Statistical considerations in the quantitation of serum immunoglobulin levels using the enzyme-linked immunosorbent assay (ELISA).

Several methods for analyzing ELISA data have been evaluated using optical density values derived by reacting serial two-fold dilutions of a rhesus monkey (Macaca mulatta) reference serum with dilutions of peroxidase-conjugated monospecific antisera to human IgG and IgM in the micro-ELISA 'sandwich' technique using microplates coated with appropriately diluted antisera to human IgG and IgM. Representation of optical density as a linear function of log serum dilution was shown to be inappropriate and potentially misleading. Weighted non-linear least squares analysis of a 4-parameter logit was demonstrated to be inappropriate because it required the specification of a somewhat arbitrary variance function and weight estimates varied substantially depending on the function used. Representation of optical density as a 4-parameter logistic function with estimation carried out on the log scale was shown to be the most appropriate procedure for determining the concentration of antigens or antibodies by the ELISA method.

Approaches to detecting immunotoxic effects of environmental contaminants in humans.

Experimental animal studies indicate that environmental contaminants can have adverse effects on several organs and tissues of the immune system. Such effects are known to lead to increased host susceptibility to microbial infections and to compromised immunosurveillance mechanisms normally instrumental in the elimination of neoplastic cells and the prevention of autoimmune diseases. Evaluation of the potential risk environmental contaminants pose to the human immune system is currently accomplished via extrapolation of experimentally derived animal data to humans. Presently, this process requires that uncertainty factors such as interspecies differences and genetic variability be considered. Naturally, the process of risk assessment would be greatly facilitated if it were based on clinically relevant data derived from studying humans known to be exposed to environmental contaminants. However, the existing human data are scarce and often described as very limited in scope. To generate the much-needed human data we need to identify a set of clinically relevant immunologic end points that, when adequately standardized, can be incorporated easily into the design of prospective epidemiologic studies.

Immunotoxicity of PCBs (Aroclors) in relation to Great Lakes.

Polychlorinated biphenyls (PCBs) are among the most widespread environmental pollutants and a prominent contaminant of the Great Lakes basin. Due to their resistance to biodegradation and lipophilic properties, PCBs bioaccumulate in fish tissues and in fish-eating humans. PCBs are also known to cross the placenta and to be excreted into the mother's milk, thus predisposing the infant to potentially adverse health effects. For example, a higher incidence of bacterial infections was reported for breast-fed infants born to mothers who consumed large amounts of Great Lakes fish compared to the incidence in control infants whose mothers ingested low amounts of fish. While data regarding the PCB-induced immunotoxic effects in humans are scarce, data derived from the use of experimental animals, including nonhuman primates, indicate that the immune system is a potential target for the immunotoxic effects of PCBs. Such studies have used the commercially available PCB mixtures alone. However, PCBs have the potential of partially antagonizing the effects of other structurally related compounds including the highly toxic dioxins, which are also present in small amounts in the Great Lakes. Thus, to fully evaluate the magnitude of the immunotoxic risk PCBs pose to humans, consideration should be given to investigations in which the interactive effects of PCBs are combined with other contaminants present in the Great Lakes.

Approaches to the evaluation of chemical-induced immunotoxicity.

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.

Immunotoxicity of heavy metals in relation to Great Lakes.

Heavy metals including mercury, lead, and cadmium are present throughout the ecosystem and are detectable in small amounts in the Great Lakes water and fish. The main route of exposure of humans to these metals is via the ingestion of contaminated food, especially fish. Extensive experimental investigations indicated that heavy metals alter a number of parameters of the host's immune system and lead to increased susceptibility to infections, autoimmune diseases, and allergic manifestations. The existing limited epidemiologic data and data derived from in vitro systems in which human peripheral blood leukocytes were used suggested that the human immune system may also be at increased risk following exposure to these metals. The magnitude of the risk that the presence of such metals in the Great Lakes may pose to the human immune system, and consequently to their health, is not known. In this review, the available data with respect to potential adverse effects of heavy metals on the immune system of humans and experimental animals are discussed, and additional data requirements are suggested.

Effect of deoxynivalenol (vomitoxin) on the humoral immunity of mice.

