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Immune Study Reviews 23-45
The following reviews show a strong link between PCBs and a weakened
immune system. For more information, see the Introduction.
Study Review #23
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PCBs may be involved in the immune response
An article summarizing the toxicology of polychlorinated-biphenyls
(PCBs) is reviewed. The problem of determining carcinogenicity of PCBs
in light of experimental data is presented. Animal data suggests involvement
of PCBs on the immune response, in addition to fetotoxicity and
carcinogenicity; chloracne and effects on liver function and serum lipids
are found in humans. The first Yusho outbreak is cited as the beginning
of concern about chronic toxicity of PCBs. The extensive spread of PCBs
in the environment is discussed, along with the presence of PCBs in foods.
About 50 percent of PCBs ever made are still in transformers and capacitors
and present considerable management and disposal problems. Body burdens
of PCBs in humans are assessed; PCBs are lipid soluble, are stored in adipose
tissue, and are present in serum and some organs. The impacts of trace
amounts of PCBs in tissue or serum on human health are not known. The biological
half life of PCBs in the human organism, and the achievement of a steady
state is considered. Flaws in assessment of toxic effects in workers and
in the general population are described; younger members of the population
have been exposed in-utero and during childhood. The author concludes that
because PCBs are extremely persistent and have chronic toxic and carcinogenic
effects in animals, it is necessary to reduce human exposures as much as
possible. (Kimbrough, 1983)
Study Review #24
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PCBs suppress the immune system
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 Review #25
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environmental chemicals that modify the immune functions
may also interact with chemical carcinogens
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immunotoxicity of one chemical can sometimes be modified
by a second chemical
Only a limited number of reports are available on interactions
between chemicals in relation to their effects in modifying immune functions.
In many cases the exact site of chemical immunotoxicity is not well understood
because immune functions are highly complex and multifaceted. Chemical
interactions that have been proposed are difficult to investigate. In several
cases the immunotoxicity of one chemical has been modified by a second
chemical that alters xenobiotic metabolism. Immunomodulation by drugs
having opposite effects on the immune system has been reported. Metals
can either enhance or suppress immune responses and studies involving interactions
of metals suggest both synergistic and antagonistic effects on immune responses.
Various environmental chemicals that modify the immune functions may
also interact with chemical carcinogens, especially since several carcinogens
are also immunosuppressive. (Sharma, 1984)
Study Review #26
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PCBs interfere with the immune system
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the fetus appears to be particularly vulnerable
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different PCBs cause different effects
Polychlorinated biphenyls (PCBs) were manufactured and used
widely for many years. Because they are very persistent in both the environment
and biological systems, there has been significant global contamination.
This review presents a summary of known or suspected health effects of
various PCB congeners, documented on the basis of both human and animal
studies. As our knowledge increases several important points become apparent.
PCBs interfere with many biological functions, including the immune
system, the nervous system, and several endocrine system, and the fetus
appears to be particularly vulnerable to these actions. PCBs cause certain
cancers in animals. PCBs are mixtures of multiple congeners, differing
on the basis of the numbers and positions of chlorines around the biphenyl
ring, and it is becoming increasingly apparent that different congeners
may have very different actions. These observations suggest that the potential
human health hazards from PCB exposure have been underappreciated. (Carpenter,
1998)
Study Review #27
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the immune systems of humans are not affected by PCBs (1993)
Health effects associated with exposure to polychlorinated
biphenyls (PCBs) were reviewed. Workers with the greatest PCB exposure
have been employed in the manufacture or repair of electrical capacitors
or transformers in which PCBs have been used as heat transfer fluids. The
health effects unequivocally associated with PCB exposure were chloracne,
skin hyperpigmentation, and chronic eye and skin irritation. These effects
have only been seen in workers with relatively high dermal or inhalation
exposures. The possibility that the skin problems could have been caused
by polychlorinated dibenzofuran contaminants, some of which are potent
chloracnegens, cannot be excluded. Clinical studies of the health effects
of PCB exposure have shown that the skin is the only organ system affected
by PCB exposure and that the skin disorders, primarily chloracne, occurred
only in persons occupationally exposed to relatively high PCB concentrations.
