lymphocyte subpopulations and detriments in neurological development,
have been consistently seen. In most instances, negative associations were
made between in utero exposure to contaminants compared with lactational.
Although the observed neurodevelopmental deficits have been described as
subtle, there could be unknown consequences related to future intellectual
functionality. Current regulatory efforts should focus on identification
and control of environment and food chain contamination as in utero exposure
is a direct consequence of the accumulated maternal body burdens. (Feeley
et al, 2000)
Study Review #9
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dioxin-like PCBs decrease immune response
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one biomarker (test) for this effect measures the CD4/CD8
ratio (a measure of certain lymphocytes)
Studies of perinatal exposures to dioxin-like compounds
(DLCs), coplanar polycyclic halogenated aromatics whose prototype is 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD), have employed a variety of outcome measures to investigate effects
on the reproductive/developmental, endocrine, immune, and neurobehavioral
systems. The effects include infertility, growth retardation, fetal loss,
changed sexual differentiation, reduced cognitive/motor function, dermatologic
and other ectodermal effects, and decreased immune response. Significant
biomarkers have included sperm count; CD4/CD8 ratio; and levels
of testosterone, T4, and dopamine. Using specific dioxin or PCB congeners,
these and other markers were used to investigate the mechanisms of the
observed effects. The DLCs, which include some PCB congeners, are characterized
by high-affinity binding to the Ah receptor; most biological effects are
thought to be mediated by the ligand-Ah receptor complex. Other PCB congeners
have low affinity for the Ah receptor, and operate by non-Ah receptor mechanisms.
The biologic activity of a PCB mixture is the sum of the agonist and antagonist
activities of the different constituents in the mixture. Animal studies
with specific PCB congeners can help to clarify these activities. With
similar approaches, biologic markers of effect can be developed and applied
in epidemiologic studies to monitor for, and predict, adverse effects in
humans. (Hooper et al, 1995)
Study Review #10
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immune system damage is more dramatic and persistent for
PCB exposed fetuses and babies, as opposed to PCB exposed adults
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autoimmune and hypersensitivity disorders diseases may be
linked to early exposure to immunotoxicant chemicals
Fetal and early postnatal life represent critical periods
in vertebrate immune system development. Disruption of such development
by perinatal immunotoxic chemical exposure has been widely described in
experimental animal models. The resultant inhibited postnatal immune responses
in such animals are often more dramatic and persistent than those after
exposure during adult life. Further, recent reports suggest that prenatal
exposure to immunotoxicants may exacerbate postnatal aberrant immune responses
(e.g., hypersensitivity disorders and autoimmune disease) in genetically
predisposed rodents. Limited information is available regarding the possibility
of inhibited postnatal immune capacity in humans as a result of developmental
immunotoxicant exposure. The multifactorial nature of hypersensitivity
and autoimmune responses will further complicate the elucidation of possible
relationships between chemical exposure during ontogeny of the human immune
system and immune-mediated disease later in life. Taken together, however,
the available animal data suggest the potential for altered postnatal
immune function in humans exposed to immunotoxicants (e.g., environmental
chemicals and therapeutic agents) during fetal and/or early postnatal life.
(Holladay et al, 2000)
Study Review #11
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the immune system of the developing fetus and the newborn
is particularly vulnerable to the toxic effects of chemicals
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more studies are needed
Environmental contaminants include the potentially toxic
metals lead, cadmium and mercury; the chlorinated pesticides mirex, toxaphene
and hexachlorobenzene; chlorinated dioxins and furans; polyaromatic hydrocarbons;
and polychlorinated biphenyls. While many of these chemicals are
resistant to degradation in the natural environment, they dissolve readily
in oils and thus accumulate in the fatty tissues of fish, birds and mammals.
Human exposure is predominantly through the ingestion of contaminated food.