The effects of vomitoxin (deoxynivalenol; DON) on the immune system were studied in groups of weanling male Swiss Webster mice administered by gavage 0.75, 2.5, and 7.5 mg of vomitoxin per kg body weight. Untreated controls and solvent controls (propylene glycol, ethanol, and distilled water in a ratio of 4:1:5) were also included in this study. Serum antibody (IgM) levels to sheep red blood cells (SRBC) were significantly reduced in the treatment groups compared to the control groups. Plaque-forming cell (PFC) numbers were also lower in the treated groups compared to the control groups. Furthermore, vomitoxin at a dose of 0.75 mg/kg resulted in a significant increase in the albumin, albumin/globulin ratio and a decrease in the alpha-2 globulin fraction compared to the control groups. Administration of 7.5 mg/kg of vomitoxin resulted in deaths, due to toxicity, in all animals of this group within 3 weeks. These preliminary findings are indicative of a potential effect of vomitoxin on the immune system which could have serious implications to man.

Effects of deoxynivalenol (vomitoxin) on the humoral and cellular immunity of mice.

Sublethal doses (0.00, 0.25, 0.50 and 1.00 mg/kg b.w./day) of vomitoxin (deoxynivalenol; DON) were studied for their effects on humoral and cellular immunity and serum proteins of inbred, male Swiss Webster mice in a series of 4 separate experiments. Vomitoxin was added to basal diet (less than the detection limit, i.e., less than 0.05 micrograms of vomitoxin per g of feed) and administered to mice for 5 weeks beginning at 21 days of age. Mice in experiment 2 were fed the basal diet for 40 days in addition to the 5-week treatment with vomitoxin. The 1.00 mg/kg dose of vomitoxin resulted in a statistically significant reduction in the serum levels of alpha 1 and alpha 2-globulins, an increase in total serum albumin, and a reduction in feed consumption and body weight gain compared to the control group. The 0.50 mg/kg dose of vomitoxin resulted in significantly reduced serum levels of alpha 2- and beta-globulins while a significant reduction of feed consumption was evident only during Week 4. Similarly, body weight gain in this group of mice was significantly reduced during Week 2 but increased to normal levels during Week 3 and remained parallel to the control for Week 4 and 5. Both levels (0.50 and 1.00 mg/kg) of vomitoxin resulted in a reduced, dose-related, time-to-death interval following a challenge with L. monocytogenes and increased proliferative capacity of splenic lymphocyte cultures stimulated with the phytohemagglutinin P (PHA-P) mitogen compared to the control group of mice. The 0.25 mg/kg dose of vomitoxin did not have any significant effects on the parameters studied. A reasonable estimation of a 'no effect' level for immunologic effects in mice based on these and previous immunological studies would seem to be between 0.25 and 0.50 mg/kg b.w./day.

Enumeration of lymphocyte subsets in peripheral blood of rhesus monkeys prior to and following monocyte removal using a modified indirect avidin-biotin immunoperoxidase technique.

A modified avidin-biotin immunoperoxidase technique has been used to enumerate B lymphocytes, T inducer/helper (TH) and T cytotoxic/suppressor (TS) cells in the peripheral blood of normal and immunosuppressed rhesus monkeys (Macaca mulatta) prior to and following adherent-cell depletion. The levels of each of the B, TH and TS cells detected in the normal monkeys using monoclonal antibodies which recognized specific surface antigens on human lymphocytes were comparable to the levels reported in human peripheral blood using direct immunofluorescence, immunoperoxidase or flow cytometry techniques. Adherent cell depletion did not result in a significant loss of any of the lymphocyte subpopulations examined. The technique is reproducible and sensitive in detecting differences between normal and immunosuppressed animals, and would prove to be useful in studies pertaining to chemical and drug immunomodulation.

Oral (gavage), in utero and postnatal exposure of Sprague-Dawley rats to low doses of tributyltin chloride. Part 1: Toxicology, histopathology and clinical chemistry.