In contrast to experimental animal studies, other organ systems such as
the liver and immune and hematopoietic systems of humans are not
affected. The divergence between the effects observed in humans and animals
may reflect differences in interspecies susceptibility and exposure. The
authors conclude that there appears to be little basis for the concern
for internal organ system toxicity, especially since use and disposal of
PCBs is now strictly controlled. [Editor’s Note: please read all the other
human studies on this website for clear evidence of PCB effects on human
internal organs.] (James et al, 1993)
Study Review #28
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with the exception of sensitization, most of the PCB effects
observed in animals have not yet been observed in humans (1988)
Assessing the relevancy of tests of immunotoxic chemicals
in experimental animals to humans was discussed. The nature of the immune
system and immunotoxicity was summarized. The immunotoxic effects of chemicals
in humans were reviewed. Studies of the effects of polychlorinated-biphenyls
(1336363) (PCBs), polybrominated-biphenyls (59536651) (PBBs), and 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD), heavy metals such as lead (7439921), cadmium (7440439),
or mercury (7439976) were discussed. Although some of these studies have
indicated that certain parameters of immune function such as circulating
T-lymphocytes or serum immunoglobulins have been altered, few conclusive
data exist that show that industrial chemicals can cause clinically significant
immunosuppressive effects. A number of industrial chemicals such as diisocyanates
or phthalic-anhydride (85449) or similar acid anhydrides have been shown
to cause immunopotentiation in exposed workers resulting in allergic occupational
asthma and contact dermatitis. The immunotoxic effects of chemicals in
experimental animals were discussed. A large number of chemicals have been
found to affect cell mediated and humoral immunity and nonspecific defense
mechanisms. The immunosuppressive effects of PCBs, PBBs, TCDD, and
organotin compounds were summarized. It was noted that with the exception
of sensitization, most of the effects observed in animals have not yet
been observed in humans. The poor correlations could result from using
very high doses which cause overt toxicity, inappropriate methods of administration,
or species differences. Methods for assessing immunotoxicity in experimental
animals were discussed. Strategies for assessing immunotoxic effects of
chemicals in humans were considered. [Editor’s Note: please read all the
other human studies on this website for clear evidence of PCB immune effects.]
(Trizio et al, 1988)
Study Review #29
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the effect of many chemicals or their metabolites on immune
function are due to their direct effects or on lymphoid tissues.
The effects of environmental chemicals on the immune system
are reviewed. A number of chemicals of environmental concern may either
enhance or suppress various immune parameters. Environmental chemicals
affect host defense mechanisms as well; such chemicals include aromatic
halogenated hydrocarbons such as polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD). The salient features of the immune system are summarized,
cellular and humoral immune mechanisms are described. The development and
interactions of the different compartments of the immune system are illustrated.
The role of B-lymphocytes and T-lymphocytes in the immune process are outlined.
The role of macrophages and the process of phagocytosis are examined. The
immunotoxicology of polybrominated biphenyls, TCDD, and 2,3,7,8-tetrachlorodibenzofuran
(51207319) is discussed; in this discussion, studies of in-vivo and in-vitro
experiments are described. Studies on the effect of hexachlorobenzene (118741)
on the immune system are examined. The effects of pesticides, such as DDT
(50293), methylparathion (298000), and carbofuran (1563662), and inorganic
metals, such as lead (7439921) and cadmium (7440439), on immune function
are discussed; the effects of organometallics such as methylmercury (22967926)
are summarized. The methods of testing immune function for immunotoxicological
studies are enumerated. The effects of agents such as hormones and alpha-fetoprotein
on immune function are discussed. The authors conclude that the effect
of many chemicals or their metabolites on immune function are due to their
direct effects or on lymphoid tissues. (Faith et al, 1980)
Study Review #30
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a single assay of immune function may not be appropriate
to detect chemical induced immune dysfunction
It is therefore proposed that: 1) environmental chemicals
can have specific mechanisms of toxicity and can influence antibody-mediated
immunity while having no detectable effect on cell-mediated immunity, 2)
immune dysfunction is related to exposure time to a chemical and the tissue
concentration of that chemical, 3) recovery of immune function may occur
even though chemical exposure continues, and 4) a single assay of immune
function may not be appropriate to detect chemical induced immune dysfunction.
(Silkworth et al, 1979)
Study Review #31
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halogenated polyaromatic hydrocarbons (including PCBs) are
causative agents of immunodeficiency or immunosuppression
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PCBs are associated with autoimmunity and immune enhancement,
as well
The field of immunotoxicology was discussed with reference
to the cellular and molecular foundation of the immune system, the pathotoxicology
of the altered immune system, and several immunotoxic agents. The immune
defense system was described. Various cells which store or synthesize chemical
mediators of immunologic inflammatory responses were listed. The immune
response was discussed with emphasis on immunogens, antigens, and allergens;
the development and maturation of lymphoid tissues; characteristics of
the immune system; specifically reactive T-cells; immunologic memory; and
immunologic tolerance. The effector molecules of the immune responses,
such as immunoglobulins and interferons, were described as well as the
effector molecule responses from antigen/antibody interactions. Pathotoxicologic
mechanisms were classified in one of four categories: immunodeficiency
disease, cancer, autoimmunity and autoimmune reactions, and immunologic
tissue injuries. Several environmental agents were reported to have caused
immunologic alterations. Pesticides and insecticides, metals, halogenated
polyaromatic hydrocarbons, ozone (10028156), tobacco smoke and ionizing
radiation were noted as causative agents of immunodeficiency or immunosuppression.