An array of toxic effects including effects on the immune system
have been described in experimental animals and in humans accidentally
exposed to these chemicals. Such studies suggest that the immune system
of the developing fetus and the newborn is particularly vulnerable to the
toxic effects of chemicals. To fully appreciate the magnitude of risk
these chemicals pose to children's health, there is a need for additional
carefully focussed epidemiologic and mechanistic studies. (Tryphonas, 1998)
Study Review #12
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dioxin and related compounds (PCBs) are linked to long-term
alterations in immune functions
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children exposed prenatally to PCBs and furans suffer increased
respiratory disease
Alteration of hormonal systems has long been known to cause
developmental problems. TCDD and other structurally related PHAHs modulate
the levels of many different hormones and their receptors. These effects
are all mediated through binding to the Ah receptor, dioxin and related
compounds are developmental toxicants, causing a spectrum of morphological
and functional deficits. At doses below those where maternal toxicity is
observed dioxins cause fetotoxicity. In the mouse, exposure of the dam
results in hydronephrosis and cleft palate in the pups. Thymic atrophy
and hemorrhage are observed in many species at doses which are not
maternally toxic. Prenatal exposure to both rats and hamsters results in
alterations to the genitourinary tract of the spring, which is not detectable
until puberty. Delays in puberty, permanent reduction in sperm counts,
and long-term alterations in immune functions have also been observed.
Prenatal exposure to PCBs has been shown to cause similar effects in rats
and guinea pigs, as well as decrements in the auditory threshold. Children
exposed prenatally to complex mixtures of PCBs and PCDFs are smaller and
have problems at puberty, hearing deficits, increased respiratory disease,
and IQ and behavioral deficits. Many of these effects are similar to those
observed with known hormone modulators. These complex alterations of multiple
endocrine systems is likely associated with the spectrum of adverse developmental
effects caused by dioxin and related compounds. (Birnbaum, 1995)
Study Review #13
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PCBs have been reported to cause immune suppression and increase
susceptibility to infection in animals
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atrophy of major lymphoid organs
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apoptotic cell death may lead to altered T-B cell ratios,
and loss of regulatory cells in critical numbers leading to perturbations
in immune function
Several organochlorinated pesticides including DDT, PCBs
and dieldrin have been reported to cause immune suppression and increase
susceptibility to infection in animals. Often this manifestation is
accompanied by atrophy of major lymphoid organs. It has been suggested
that increased apoptotic cell death leading to altered T-B cell ratios,
and loss of regulatory cells in critical numbers leads to perturbations
in immune function. The major objective of our study was to define
the mechanism by which endosulfan, an organochlorinated pesticide, induces
human T-cell death using Jurkat, a human T-cell leukemic cell line, as
an in vitro model. We exposed Jurkat cells to varying concentrations of
endosulfan for 0-48 h and analyzed biochemical and molecular features characteristic
of T-cell apoptosis. Endosulfan lowered cell viability and inhibited cell
growth in a dose- and time-dependent manner. DAPI staining was used to
enumerate apoptotic cells and we observed that endosulfan at 10-200 microM
induced a significant percentage of cells to undergo apoptotic cell death.
At 48 h, more than 90% cells were apoptotic with 50 microM of endosulfan.
We confirmed these observations using both DNA fragmentation and annexin-V
binding assays. It is now widely being accepted that mitochondria undergo
major changes early during the apoptotic process. We examined mitochondrial
transmembrane potential (deltapsim) in endosulfan treated cells to understand
the role of the mitochondria in T-cell apoptosis. Within 30 min of chemical
exposure, a significant percentage of cells exhibited a decreased incorporation
of DiOC6(3), a cationic lipophilic dye into mitochondria indicating the
disruption of deltapsim. This drop in deltapsim was both dose- and time-dependent
and correlated well with other parameters of apoptosis. We also examined
whether this occurred by the down regulation of bcl-2 protein expression
that is likely to increase the susceptibility of Jurkat cells to endosulfan
toxicity. Paradoxically, the intracellular expression of bcl-2 protein
was elevated in a dose dependent manner suggesting endosulfan-induced apoptosis
occurred by a non-bcl-2 pathway. Based on these data, as well as those
reported elsewhere, we propose the following sequence of events to account
for T-cell apoptosis induced by endosulfan: uncoupling of oxidative phosphorylation
--> excess ROS production --> GSH depletion --> oxidative stress --> disruption
of deltapsim --> release of cytochrome C and other apoptosis related proteins
to cytosol --> apoptosis. This study reports for the first time that endosulfan
can induce apoptosis in a human T-cell leukemic cell line which may have
direct relevance to loss of T cells and thymocytes in vivo. Furthermore,
our data strongly support a role of mitochondrial dysfunction and oxidative
stress in endosulfan toxicity. (Kannan et al, 2000)
Study Review #14
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disruption of the immune system could disrupt other vital
systems, during early development in the womb or infancy
Large numbers and large quantities of endocrine-disrupting
chemicals have been released into the environment since World War II. Many
of these chemicals can disturb development of the endocrine system and
of the organs that respond to endocrine signals in organisms indirectly
exposed during prenatal and/or early postnatal life; effects of exposure
during development are permanent and irreversible. The risk to the developing
organism can also stem from direct exposure of the offspring after birth
or hatching. In addition, transgenerational exposure can result from the
exposure of the mother to a chemical at any time throughout her life before
producing offspring due to persistence of endocrine-disrupting chemicals
in body fat, which is mobilized during egg laying or pregnancy and lactation.