Tributyltin (TBT) is a biocide that contaminates foods, especially shellfish. TBT is an endocrine disrupter in several marine species and is neurotoxic and immunotoxic in mammals. We have examined the effects of exposure to low doses of tributyltin chloride (TBTC) from day 8 of gestation until adulthood. Pregnant rats were gavaged daily with 0, 0.025, 0.25 or 2.5 mg TBTC/kg body weight from day 8 of gestation until weaning. Stomach contents of suckling pups contained undetectable levels of TBT and dibutyltin (DBT) levels were detectable only in the highest TBTC dose used, indicating negligible lactational transfer to pups. Post weaning, pups were gavaged daily with the same dose of TBTC administered to their mothers and sacrificed on post-natal days (PND) 30 (males and females), 60 (females) and 90 (males). TBTC had no effects on dams' body weights, food consumption, litter size, sex ratio or survival of pups to weaning. However, all doses of TBTC significantly affected parameters of the growth profile of the pups (mean body weights, average slope, curvature) and the ratio of weekly food consumption to weekly body weight gain indicated enhanced food conversion to body mass in females but a decreased conversion in males. Liver, spleen and thymus weights were also affected by TBTC. In male pups dosed at 2.5 mg/kg/day, reduced serum thyroxine levels were evident, indicating that the thyroid is a target for TBTC toxicity. No histopathological lesions were seen in the liver but elevated serum alanine aminotransferase, gamma-glutamyl transferase and amylase indicated hepatotoxicity. Significant decreases in liver weights in female pups exposed to 0.025 mg/kg/day TBTC were observed at PND 60. Decreases in spleen and thymus weights also pointed towards toxic effects of TBTC on the immune system. The 0.025 mg/kg/day TBTC should have been a no affect dose and yet this dose caused significant effects on growth profiles, decreased liver weights and elevated serum GGT levels in females.

Oral (gavage), in utero and post-natal exposure of Sprague-Dawley rats to low doses of tributyltin chloride. Part II: effects on the immune system.

The immunotoxic effects of tributyltin chloride (TBTC) were examined in the offspring of Sprague-Dawley rats exposed in utero from day 8 of gestation, through lactation and post-weaning until pups reached the age of 30 days (male and female), 60 days (female) and 90 days (male). Daily oral (gavage) doses of 0.025, 0.25 and 2.5 mg/kg body weight/day were administered in olive oil 7 days/week. Immunologic endpoints were investigated at the termination of each study. Statistically significant results (P<0.05) included the following: At 30 days, the mean percent and absolute natural killer (NK) cell numbers were increased in male and female rats treated with the high TBTC dose. At 60 days, female rats had increased mean serum IgM levels at the low and high TBTC doses, increased mean percentage CD4(+)8(+) (immature) T lymphocytes at the middle and high doses, a non-linear dose-response increase in NK cell activity at the 50:1 and 100:1 effector:target cell ratios (pairwise comparisons significant at the low dose compared with control), and increased mean numbers of L. monocytogenes colony-forming bacteria on Day 2 post-infection (significant for trend) and Day 3 post infection (pairwise comparisons significant only in the middle dose). The 90-day male rats had decreased mean serum IgA levels at the middle dose group; increased IgM levels at the high dose group, increased IgG levels at the middle and high doses; decreased IgG2(a) in the high dose compared to the control; a dose-related increase in the mean percentage NK cell numbers (pairwise comparisons significant at the high dose compared with the control) and increased mean NK cell activity (pairwise comparisons significant at all dose groups compared with the control). The delayed-type hypersensitivity response to oxazolone was increased in the low and middle doses and decreased in the high dose. Thymus atrophy was observed in the high TBTC dose across all ages. Thus, in utero and post-natal treatment of F1 rats with low levels of TBTC affected some aspects of humoral and cell mediated immunity as well as the number and function of cells which are involved in the host's immunosurveillance mechanisms against tumours and viral infections.

Effects of cis-nonachlor, trans-nonachlor and chlordane on the immune system of Sprague-Dawley rats following a 28-day oral (gavage) treatment.