Autoimmunity and immune enhancement have also been associated with
pesticides and metals. In addition, many pharmaceuticals, polychlorinated
biphenyls, quartz (14808607), and vinyl-chloride (75014) have been
noted to cause these effects. Allergic or hypersensitivity reactions have
been linked to pesticides,metals, pharmaceuticals, and trimetallic anhydrides.
Pesticides and metals have been implicated as immune system carcinogens.
(Szentivanyi et al, 1995)
Study Review #32
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in 1974, scientists already had evidence of PCBs causing
immune system damage
The toxicity of polychlorinated polycyclic compounds such
as polychlorinated biphenyls (PCB), polychlorinated terphenyls (PCT),
polychlorinated dibenzofurans (PCDF), polychlorinated dibenzodioxins (PCDD),
and polychlorinated naphthalenes (PCN) and similar compounds are reviewed.
Development, use, and occurrence of PCB, PCT, PCDF, PCDD, and PCN are discussed.
Analytical methods for determining the compounds are described. Photolysis
of the compounds is considered. The general toxicity and effects of PCB,
PCT, PCDF, PCDD, and PCN are examined. The acute toxicity of PCB, PCN,
and PCT is very low. These compounds, however, are not very biodegradable.
Metabolism of PCB containing more than 4 chlorines seems to be negligible.
PCN and PCT thus far have not been shown to present a pollution problem.
PCDD and PCDF are highly toxic; the most toxic being 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016). PCDD without any chlorine and those containing more than 8 chlorine
atoms are considerably less toxic. The difference in toxicity may reflect
differences in solubility and absorption capacity. Specific toxic effects
such as chloracne, photocontact dermatitis and skin irritation, chick edema,
Yusho disease, and immunosuppression are reviewed. Biochemical effects
such as porphyria, effects on vitamin-A, enzymes, and methemoglobinemia
are considered. Morphological effects of the compounds on the liver are
described. The neurotoxicity of the compounds is noted. Experimental
studies have indicated that chlorinated polycyclic hydrocarbons may affect
the immune responses of certain animal species. Additional research
on these findings is needed. Depending on the outcome of these studies,
the current tolerance dose of 5 parts per million set for these compounds
in food products by the Food and Drug Administration may have to be revised.
(Kimbrough, 1974)
Study Review #33
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immunotoxicity is one of the most significant health effects
of dioxins
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a number of PCBs (the planar and the mono-ortho planar PCBs)
cause effects corresponding with those of the 2,3,7,8-PCDDs (dioxins) and
PCDFs (furans)
Summary and toxicological recommended levels. Humans. In
mammals and humans selective retention occurs of 2,3,7,8,-substituted PCDDs
and PCDFs. Since these compounds have very long half-lives they accumulate
in body fat. There is great variance in susceptibility of various experimental
animals for 2,3,7,8,-TCDD, which may only partly be explained by differences
in toxicokinetics and variations in cellular levels of Ah-receptors (to
which 2,3,7,8-TCDD binds). The most significant effects following longterm
exposure are liver- and immunotoxicity and effects on the reproduction
and teratogenicity in experimental animals. 2,3,7,8-TCDD is carcinogenic
in experimental animals, however, insufficient evidence exists to prove
its carcinogenicity in humans. It has also been shown to possess a strong
promotor action in the liver of rats, whereas no initiating action was
demonstrated. There is insufficient evidence to consider 2,3,7,8-TCDD to
be genotoxic. With respect to the mechanism of action of 2,3,7,8-TCDD it
is internationally concluded that in order for 2,3,7,8-TCDD to cause any
effects it must first bind to an intracellular receptor, the Ah-receptor.
Following binding to this "dioxin-receptor" the induction of P450 IA1 occurs
as the first observable effect, via (as yet) unknown mechanisms. The other
effects are assumed to be related with this induction. In the determination
of a toxicological recommended value based on these data a threshold value
is assumed to exist. In a great number of epidemiological studies among
occupationally exposed persons as well as among population groups exposed
due to industrial accidents, chloracne was the only effect consistently
related to dioxin exposure. In all of these studies mixed and not properly
quantified exposure was involved. Of all the human data those concerning
Seveso are the most important. However, as the exposure there could not
be properly quantified also, these data are not suitable for the determination
of a recommended value. At the WHO/EURO meeting (1990) the following method
was used to determine the tolerable daily intake (TDI) for 2,3,7,8-TCDD.