Mechanisms underlying the disruption of the development of vital systems,
such as the endocrine, reproductive, and immune systems, are discussed
with reference to wildlife, laboratory animals, and humans. (Colburn et
al, 1993)
Study Review #15
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immune disruption may alter reproductive functions
Reviewed published literature about the effects of endocrine
disruptors, heavy metals, solvents, pesticides, plastics, industrial chemicals,
and cigarette smoke on female reproduction. Published data indicate that
chemical exposures may cause alterations in reproductive behavior and contribute
to subfecundity, infertility, pregnancy loss, growth retardation, intrauterine
fetal demise, birth defect, and ovarian failure in laboratory animals and
wildlife. Data on the association of chemical exposures and adverse reproductive
outcomes in humans are equivocal and often controversial. Some studies
indicate that chemical exposures are associated with infertility, spontaneous
abortion, or reproductive cancer in women. In contrast, other studies indicate
that there is no association between chemical exposures and adverse reproductive
outcomes. The reasons for ambiguous findings in human studies are unknown
but likely include the fact that many studies are limited by multiple confounders,
inadequate methodology, inappropriate endpoints, and small sample size.
The mechanism by which chemicals alter reproductive function in all species
is complex and may involve hormonal and/or immune disruption, DNA
adduct formation, altered cellular proliferation, or inappropriate cellular
death. Studies are needed to clarify which toxicants affect human reproduction
and by which mechanisms of action. Furthermore, methods should be developed
to minimize exposure to known reproductive toxicants such as dioxins and
cigarette smoke. (Sharara et al, 1998)
Study Review #16
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non-cancer effects of chemical exposure may occur at low
concentrations
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chemical regulatory programs should be reevaluated to address
concerns about non-cancer effects
While a variety of effects of toxic chemicals are known in
animals exposed both in the laboratory and in situ, it has proven more
difficult to obtain definitive information relating harm to humans resulting
from environmental contamination. Until quite recently it has been generally
assumed that cancer was the human disease of greatest importance. In fact,
the majority of regulations of exposure to toxic chemicals by most governments
are designed on the basis of presumed cancer risk. The evidence that hazardous
chemicals can cause cancer is strong, and concern of cancer risks is appropriate.
However, recent evidence has triggered a reevaluation of the assumption
that cancer is the sole disease of concern. New evidence has emerged suggesting
that exposure to hazardous chemicals may lead to a variety of non-cancer
endpoints, and that these effects may occur at low concentrations.
Of particular concern is evidence for irreversible effects on the embryo
and very young children which influence intelligence, attention span,
sexual development and immune function. Some of these actions appear
to be direct effects on the brain and other organ systems while others
are mediated via disruption of endocrine systems. While these effects are
subtle and difficult to quantify, the aggregated evidence is sufficiently
compelling as to necessitate reevaluation of those health outcomes upon
which regulations are based. (Carpenter, 1998)
Study Review #17
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immunotoxicity is one of the 3 main PCB effects used for
risk assessment
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long-term, low-level exposure to one commercial PCB mixture
(Aroclor 1254) produced moderate, but statistically significant, effects
on certain immunological parameters in Rhesus monkeys.