The immunotoxicity of cis- and trans-nonachlor and chlordane were investigated in adult male and female Sprague-Dawley rats following a 28-day oral (gavage) treatment. Rats were randomly assigned to six experimental groups: cis-nonachlor, females; trans-nonachlor, females; technical chlordane females; cis-nonachlor, males; trans-nonachlor, males; technical chlordane, males. The immunologic endpoints included: quantification of the total serum immunoglobulin (Ig) levels and subclasses and flow cytometric analysis of peripheral blood leukocytes and T-lymphocyte subsets, evaluation of the lymphoproliferative activity of splenocytes in response to concanavalin A (Con A) and Salmonella typhimurium (STM) mitogens, and natural killer (NK) cell activity of splenocytes. Satellite experiments to examine the delayed-type hypersensitivity (DTH) response to oxazolone, and resistance to Listeria monocytogenes were set up for female rats treated with cis- or trans-nonachlor. Statistically significant (P<0.05) effects included: increased serum immunoglobulin M (IgM) levels in the chlordane-treated females at the 25 mg/kg dose (pairwise comparison); increased serum IgG(1) and IgG(2c) in the cis-nonachlor-treated males at the 2.5 and 25 mg/kg doses and increased serum IgG(2a) levels at all doses; increased serum IgG(2b) at the 25 mg/kg dose and decreased (dose-related) serum IgM levels in the cis-nonachlor-treated male rats; increased (linear trend) IgG(1) and IgG(2a) in the cis-nonachlor-treated females with effects on IgG(2a) significant at the 25 mg/kg dose compared with control; increased serum IgG(2a) in the trans-nonachlor-treated male and female rats at the 2.5 mg/kg dose; increased absolute numbers (linear trend) of peripheral white blood cells, B lymphocytes, natural killer (NK) cells, T-suppressor/cytotoxic lymphocytes, and the double positive (T-helper/inducer, T-suppressor/cytotoxic) cells in the trans-nonachlor-treated females; increased (non-linear trend) lymphoproliferative activity in the Con A-stimulated splenocytes and decreased (linear trend) activity in the S. typhimurium mitogen-stimulated splenocytes of the cis-nonachlor-treated females; reduced resistance to L. monocytogenes in the cis-nonachlor (day 3, P=0.034)- and trans-nonachlor (day 2, P=0.0001)-treated females, and reduced (linear trend) NK cell activity in the cis-nonachlor-treated males. The present data indicated that the chlordane compounds tested in this study had significant effects on a number of immunologic endpoints. In comparison to technical chlordane, cis- and trans-nonachlors were more immunotoxic. Therefore, an evaluation of the risk these chlorinated compounds may pose to human health should consider the potential effects different chlordane compounds may have on the immune system.

Toxicological consequences of feeding PCB congeners to infant rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys.

In a study designed to minimize interspecies extrapolation of toxicological data, nine rhesus (Macaca mulatta) and 15 cynomolgus (M. fascicularis) day-old infant monkeys were separated from their dams following parturition and hand-reared using a liquid non-human primate formulation. The infants were randomly divided into a control and a treated group which received a mixture of polychlorinated biphenyl (PCB) congeners analogous to those found in breast milk from Canadian women. The concentration of congeners in the dosing media resulted in each infant receiving a total of 7.5 microg PCB congeners/kg body weight/day. The congeners were added either to the liquid formulation or to corn oil and administered to the back of the monkey's mouth for 20 weeks. Monthly blood and adipose specimens were obtained during the dosing period and then periodically until the monkey was necropsied or taken off test (minimum of 66 weeks on test) for congener analysis. Parameters such as body weight, formula consumption, tooth eruption, somatic measurements, haematology and serum biochemistry were monitored throughout the study. In addition, a qualitative evaluation of the absorption and depletion of the various congeners was undertaken as was an immunological evaluation. For the monitored parameters, very few differences were found to be statistically significant. For the immunological parameters, the only statistically differences found were a reduction over time for immunoglobulins M and G antibodies to sheep red blood cells (cyno, P = 0.025; rhesus, P = 0.002) and a treatment-related reduction in the levels of the HLA-DR cell surface marker (mean percent, P = 0.016; absolute levels, P = 0.027). There were some qualitative differences regarding absorption and depletion rates for the various congeners, but it could not be definitely ascertained whether these differences were due to species differences or dosing mode. However, statistically significant differences were found for treatment (P = 0.0293) as well as for species and vehicle regarding the concentration of PCB in blood (species;--P = 0.0399; treatment--P = 0.0001) and adipose tissue (species--P = 0.0489; treatment--P = 0.0001).