Data from Seveso and those from animal experiments showed that serum levels
in humans which could not be associated with effects, did cause effects
in experimental animals. From this it could be safely concluded that humans
are not more susceptible than are experimental animals. In further calculations,
to be on the safe side, the WHO assumed the susceptibility of humans and
experimental animals to be the same. This holds that at a similar internal
concentration (in a specific target organ) the effects in humans and in
experimental animals will be similar. Since the liver is a primary target
organ, the internal concentration in the liver was taken as a starting
point. By means of pharmaco-kinetic calculations, based on a specific intake
by experimental animals, the resulting internal concentration in the liver
may be calculated, and subsequently the intake by humans resulting in similar
internal concentrations. Hence the no effect dose in experimental animals
can be converted into a no effect dose in humans. Chronic studies with
rats show a no effect dose of 1 ng.kg-1 body weight per day for liver toxicity
as well as for effects on the reproduction. Via the pharmacokinetic approach,
based on a steady-state situation, it was determined that a daily exposure
to 1 ng.kg-1 body weight in rats over 2 years results in a liver concentration
which in humans will be reached at a daily intake of 100 pg.kg-1 body weight
over 70 years. Thus the no effect dose for humans is 100 pg.kg-1 body weight
per day. For effects on the production it may not be assumed that humans
are not more susceptible, due to the unreliable data from Seveso. Furthermore
the data from Seveso show a great variability in susceptibility for dioxin
exposure within the population. Therefore the WHO recommended a tolerable
daily intake in 1990 of 10 pg 2,3,7,8-TCDD per kg body weight per day,
using the no effect dose of 100 ng 2,3,7,8-TCDD per kg body weight, with
a safety factor of 10 (WHO, 1991; Theelen et al., 1991). This WHO-recommendation
was supported by the RIVM (note Knaap, 1991). Assessment of mixtures. With
regard to 2,3,7,8-TCDD related compounds the WHO has (as yet) not made
any recommendations. According to the WHO the TEF principle for the determination
of the risk is useful, although according to them the risk will be slightly
overestimated. Since no data are available to quantify the degree of overestimation,
the RIVM for the time being recommends in the assessment of mixtures to
interpret the recommended value as 10 pg TEQ per kg body weight per day.
Hereby the TEF values recommended by the TEF working group need to be taken
up. A number of PCBs (the planar and the mono-ortho planar PCBs) cause
effects corresponding with those of the 2,3,7,8-PCDDs and PCDFs. Therefore,
in a number of articles, these compounds are considered to be dioxin related
(McKinney et al., 1985; Leece et al., 1985; Safe, 1987). Since humans and
animals are exposed to PCBs as well as to PCDDs and PCDFs, Safe et al.
(1990) and the Dutch TEF working group have proposed TEF-factors for these
compounds as well. In a RIVM study recently carried out (Liem et al., 1991),
levels of PCB have also been determined in foodstuffs, in addition to those
of 2,3,7,8-substituted PCDDs and PCDFs. Based on these data the median
intake of planar PCBs by adults and children is calculated. Based on the
TEF-factors of the Dutch TEF working group the median intake for adults
amounted to 1 pg TEQ.kg-1 body weight per day. For children and adolescents
(up to 20 years) the daily intake was slightly higher (due to a lower body
weight). These figures mean that the median exposure to TEQ is doubled
when the TEQ is considered as the sum of TEQ as a result of 2,3,7,8-substituted
PCDDs and PCDFs, and TEQ as a result of planar PCBs. Aquatic and terrestrial
environment. In the determination of ecotoxicological recommended values
(maximally tolerable risk levels, MTRs) it was departed from the RIVM guidance
document (Slooff, 1992). In the current report it is indicated which extrapolation
methods are currently used within the RIVM. If the data allow, two MTRs
are determined per environmental compartment, one based on the results
of single species toxicity data, for the protection of aquatic ecosystems
(MTRecosystem) and one on food-chain poisoning, for the protection of predators
(MTRpredator). In both cases different extrapolation methods are available,
a more advanced refined effect assessment method (used to calculate a 95
% protection level based on the distribution of chronic NOEC values or
chronic NO(A)EL-values) and a less advanced preliminary effect assessment
method, whereby fixed extrapolation factors are used. For the application
of the refined effect assessment method for the determination of a MTRecosystem
and a MTRpredator a minimum of 4 chronic NOEC-values (for different species)
and 4 chronic NO(A)EL-values (for different mammalian species), respectively,
are required. In the determination of MTRs for dioxins, due to the limited
number of reliable toxicity data, only the preliminary effect assessment
method can be applied, based on the data for 2,3,7,8-TCDD. The MTRs determined
are therefore considered as indicative values. For a further general elucidation
of the extrapolation methods reference is made to Slooff et al. (1992).
An overview of (incomplete abstract) (Bremmer et al, 1993)
Study Review #34
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immunotoxicity studies produce variable results, using a
wide variety of measures
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a broad database of normal human immunological endpoints
needs to be established for use in immunotoxicity assessments
Recent developments in the study of the immunotoxicity of
halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD) and related polychlorinated dibenzo-p-dioxins (PCDDs),
polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls
(PCBs) were discussed. Cited studies of host resistance showed that
TCDD exposure increased susceptibility to bacterial, viral, parasitic,
and neoplastic disease. Numerous studies demonstrated that while TCDD/induced
thymic atropy in adult animals does not affect immunological response,
prenatal and neonatal TCDD exposure induces thymic atropy and impairs the
immune system. Studies in inbred mice relating HAH immunotoxicity to aromatic
hydrocarbon (Ah) receptor dependent events were described. The Ah relationship
has only been demonstrated in mice and its importance in chronic, low level
HAH immunotoxicity has not been established. Several studies on the mechanism
of HAH immunotoxicity in which helper T-cells, B-lymphocytes, and macrophages
were implicated as target cells were discussed. The involvement of interleukin-1
and tumor necrosis factor were also mentioned as possible mechanisms. The
inconsistency of in-vivo with in-vitro and ex-vitro results in the study
of HAH immunotoxicity was acknowledged. The possible role of endocrine
hormones as part of an indirect mechanism for immunotoxicity was discussed.