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it is not known how these effects are related to functional
impairment of the immune system
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PCBs are potent inducers of certain cytochrome enzymes
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the PCB composition of a commercial mixture is different
from the PCB composition of the mixtures which humans will be exposed to,
especially from food
The risk assessment from exposure to PCBs presents problems
which are more complicated than are usually encountered when dealing with
a group of compounds. Indeed, it is certainly much more complicated than
the earlier risk assessment of dioxins (Ahlborg el al. 1988). The PCBs
constitute a series of 209 individual congeners, varying in the number
and sites of chlorine substitution. The biological effects caused by the
various congeners differ, not only in potency but also qualitatively. Our
knowledge of the mechanisms of toxicity indicates that some of the PCB
congeners act by the same mechanisms as the chlorinated dioxins, i.e. the
toxicity is probably mediated through interaction with the Ah receptor,
and they are potent inducers of certain cytochrome enzymes.
Other PCB congeners presumably act by different mechanisms and are potent
inducers of a different set of cytochromes. In addition, there are PCB
congeners which are intermediate in this respect, i.e. they elicit a mixed
spectrum of enzyme induction. Some typical toxic effects of PCBs, such
as tumour promotion, are caused by PCB congeners in all of these three
classes, but the underlying mechanisms involved are probably different.
Our knowledge of possible interactions between the various groups of PCBs
is still very limited. Almost all animal studies with PCB mixtures have
been performed using commercially-available PCBs. Due to differences between
individual congeners, with regards to resistance to degradation and metabolism,
the
composition of a commercial mixture is different from the composition of
the mixtures which humans will be exposed to, especially from food.
A further complication in the risk assessment is the fact that many PCB
congeners are metabolized to yield hydroxy- and methyl sulphone metabolites.
The available data on the possible biological and toxicological effects
of these metabolites are, however, very limited and preclude consideration
of these metabolites in the present risk assessment. The risk assessment
of PCBs has been approached in two different ways. Assessing the risk from
the exposure to mixtures of PCBs utilizing data from human studies and
experimental animal studies. The various end-points which can be used for
such an assessment are immunotoxicity in animals, cancer in humans
and animals, and developmental/behavioural effects in humans and animals.
Assessing the risk from exposure to individual PCB congeners. In this case,
only data from animal studies are at present available for evaluation.
Furthermore, the present data-base will only allow for this exercise to
be performed on congeners acting through the same mechanisms as the chlorinated
dioxins. Mixtures of PCBs: The critical endpoints for risk assessment of
PCBs arc identified as cancer, immunotoxic and behavioural effects.
Cancer: Positive, long-term bioassays in the rat have all been performed
with one dose level, 100 ppm, of either of two commercial mixtures (Aroclor
1260 or Clophen A60), roughly corresponding to 5 mg/kg b.w. and day. An
increased frequency of liver tumours is reported in several strains. Due
to the lack of dose-response data from animal bioassays, it is presently
impossible to perform any quantitative risk evaluation, including the establishment
of a no observed adverse effect level (NOAEL). Discrepancies between the
commercial mixtures and environmental exposures, with regards to congener
composition, also imply that the predictive value of these studies is limited
with respect to judgement of the risks from environmental exposure. However,
intake estimates for humans indicate that non-occupational exposure in
men is several orders of magnitude lower than the tested carcinogenic dose
of the commercial mixtures. A few epidemiological studies of occupationally-exposed
workers have indicated an increased incidence of cancer of the liver and
of the biliary tract. However, in all of these studies the exposure occurred
to commercial PCB mixtures, the compositions of which clearly differ from
those of PCBs in food. In addition, the PCB mixtures were contaminated
to various extents with other chlorinated compounds, especially polychlorinated
dibenzofurans (PCDFs), which might have contributed to the observed effects.
Taken together with the lack of good exposure measurements, it is not possible
to use these qualitative data for the present risk assessment. Immunotoxicity:
Long-term, low-level exposure to one commercial mixture (Aroclor 1254)
has been shown to produce moderate, but statistically significant, effects
on certain immunological parameters in Rhesus monkeys. The significance
to health of these findings is difficult to evaluate since it is not known
how they are related to functional impairment of the immune system.