Effects of toxaphene on the immune system of cynomolgus (Macaca fascicularis) monkeys. A pilot study.

Toxaphene in glycerol/corn oil was administered at 1mg/kg body weight/day, 7 days/week in gelatin capsules to four healthy young adult cynomolgus (Macaca fascicularis) (two male and two female) monkeys for 52 weeks. Control monkeys ingested glycerol/corn oil only. Testing for immune effects was initiated at 34 weeks of treatment. Results included: reduced anti-sheep red blood cell (SRBC) titres for immunoglobulins (Ig) M and G; increased IgG titres to pneumococcal antigens, but not to the tetanus toxoid antigen; reduced T-helper/inducer mean lymphocyte numbers and the mean T-helper/inducer:T-suppressor/cytotoxic cell ratio and reduced respiratory burst activity in peripheral blood monocytes and granulocytes, albeit no changes on the phagocytic activity of these cells were detected. The above noted effects although not statistically significant (P0.05) suggest that chronic exposure to low levels of toxaphene may be immunosuppressive in cynomolgus monkeys and may pose a hazard to human health. To advance our understanding of the degree of hazard that toxaphene may pose to human health, we have undertaken additional chronic studies with a larger number of animals. Particular attention is focused on determining the potential immunotoxic effects of toxaphene in offspring following in utero exposure.

The effect of butylated hydroxytoluene on selected immune surveillance parameters in rats bearing enzyme-altered hepatic preneoplastic lesions.

Selected immune function parameters were examined in male Fischer 344 rats following (a) induction of enzyme-altered preneoplastic liver foci (EAF), and (b) growth modulation of EAF by 30-day feeding with the food antioxidant butylated hydroxytoluene (BHT). Glutathione S-transferase-P (GSTP)-positive EAF were observed in livers of rats receiving diethylnitrosamine (DEN), 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH) (Solt-Farber procedure), with or without BHT treatment. The induction of EAF and/or 0.5% BHT treatment resulted in a significant reduction in the natural killer (NK) cell activity of splenocytes. PH did not affect NK activity significantly compared with control (no PH) rats. The concanavalin A-induced lymphoproliferative activity of splenocytes was increased in rats with PH compared with those without. A lag in time needed to attain maximum calcium release was observed only in the rats with PH compared with those without PH. None of the treatments affected the phagocytic activity of resident peritoneal macrophages. Only EAF-bearing rats without BHT treatment had increased granulocyte and monocyte levels, while the leucocyte and lymphocyte levels were reduced by the initiator DEN. but not by BHT treatment. Further investigations are necessary to determine whether the observed suppression of NK cell activity during EAF induction and growth modulation by BHT is a contributing factor in enhancement of rodent liver neoplasia by this non-genotoxic food antioxidant.

Toxicological consequences of Aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 1B. Prebreeding phase: clinical and analytical laboratory findings.

A group of 80 menstruating rhesus (Macaca mulatta) monkeys, with an average estimated age of 11.1 +/- 4.1 yr SD were first randomly allocated to four similar test rooms (20 monkeys/room), and then randomly allocated to one of five dose groups (four females/dose group/room). Each day, the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of daily dosing, approximately 90% of the treated females attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their adipose tissue. Subsequently, oestrogen and progesterone concentrations in serum were determined for one complete oestrous cycle and various immunological tests were conducted, while the monkeys continued to receive their daily dose of PCB. During the prebreeding phase of the study, blood for clinical and analytical monitoring including haematology, serum biochemistry, serum hydrocortisone, serum proteins (alpha 1, alpha 2, beta and gamma-globulins), serum immunoglobulins (A, G and M) and thyroid variables (thyroxine/triiodothyronine (T3) uptake ratio, percentage T3 uptake and free thyroxine index), were obtained monthly, as were specimens to ascertain the concentration of PCB in the blood, adipose tissue and faeces. Major findings among treated monkeys included the following: changes in haematology (decreased erythrocyte count, haematocrit, reticulocyte count, and mean platelet volume), serum biochemistry (decreased cholesterol and total bilirubin), immunotoxicity (decreased antibody production to sheep red blood cells and alterations in the percentage of T helper and T suppressor cells) and pathology (the number of regions of sebaceous gland lobules per unit of histological length was significantly reduced). These effects were observed at PCB doses lower than those previously reported for non-human primates.