Antibody response to sheep red blood cells (SRBC) was identified as an
immunological parameter consistently suppressed by HAH across most animal
species. Studies of exposed nonhuman primate response to SRBC were discussed.
Immunotoxic effects of accidental HAH exposure in the victims of rice-oil
contamination, Michigan dairy farmers, Missouri residents, and children
from Seveso, Italy were described. Several explanations for the lack of
a definite pattern of immunotoxicity to these exposures were presented.
The author concludes that a broad database of normal human immunological
endpoints needs to be established for use in immunotoxicity assessments.
(Kerkvliet, 1994)
Study Review #35
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chemical exposures may lead to immunosuppression, immunopotentiation,
hypersensitivity or perturbed innate host resistance
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No one infectious model has yet emerged as a routine screening
tool to detect and assess the subtle effects that may occur in immune responses
There is increasing evidence that chronic, subclinical exposure
to certain environmental pollutants may upset immune responsiveness and
alter susceptibility of animals to infectious agents. Environmental
chemicals or drugs may affect diverse aspects of the immune system,
leading to immunosuppression, immunopotentiation, hypersensitivity or
perturbed innate host resistance. A variety of infectious models is
available that involves relatively well defined target organs and host
defense mechanisms; for example, infections with encephalomyocarditis virus,
Herpesvirus simplex, Listeria monocytogenes, Streptococcus pneumoniae,
Escherichia coli or Plasmodium berghei. Important variables in infectious
models used to assess immunotoxicity include species and strain of animal
used, their age and sex, the route of exposure, and dose of the chemical.
No
one infectious model has yet emerged as a routine screening tool to detect
and assess the subtle effects that may occur in immune responses when
animals are exp (incomplete abstract) (Bradley et al, 1982)
Study Review #36
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effects on the immune system have been demonstrated in the
low dose range but clear dose-effect relationships are lacking
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immunological effects have been demonstrated in humans but
data so far do not allow any quantitative conclusions to be drawn. Due
to the lack of quantitative data from studies in humans, the risk assessment
has to be based on experimental animal data
Critical effects in the low dose range: Based on animal studies,
critical effects in the low dose range can be identified in 3 areas: -
carcinogenic effects - adverse effects on reproduction - immunological
effects. With regard to carcinogenic and reproductive effects, quantitative
dose-response or dose-effect relationships can be obtained and no effect
levels (NOEL) or lowest effect levels (LOEL) for TCDD be determined at
1 ng/kg bodyweight and day. Effects on the immune system have been demonstrated
in the low dose range but clear dose-effect relationships are lacking.
Studies verifying a connection with carcinogenic or reproductive effects
in humans are lacking. Immunological effects have been demonstrated
in humans but data so far do not allow any quantitative conclusions to
be drawn. Due to the lack of quantitative data from studies in humans,
the risk assessment has to be based on experimental animal data. Due
to the long biological half-life of most of the PCDDs and PCDFs and taking
into account that life-long exposure occurs, the group recommends that
a concept of a tolerable weekly intake (TWI) should be used. Bearing in
mind that the dose 1 ng/kg bodyweight and day from the animal data has
not been established beyond doubt as a NOEL, a safety factor of 200 is
proposed. Thus: TWI = 0 - 35 pg TCDD / kg bodyweight and week The group
considered the safety factor approach as relevant, taking into account
available information regarding the probable underlying mechanism for TCDDs
carcinogenic effect. The present data base does not allow for any proposals
as regards tolerances for specified food items. Considerations concerning
consumption of e.g. fish from certain locations have to be made in each
individual case, taking into account levels, species, patterns of consumption
and possible exposure from other sources (see below). Identified risk groups:
At the moment, based on available exposure data, 3 different risk groups
can be identified. Infants: Results from the analysis of 48 individual
human milk samples from Norway and Sweden show a mean level of 18 pg TCDD-
equivalents/g fat (individual variation 10 - 47). Based on an average intake
of 0.7 l milk daily with an average fat content of 3.5 % this will give
a child of 5 kg a weekly intake in the order of 600 pg/kg bodyweight. This
is considerably higher than the recommended TWI of 0 - 35 pg/kg. However,
the TWI assumes life-long intake and cannot be directly compared with the
time- limited intake of milk by the infant. Furthermore, a WHO expert group
meeting has calculated that the present intake of PCDDs/PCDFs through mother's
milk will not result in significantly increased concentrations of these
compounds in the infant's body. This is due to the considerable increase
in fat content (about 2 kg) of the infant during the breast feeding period.