Behavioural effects: Hyperactivity and impaired learning ability have been
reported for Rhesus monkey infants exposed to Aroclors 1248 and 1016 in
utero and during lactation. The congener patterns of these mixtures are
quite different from those seen in most biological samples, including fish
and human milk. It is thus difficult to utilize the data on these monkeys
directly for the present risk assessment. However, supportive data are
available from studies in rats, mice and quails. Behavioural effects similar
to those seen in monkeys have also been reported for human infants whose
mothers were exposed to PCBs through the intake of contaminated fish in
Michigan, U.S.A. The effects recorded in infants were slight, but should
still be regarded as adverse. However, the study is not fully conclusive
from an epidemiological point of view. Thus, a causal relationship between
PCB and the effects is not proven due to some potentially important confounding
factors. On the other hand, a causal relationship is definitely possible.
Furthermore, supportive evidence comes from a similar study performed in
North Carolina, U.S.A. Although there are great uncertainties involved,
a lowest observed effect level (LOEL) for slight neurotoxic effects in
infants from exposed mothers can be calculated to be in the range 0.014
- 0.9 ug/kg b.w./day. This can be compared with an estimated intake in
Nordic countries of around 0.2 ,ug/kg b.w./day. People with a higher
than average fish intake may have considerably higher intake of PCB.
Dioxin-like PCB congeners: Several non- and mono-ortho-substituted PCB
congeners induces effects similar to those caused by chlorinated dioxins
and dibenzofurans. In common with that established for chlorinated dioxins
and dibenzofurans, the toxicity of such PCB congeners can be expressed
in terms of TCDD-equivalency factors (TEFs), i.e. expressed as a fraction
of the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For the
calculations performed in this document, data mainly from in vivo studies
have been utilized. However, it should be noted that the derived TEFs are
still based on acute effects at relatively high doses. Applying such TEFs
to samples of fish and human milk demonstrates that the contribution from
PCBs to large total dioxin-like toxicity is very important. Thus, in fish
the contribution from PCBs is at the same level as that from dioxins and
dibenzofurans although, so far, only non-ortho congeners have been analyzed.
In human milk, the total contribution from non-ortho and mono-ortho substituted
congeners is higher than that from dioxins and dibenzofurans. However,
not all of the mono-ortho-substituted PCB congeners have yet been an (incomplete
abstract) (Ahlborg et al, 1992)
Study Review #18
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PCBs alter immune function
The toxicity of polychlorinated biphenyls (PCBs) was discussed.
The uses of PCBs were summarized. The historical background leading to
the discovery that PCBs were a serious environmental contaminant was outlined.
Laboratory animal studies of PCB toxicity were reviewed. These have shown
that PCBs induce the hepatic cytochrome-P-450 isozyme system and amino-N-demethylase,
and aniline-hydroxylase activities. Prolonged dietary exposure to high
doses of aroclor-1254 (11097691) and aroclor-1260 (11096825) have caused
liver cancer in rodents. Industrial and environmental poisoning by PCBs
was considered. Induction of chloracne by industrial and environmental
PCB exposures was discussed. The Yusho poisoning incident was described.
The use of serum PCB concentrations as markers of PCB exposure was considered.
Alterations
in immune function induced by PCB exposure were discussed. Studies
of PCB metabolism in experimental animals were reviewed. These have shown
that PCBs accumulate in the body fat and lipotropic organs such as the
adrenals, brain, skin, and liver. Ingested PCBs are metabolized and excreted
primarily through the hepatobiliary system and kidneys. The carcinogenic
risk of PCBs for humans was discussed. Epidemiologic studies have suggested
that exposure to PCBs can cause liver and colorectal cancer and possibly
cancers at other sites. It was noted that although it is not possible to
extrapolate the results of animal studies to human exposure, PCBs can be
classified as category-I carcinogens. Treatment for PCB poisoning was discussed.
(Lemesh, 1992)
Study Review #19
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Aroclor PCB mixtures have been shown to produce immunosuppressive
effects
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.
(ATSDR, 1989)
Study Review #20
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PCB exposure has been reported to cause immune changes.
The adverse health effects associated with exposure to polychlorinated
biphenyls (PCBs) were explored in this chapter. A review of the acute and
chronic toxic effects of PCBs in laboratory animals demonstrated that the
primary target in rats and mice was the liver, while in chickens PCBs have
caused edema of the skin, pericardium, and the chest and abdominal cavities.
