Fact Sheets

Immune System

Issue: Interaction between the immune and endocrine systems is well documented and therefore it has been suggested that the immune system may be susceptible to endocrine disruption. The immune system can be affected by the direct actions of chemicals on specific target components of this system characterized by immunosuppression, which can lead to decreased resistance to microbial agents or immunoenhancement, leading to allergy.

Trends: Generally, mortality from infectious diseases in industrialized countries has decreased in the last century. This can be attributed to improved sanitation, housing and nutrition and the introduction of effective immunizations and therapeutic agents. In the past twenty years, however, a small rise in the mortality rate from infectious diseases has occurred due to increased antibiotic resistance and the emergence of AIDS and other viral infections. The incidence of asthma, an immune disorder, has increased world-wide at the rate of about 50% per decade. Risk factors for asthma include exposure to indoor allergens (dust mites, cats, cockroaches), tobacco smoke, chemical irritants and genetics. It is suspected that the rise in asthma incidence is related to the increase in urbanization, but this requires further study. Asthma is associated with inflammation of the air passages in the lungs resulting in swelling and restriction of the airways. An underestimated risk factor for asthma is allergic rhinitis, another hypersensitivity disorder, characterized by allergen-induced inflammation of the membranes lining the nose.

Consistency of the data: Evidence regarding a cause-effect relationship between endocrine-disrupting chemicals and immune system dysfunction is controversial. Many studies have reported that accidental exposures to environmental toxicants (PCBs, PCDFs) have been associated with immune dysfunctions including respiratory ailments and skin lesions in both exposed individuals and in children exposed in utero. However, in many cases immune parameters reported for exposed individuals were within the normal range. In another example of accidental exposure, Vietnam veterans exposed to TCDD (Agent Orange) have reported health effects as a result of their exposure; however, immune parameters are not significantly different from unexposed men. Chronic occupational exposure to low levels of chemicals is not strongly associated with immune dysfunction. While there are some changes in the levels of immune system parameters, there is no evidence of increased incidence of disease. Lactational transfer of endocrine-disrupting chemicals to children has been shown to be associated with alterations in lymphocytes and immunoglobulins. There are several studies demonstrating an increased risk of developing otitis media with pre- and post-natal organochlorine exposure, while other studies failed to find an association. In general, epidemiological studies may report increased incidences of a particular health concern, however, changes in immune parameters (antibodies, lymphocytes) are often not observed.

Experimental evidence: It is well-established that environmental toxicants can affect immune system parameters; however, it is controversial whether these observed adverse effects are mediated by an endocrine-disrupting mechanism of action as opposed to direct toxicity. Children and adolescents exposed to PCBs and PCDFs in Taiwan through consumption of contaminated rice oil (YuCheng disease) exhibited decreased serum IgA, IgM, cytotoxic T cells and suppressor T cells with cell-mediated immune system dysfunction. Infants born to mothers exposed during pregnancy had increased incidence of respiratory infections and middle ear diseases. In a study of Inuit children, breast milk levels of organochlorines (p,p'-DDE, hexachlorobenzene, dieldrin) were correlated with increased incidence of ear disorder otitis media. Contamination of the arctic food chain by organochlorines has led to the bioaccumulation of contaminants in human populations inhabiting the arctic region. Contaminants, particularly lipophilic organochlorines, are transferred to nursing infants through breast-feeding. The incidence of non-Hodgkin lymphoma (NHL) has increased in many countries with risk factors for the disease including exposure to certain pesticides, organochlorines and Epstein-Barr virus. In a case-control study serum levels of PCBs, p,p'-DDE, chlordanes, hexachlorobenzene and other contaminants were measured in individuals with NHL (cases) and controls. Antibody titers to the Epstein-Barr antigen were correlated to an increased risk for NHL and were correlated to concentrations of organochlorines. High serum concentrations of the PCB-type chemicals and the chlordanes were associated with increased risk for NHL. The effects of environmental toxicants on the immune system have been widely studied using animal models. TCDD has been shown to induce premature terminal differentiation of thymocytes leading to changes in the thymic cortical epithelium resulting in atrophy of the thymus in rodents. TCDD suppresses cell-mediated immunity, delayed hypersensitivity and generation of cytotoxic T cells in a dose-dependent manner. In wildlife studies, birds exposed to organochlorines exhibit immunosuppression. However, the mechanisms for these effects are not known.

Biological plausibility: Many potential endocrine toxicants have been shown to be immunotoxic; however, it is controversial whether the effects on the immune system are mediated through disruption of the endocrine system or are the result of direct toxicity. In animal models and cell lines, chemicals such as TCDD, some PCBs, PCDD, PCDFs have been shown to bind to the aryl hydrocarbon receptor (AhR). Thus, by binding to the receptor, these organochlorine chemicals trigger AhR-mediated expression of genes involved in cell proliferation and differentiation causing myelosuppression, immunosuppression, thymic atrophy and inhibition of immune complement system components in many animal species. Timing of exposure is relevant as impairment to the immune system is more severe if exposure occurs during pre- or post-natal life compared to exposure in adult animals. Maturation of the immune system in rodents is especially vulnerable to adverse effects of dioxin-like compounds, chlordane, hexachlorobenzene, polycyclic aromatic hydrocarbons, DDT, and kepone. Similarly in humans, the immune system is vulnerable to chemical exposure during fetal and post-natal development.

Reproductive hormones have been shown to regulate the immune system. Pre-menopausal women tend to have higher immunoglobulin concentrations, stronger primary and secondary responses and increased resistance to the induction of immunological tolerance. The predominance of autoimmune diseases (Graves' disease, systemic lupus erythematosis, multiple sclerosis, rheumatoid arthritis) among women suggests that reproductive steroid hormones may modulate immunologic susceptibility. Estrogen has been shown to regulate the expression, distribution and activity of immune chemicals called cytokines. Studies using mouse lymphocytes have shown that estrogen enhances production of immune chemicals such as interleukins and interferons while androgens decreased the production of these chemicals. The immune system, through cytokine and interleukin-mediated pathways can regulate the reproductive system by inducing the release of gonadotropins LH and FSH.

Conclusions: There is insufficient evidence to demonstrate that exposure to toxicant-induced disruption of the immune system involves an endocrine mechanism. Many studies report increased incidence of adverse health effects following exposure, however, immune parameters, where measured, are often within the normal range. Animal studies provide some evidence that endocrine toxicants may impair the immune system, but additional studies are required. The regulation of the immune system by the endocrine system may render the immune system vulnerable to endocrine disruption. A greater understanding of both systems, along with sound epidemiological data are required to determine whether chemicals alter immune function via an endocrine disruption mechanism of action.