The WHO group concluded that there is still a margin between the intake
in infants and the body burden that might be expected to cause health effects.
The Nordic expert group supports that conclusion. Nevertheless, this margin
is not large and it cannot be excluded that the infant may be more sensitive
to these contaminants. The positive impact of breast feeding, however,
is so notable that it should be promoted regardless of these uncertainties
but the limited margin of safety does call for powerful attempts to further
reduce the emissions of these contaminants into the environment. Populations
with high consumption of fish: At the present time the contribution from
diet to overall exposure to PCDDs/PCDFs cannot clearly be ascertained,
but it is clear that certain food items may contribute and it is likely
that diet is the main source of human exposure to these compounds. Assuming
a weekly intake of 7 l cow's milk (3 % fat) containing 30 pg/l TCDD-equivalents,
this will give a weekly intake of TCDD-equivalents of = 3 pg/kg and = 12
pg/kg for grown-ups and children, respectively. So far only a limited number
of fish samples have been analyzed and the data indicate large variations
in levels depending upon species and location. However, taken together,
the data so far indicate that fish might be an important source of human
exposure. Cod, herring (not from the Baltic), pike and cultivated salmon
can be eaten even by consumers with a high fish intake (840 g per week
and person), without exceeding the TWI. Herring from the Baltic can be
eaten by average consumers (210 g per week and person) without exceeding
the TWI. Heavy consumers eating only herring from the Baltic will exceed
the TWI with a factor 2-3. An average consumer eating only salmon from
the Baltic or arctic char from the lake Vättern in Sweden, will exceed
the TWI with a factor 2-4. The corresponding factor for a heavy consumer
will be 8-16. The examples given above are worst case calculations assuming
exclusive intake of a specified number of fish species. The intake of a
more general fish diet will probably neither present a problem for normal
consumers nor for heavy consumers. Special groups with a high intake of
certain fish species, however, might represent a risk group. Occupationally
exposed: Exposure can probably occur in several occupational situations
but mainly in connection with work involving chlorinated phenols. The limited
number of analytical measurements (with modern techniques) performed on
workers with suspected exposure have only demonstrated one example with
elevated serum levels of PCDDs/PCDFs (chain saw operators) as compared
to local controls. When compared with larger control data however, the
levels were within normal limits of variations. Workers exposed to PCDFs
in connection with PCB-fires have, besides classical acute PCB-related
effects, shown effects on the cell-mediated immune system and the
peripheral nervous system. Quantitative risk estimates: The 3 risk groups
specified above are characterized in that the exposure to PCDDs/PCDFs might
be higher than the would-be tolerated life-long exposure. A comparison
of intake or body fat levels in these groups with what has been measured
in an intoxicated Japanese population (Yusho), indicates that both the
high intake in adults with a high consumption of certain fish species as
well as what can be estimated for children or has been measured in fat
from adult in the Nordic countries, are 1-2 orders of magnitude lower.
The precision in such an estimate, however, is low and the margin of safety
limited. Furthermore, it cannot be excluded that an individual might
belong to several risk groups. Taken together, this strongly indicates
that further reduction of the exposures should be initiated. The major
way to achieve that will be through reduction of the discharge of these
compounds to the environment. The present data base does not suggest that
any dietary restrictions should be made. However, the limited margin of
safety may make such restrictions necessary when the data base has been
enlarged. Ecotoxicological aspects: Based on our knowledge of the effects
of PCDDs/PCDFs on experimental animals, effects on the fauna may be expected,
at least on organisms at the top of the food chain. However, the available
data base does not allow any conclusions to be drawn. [Note: much more
information is available now demonstrating low-level PCB effects] (Nordic
Expert Group, 1988)
Study Review #37
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immune suppression may increase the risk of tumors or cancer
-
PCBs have been shown to alter tumor transplantation resistance
Effector mechanisms and modeling of neoplastic consequences
of immune suppression were reviewed. The hypothesis of immune surveillance
as a host system of resistance to tumor development was discussed. Descriptions
were offered of natural tumor resistance effectors, including natural killer
or cytotoxic cells and macrophages, and acquired resistance effectors,
including cytotoxic T-lymphocytes and macrophages activated by antibody
dependent cellular cytotoxicity or by macrophage activation factor. Animal
tumor systems were discussed in terms of their use in assessing immunosuppressive
or immunoenhancing effects of compounds, depending on the tumor challenge
dose used. Chemicals and metals which have been shown to alter tumor
transplantation resistance in mouse models include arsenic (7440382),
cadmium (7440439), chromium (7440473), cyclophosphamide (50180), diethylstilbestrol
(56531), dieldrin (60571), 7,12-dimethylbenzanthracene (57976), hexachlorobenzene
(118741), lead (7439921), nitrobenzene (98953), pentachlorophenol (87865),
polychlorinated-biphenyls
(1336363), phorbol-myristate-acetate (17673255), 2,3,7,8-tetrachlorodibenzo-p-dioxin