PCB exposure has also been reported to cause immune changes. Different
PCB isomers have been reported to have different effects resulting in difficulties
in interpreting the results of many studies. Epidemiological studies in
humans have reported adverse health effects such as increased blood pressure
and abnormal liver function following exposure to PCBs. Problems in the
interpretation of such studies were discussed. Studies have also demonstrated
reproductive effects following PCB exposure in animals; however, conclusive
evidence of such effects in humans has not been found. Studies on the effects
of PCBs on the immune system and the development of cancer in humans were
reviewed and the results were evaluated. The author concludes that in high
doses PCBs are toxic to animals; however, strong associations between low
level environmental or high level occupational PCB exposure and adverse
health effects in humans have not been demonstrated. (Kimbrough, 1993)
Study Review #21
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humans accidentally poisoned with PCBs suffered compromised
immune system function
-
laboratory animals show immunotoxic effects and thymus atrophy
Human health effects of polychlorinated-biphenyls (1336363)
(PCBs) and polybrominated-biphenyls (59536651) (PBBs) were reviewed. Studies
have indicated that PCBs are ubiquitous and very persistent in the environment,
resulting in widespread human exposure. Most human PCB exposure in the
United States resulted from eating fish from contaminated waters. PBBs
do not occur in the environment to any significant extent because they
have less commercial use than PCBs. PBBs and PCBs accumulate preferentially
in adipose tissue. In laboratory animal studies, PCBs generally affected
reproduction, exerted immunotoxic effects, and induced liver tumors
in rodents. Epidemiological studies showed that serum PCB concentrations
were positively associated with serum triglyceride and cholesterol concentrations.
Occupational exposure resulted in chloracne, pruritus, and eye, nose, and
throat irritation. PCBs affect the liver by inducing the mixed function
oxidase system. No conclusive evidence of human liver cancer resulting
from occupational exposure to PCBs has been obtained. Poisoning incidents
resulting from PCB contamination of rice-oil were described. The rice oil
contained both PCBs and polychlorinated dibenzofurans (PCDFs) and caused
chloracne, skin pigmentation, impaired liver function, and compromised
immune system function. Widespread, low level exposure occurred to
individuals living in the lower Michigan peninsula after a commercial PBB
mixture was inadvertently mixed with cattle feed. Symptoms in exposed persons
did not correlate well with PBB body burden. In laboratory animals, PBBs
caused effects similar to those of PCBs. Teratogenicity, thymus atrophy,
and hepatocellular carcinomas have been observed. The author concludes
that acute poisoning outbreaks have occurred only after exposure to a combination
of PCBs and PCDFs. Exposures to PCBs or PBBs alone have caused only minor
acute effects. No significant chronic health effects have been causally
associated with PCB or PBB exposure. [Note: PCBs are usually not alone,
but are found together with furans and dioxins --- as in the Fox River
and Green Bay.] (Kimbrough, 1987)
Study Review #22
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the immune system is a target for PCBs and perhaps one of
the most sensitive indicators for adverse PCB-induced health effects
-
certain PCBs bind to the body’s Ah receptor, which links
to the immune system
Polychlorinated biphenyls (PCBs) are widely spread environmental
contaminants consisting of chemical mixtures containing many of the 209
possible congeners. The potential immunomodulatory properties of PCBs
have been the subject of extensive experimental investigations. The
available evidence indicates that the immune system is a target for
PCBs and is perhaps one of the most sensitive indicators for adverse PCB-induced
health effects. Recent advances regarding the mechanism of PCB-induced
immunotoxicity point to their dependency on the presence of the aromatic
hydrocarbon receptor and their ability to bind to this receptor as the
venue for their toxicological activity. Their binding affinity depends
on the degree of chlorination of the biphenyl structure and the position
of the chlorine atoms. Such advances have contributed significantly to
the determination of the relative immunotoxic potential of PCB mixtures
and to the calculation of TEFs for several of the PCB congeners. Such information
is crit (incomplete abstract) (Tryphonas, 1994)
Other pages in this Immunity section:
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