Toxicological consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 2. Reproduction and infant findings.

A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar test rooms (20 monkeys/room) and then randomly allocated within each room to one of five dose groups (four females/dose group/room). Each day, the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their adipose tissue. Commencing on test month 37, each female was paired with an untreated male until either an impregnation occurred or the 29-month breeding phase of the study was completed. The females continued to receive their daily test dose during mating and gestation. To preclude an infant ingesting the mother's dosing capsule, dosing of the dam was discontinued when a nursing infant was approximately 7 wk old. Treatment was restarted when the infant was weaned at 22 wk of age. At parturition, and every 4 wk until weaning, milk and blood samples were obtained from the dam and a blood sample was obtained from the infant for PCB analysis. When the infant was 20 wk old, immunological testing was initiated and an adipose sample was obtained from the infant and dam for PCB analysis. Subsequently, further adipose and blood samples were obtained from the infant and blood specimens were obtained from the dam for PCB analysis. Concurrently, each infant was subjected to anthropometric measurements and detailed clinical examinations until it was approximately 122 wk old. At 122 wk some of the control and all of the treated infants were killed humanely and autopsied. A statistical analysis of the reproduction data provided evidence for a significant decreasing dose-related trend in conception rates and a significant increasing dose-related trend in foetal mortality. Several comparisons between impregnated and non-impregnated females did not implicate 'age' as a confounding factor regarding these results. The major findings with the infants involved some immunological test differences and mild clinical manifestations of PCB ingestion.

Effects of toxaphene on the immune system of cynomolgus (Macaca fascicularis) monkeys.

Toxaphene, dissolved in glycerol/corn oil, was administered at 0.1, 0.4 or 0.8 mg/kg body weight/day in gelatin capsules to groups of 10 young adult female cynomolgus monkeys (Macaca fascicularis), while a group of five male monkeys (Macaca fascicularis) received 0.8 mg/kg body weight/day. Control male (a group of five) and female (a group of 10) monkeys ingested the glycerol/corn oil vehicle only. Treatment continued for 75 weeks. Testing for immune effects was initiated at 33 weeks of treatment. Immunization was initiated at 44 weeks of treatment. Pairwise comparisons between each of the treated female groups to the control indicated that the mean primary (post-immunization weeks 1-4) and secondary (post-immunization weeks 5-8) anti-SRBC IgM responses were significantly reduced at the 0.4 and 0.8 mg/kg body weight/day doses compared to the control (P< or =0.05). The mean primary (post-immunization weeks 1-4) anti-SRBC IgG response was significantly reduced compared to the control (P< or =0.05), while the secondary (post-immunization weeks 5-8) anti-SRBC IgG was not significantly affected by treatment (P>0.05). The mean anti-tetanus toxoid IgG response in the 0.8 mg/kg body weight/day dose group The mean primary anti-SRBC (IgM) response in the treated males was significantly different from the control (P<0.05), while the primary anti-SRBC IgG response was not affected by treatment. The mean absolute B-lymphocyte numbers in the female group administered 0.8 mg/kg of toxaphene was significantly reduced compared to the control (P< or =0.05). All other parameters including the natural killer cell activity, the delayed-type hypersensitivity response, the lymphoproliferative response of peripheral blood leukocytes to the mitogens Con A and PWM and the serum cortisol levels were not affected significantly by treatment (P>0.05). The no-observed-adverse-effect level (NOAEL) for the female monkeys based on the toxaphene effects on humoral immunity was 0.1 mg/kg body weight/day.

The impact of PCBs and dioxins on children's health: immunological considerations.

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.

Immunotoxicity of polychlorinated biphenyls: present status and future considerations.

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 critical for evaluating the potential risk PCBs pose to human health. To fully exploit the potential contribution immunotoxicology can make to risk assessment, it is important that the data base on mechanism(s) of PCB-induced immunotoxicity and the potential agonistic/antagonistic properties of PCBs be expanded considerably.