(1746016) (TCDD), tobacco smoke, and urethane (51796). In the case of TCDD,
adult exposure and challenge were negative while in-utero exposure was
positive. Metastatic and nonmetastatic models were briefly discussed. In-vitro
assays using human or animal peripheral blood or spleen lymphocytes and
tumor cell lines were described. Natural and acquired resistance could
be measured in such assays, and they were often consistent with in-vivo
incidence of spontaneous tumors. The authors conclude that in-vivo tumor
challenge models and in-vitro tumoricidal activity assays are sensitive
endpoints for detecting immune modulation, and that in-vitro assays may
prove to be very useful for safety assessment of chemicals. (Murray et
al, 1984)
Study Review #38
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PCBs are reported to increase susceptibility to infection
or decrease immunological responsiveness
Only a limited number of chemicals have been shown in toxicity
studies to have immunosuppressive properties, and the cell-mediated immunity
in particular has been poorly studied. Current procedures for toxicity
testing underestimate the important of the immune system. The body is protected
by a specific immunity based on the establishment of immunological memory
of a substance as well as a nonspecific resistance system including lytic
mechanisms and complement (properdin pathway). There is now abundant evidence
for the existence of two distinct but not entirely independent specific
immunity systems: cell-mediated immunity and humoral immunity. The concept
of the mononuclear phagocyte system has recently been coined to replace
the concept of the reticuloendothelial system, covering fixed and free
macrophages and their precursors. A discrimination must be made from the
toxicologic viewpoint between direct effects on the immune systems and
indirect effects exerted, e.g., via nutritional deficiencies, pathogenic
organisms, and changes in endocrine balance. Procedures suitable for detecting
immune suppression in routine toxicity studies are presented, and for examining
immune system function. Industrial compounds and environmental pollutants
reported to increase susceptibility to infection or decrease immunological
responsiveness are reviewed. These compounds include dioxin, tin compounds,
lead and cadmium, arsenicals, DDT, PCB, dieldrin, and carbaryl.
(Vos, 1977)
Study Review #39
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observed immune changes are usually slight and do not allow
firm predictions of health effects
The immune system is able to recognize and neutralize potentially
harmful agents, conferring to the organism resistance to infectious and
malignant diseases. The authors have reviewed the literature and identified
a group of substances able to enhance and/or reduce different immune functions,
both in an experimental model and in occupational and environmental human
exposure. The group includes several polyhalogenated hydrocarbons, particularly
polychlorinated
biphenyls, polybrominated biphenyls, tetrachloro-dibenzo-p-dioxin (TCDD),
some metals like lead, cadmium and mercury, pesticides, i.e. dithiocarbamates
and organotin compounds, organic solvents. The observed changes are
usually slight and do not allow prognostic conclusion. In this study,
the authors propose a 3-level rank of tests suitable for the immune evaluation
of individuals occupationally exposed to xenobiotics, divided into three
levels, as follows: tier 1: immunoglobulin classes (IgG, IgA, IgM), complement
fractions (C3, C4), rheumatoid (incomplete abstract) (Colosio et al, 1998)
Study Review #40
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the capacity of chemicals to trigger autoimmune diseases
in humans is poorly studied because of basic research method difficulties
-
non-invasive tests of humans are limited
-
responses in the human population are heterogenous (we each
have different genetic susceptibilities, so we each respond differently)
-
exposure levels are often low (which may make effects more
subtle, infrequent or difficult to detect)
There is growing interest and concern in society about the
capacity of chemicals to impair immune responses and trigger autoimmune
disease. Methods to investigate chemical-induced immunosuppression have
been developed and validated in the mouse and rat. Animal models that are
suitable to investigate the ability of chemicals to induce autoimmune disease
are virtually lacking. From the plethora of tests to assess immunity in
man, panels of biomarkers to study immunotoxicity in humans have been proposed.
Such studies in humans are considerably more complex than in animals as
non-invasive tests are limited, responses in the population are heterogeneous,
and exposure levels are often low. Human risk assessment is therefore
mostly based on animal studies. As examples of compounds affecting biomarkers
in animals and man, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and hexachlorobenzene
are discussed. (Vos et al, 1995)
Study Review #41
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PCBs are immunotoxic
-
immunosuppression and immunodepression equal decreased resistance
to viral, bacterial, fungal, and other infectious agents or increased susceptibility
to cancer
-
immunoenhancement equals increased risk of autoimmune reactions
or allergic reactions
The immune system plays a crucial role in maintaining health;
however, accumulating evidence indicates that this system can be the target
for immunotoxic effects caused by a variety of chemicals including the
environmental pollutants of polychlorinated biphenyls, chlorinated
dibenzo-p-dioxins, pesticides, and heavy metals. Adverse chemical-induced
immunomodulation, which is studied within the discipline of immunotoxicology,
may be expressed either as immunosuppression/immunodepression or immunoenhancement.
The former may be manifested either as decreased resistance to opportunistic
viral, bacterial, fungal, and other infectious agents or increased susceptibility
to cancer. Immunoenhancement on the other hand may either increase the
risk of autoimmune reactions or result in allergic reactions. This paper
attempts to integrate several aspects of the immune system that are relevant
to the assessment of potentially immunotoxic chemicals. (Krzystyniak et
al, 1995)
Study Review #42
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PCBs are immunotoxic, based on evidence from agricultural
accidents
Immunotoxic reactions to polyhalogenated hydrocarbons, heavy
metals, pesticides, organic dusts and air pollutants in the agricultural
environment were reviewed. Polyhalogenated hydrocarbons and contaminants
were discussed, including chlorophenols, polychlorinated dibenzo-p-dioxins,
polychlorinated dibenzofurans and polychlorinated biphenyls, along
with their immunotoxic effects. 2,3,7,8-Tetrachlorodibenzo-p-dioxin was
named as the most toxic contaminant of chlorophenols. The disparity between
results from animal studies and human exposures to polyhalogenated hydrocarbons
was discussed. Agricultural accidents involving polybromated biphenyls,
polychlorinated
biphenyls and aniline were described, with attention
to immunotoxic
effects. Heavy metals, including cadmium, arsenic, copper, zinc, chromium,
mercury, nickel and lead were discussed in terms of health effects, with
emphasis on immunotoxicity. The immunotoxic effects of the pesticides pentachlorophenol,
diethyl-fumarate, chlorinated hydrocarbons, organophosphates, chlorpyrifos
and aldicarb were evaluated. Exposure to organic dusts was also discussed
in relation to immunotoxicity. Microbial components, cotton dust and fungal
products were implicated in the causation of immunotoxicity and specific
symptoms were discussed. Air pollutants, including ozone, wood smoke, engine
exhaust, sulfur-dioxide and nitrogen-dioxide were described in terms of
their immunotoxic effects. (Burrell, 1995)
Study Review #43
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workplace exposures to toxins affecting the blood-forming
and immune systems are of basic importance
The toxic effects of environmental factors at work places
on the hematopoietic and immune systems are of basic importance
due to the time of exposure, lasting on average 8 hours daily during one
week. Porphyrinurias and porphyrias have been observed after exposure to
hexachlorobenzene, chlorinated dibenzodioxins, polychlorinated biphenyls,
polybrominated biphenyls, vinyl chloride and lead. Aplastic anemia may
occur after exposure to benzene, pesticides, arsenic, cadmium and copper
compounds. Megaloblastic anemia has been noted in subjects exposed to arsenic,
chlordane, benzene and nitrous oxide. Methemoglobinemia is induced by aromatic
nitro and amino compounds. Hemolytic reactions caused by arsenic, methyl
chloride, naphthalene, lead, cadmium and mercury compounds represent a
separate problem. Immunodeficiencies resulting in decreased antitumor and
antiinfectious immunity have been reported in subjects exposed to asbestos,
ozone, dimethylsulphoxide, vinilidene chloride, and benzene homologues.
Lymph (incomplete abstract) (Lisiewicz, 1993)
Study Review #44
-
immunotoxicity of PCBs is a concern in silicone oil used
in eye operations
In articles about the analysis of intraocular silicone oil,
mostly the amount and toxicity of low-molecular-weight components (LMWC)
have been investigated. This study was intended to analyze the components
of silicone oil following a longer intraocular application. We analyzed
silicone
oil removed from human eyes with PVR a few months postoperatively.
The fraction of LMWC was further investigated and we separated 16 different
components belonging to hexachlorhexanes (HCH), polybiphenyls (PCB)
and dichlor-diphenyl-trichlorethane (DDT). All these substances are said
to have a toxic and cancerogenic effect as well as weakening the immune
system. The concentration of these organic chloride components measured
in intraocular injected silicone oil is about the same as fatty tissue
but exceeds the concentration in human blood enormously. Possible
damage to the retina by these toxic substances is another reason for early
removal of silicone oil if the situation of the retina is stable. (Bambas
et al, 1995)
Study Review #45
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immune systems are affected by PCBs, dioxins and dibenzofurans
An international workshop reviewed 20 ongoing or recently
completed studies of the effects of perinatal exposures to dioxins, dibenzofurans,
and PCBs on the reproductive, endocrine, neurodevelopmental, and immune
systems. Many of the observed effects are consistent with these compounds
acting as "environmental hormones" or endocrine disrupters. This report
summarizes the conclusions and future directions described at the workshop.
(Lindstrom et al, 1995)
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