Heavy Metals

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Mechanisms of Immunotoxicity

The immunotoxic effects of heavy metals, such as lead, arsenic, and mercury exposure are well recognized (Bernier et al. 1995; Schuppe et al. 1998). In comparison to most environmental toxicants, the mechanism of metal immunotoxicity is well studied (reviewed in: Schuppe et al. 1998). It is currently believed that metals initially elicit a cell-mediated immune response by binding to MHC class II molecules or MHC-bound self-peptides. The metal-MHC complex is then recognized by CD4+ T cells. Additionally, metal-induced alteration of self-peptides may also cause activation of autoreactive T cells. In hypersensitivity responses, such as contact allergy, CD8+ T cells may also be involved.

In addition, metals may alter the T cell repertoire and influence the TH1:TH2 ratio (see previous section "The TH2-bias of the Neonatal Immune System"). Results from recent in vitro studies are consistent with the hypothesis that metals, such as mercury and lead, inhibit the production of TH1 cells and enhance the production and activities of TH2 cells (Bernier et al. 1995; Selgrade, 1999). Selgrade and colleagues initiated a series of in vivo studies in mice to determine the mechanism by which metals influence the T cell balance (Selgrade 1999). Their results show that lead induces the expansion of specific CD4+ T cells, which leads to a 10-fold higher TH2:TH1 ratio in lead-exposed mice than in controls (Figure 14.1). Results from subsequent experiments suggest that lead exposure can also enhance the expression of APC accessory molecules that preferentially activate TH2 cells. The ability of metals to alter the TH1:TH2 balance may have significant impact on the developing immune system, resulting in enhancement of the atopic response and potential susceptibility to development of childhood asthma.

A Focus on Lead, and the Potential for Fetal/Neonatal Exposure

The general population has the potential for chronic low-level exposure to heavy metals primarily through ingestion of contaminated food, and, to some extent, air pollution. Metals such as lead are very persistent once they enter the human body and can accumulate in bone deposits (Agency for Toxic Substances 1997). Mobilization of maternal bone lead deposits or lead circulating in maternal blood can result in exposure to the fetus through the placenta and to a breastfed infant through lactation (Snyder et al. 2000). Lead contamination in drinking water can also lead to exposure of the fetus in pregnant women, formula-fed infants, and children.

The extreme sensitivity of the fetus, infant, and young child to the effects of relatively low-level lead exposure is well documented (Agency for Toxic Substances 1997). In both developing humans and animals, even very low blood lead levels can cause the impairment of neurobehaviorial development and permanent brain damage. At higher levels, lead causes general growth and organ development impairment and abnormalities (Agency for Toxic Substances 1997).

Epidemiological Studies

Although the effects of lead exposure on the developing central nervous system have been extensively studied, little work has been done on the effects of lead on other developing organ systems. In an important effort to fill the information gap, Lutz and colleagues have initiated a series of studies in a 5-year comprehensive evaluation of the effects of environmental lead exposure on the human developing immune system. Their most recently published study (Lutz et al. 1999) evaluated various immunological endpoints in a cohort of 279 children aged 9 months to 6 years who had been primarily exposed to lead-based paint and had blood lead levels ranging from 1 to 45 mg/dl. This range includes levels of lead that have been shown to cause neurotoxic effects in children. In contrast with previous studies of occupa-tionally exposed adults, Lutz and colleagues found that higher levels of lead in children correlated with elevated levels of IgE. The authors note that although the correlation between IgE and blood lead levels is statistically robust, it is only a correlation and there is no direct evidence of any adverse immune system effects. The authors also note that the correlation between high blood lead levels and high IgE is not consistent with the findings of other investigators.

The Lutz study was designed to control for several important variables in sensitivity to lead toxicity, such as age, gender, race, nutrition, and socioeconomic status. Other variables could not be controlled, such as exposure to specific allergens that may induce elevated IgE levels. For example, cockroach allergens and cigarette smoke in the home are linked to aggravating atopic diseases, such as asthma. The authors note it is very likely that both cockroach allergens and lead paint are endemic to particular socioeconomic levels; therefore, the immunomodulations detected in this group may not be directly attributable to lead. Although the initial results reported in this study must be interpreted with caution, future studies should provide important data to fill information gaps in the effects of lead on the developing immune system of young children.

Animal Studies: Developing Immune System

A few studies have investigated the effects of lead on the developing immune system using endpoints indicative of a hypersensitive or atopic response. A recent study by Miller and colleagues investigated whether the immune system of the fetus is more susceptible to lead exposure than that of the adult, and whether the immu-notoxic effects seen in developing animals persist into adulthood (Miller et al. 1998).

The investigators designed the study to determine effects from prenatal exposure only. Female rats were fed low to moderate doses of lead acetate during pregnancy. Their offspring received no additional lead exposure after birth. Various immunotoxic endpoints, including IgE levels, were evaluated in the offspring at 13 weeks (a developmental stage analogous to that of human adulthood). Although dams in lead-exposed groups did not show immunotoxic effects compared to controls, a number of immunomodulations were detected in their adult offspring. The offspring that had been exposed to lower (100 ppm) doses displayed elevated IgE levels. Those that had been exposed to moderate and high dose levels (250 to 500 ppm) displayed altered cytokine and interferon levels and depression of cell-mediated immunity (CMI) function (250 ppm dose group) as manifested by a decrease in their delayed-type hypersensitivity (DTH) response.

Based on these results, the authors suggest that lead exposure in utero can cause persistent effects on the immune system in the adult animal. Dams were also assessed 13 weeks after the birth of their offspring, and no immunomodulations were noted. The study was designed to assess the effects of prenatal exposure vs. the effects of combined prenatal and lactation exposure. Although previous studies have found that maternal lead deposits can accumulate in breast milk, the authors did not find significant levels of lead in milk of dams used in this study. Also, while blood lead levels in the dams during pregnancy were relatively high, bone and blood lead levels in the offspring were relatively low, suggesting lead storage did not occur. Therefore, the authors concluded that the immunomodulations found in adult offspring are attributable to in utero lead exposure and were not induced by recirculation of stored lead deposits. The results of this study strongly suggest that even short-term exposure of the fetus to lead at a critical developmental window could permanently influence the immune system. In addition, the results indicate that dose levels that do not cause immune system effects in adults can cause effects in the fetus that persist into adulthood.

The impact of these findings on asthma is that they support the concept that lead influences the TH1:TH2 ratio in favor of a predominant TH2 environment. The DTH response (associated with a TH1 response) was depressed in the 250 ppm treatment group, while elevated IgE levels in the 100 ppm treatment group suggest an enhanced TH2 response. Miller and colleagues propose the possibility that lead induces TH2 activating/TH1 inhibiting cytokines to higher levels in the fetus and neonate than normal, which could permanently suppress the TH1 response. Because the baseline TH1 response is already far below adult functional capacity, a skewed TH1:TH2 that further favors TH2 may have significant implications for the neonate. Moreover, in this situation, it is possible that resistance to many infectious challenges could be compromised and the development of atopy and autoimmunity could be enhanced. The authors also found evidence of both increased TNF-a and altered macrophage function, as manifested by increased nitric oxide production. Because TNF-a has been shown to increase airway hypersensitivity, the authors propose that lead-induced elevated TH2 cytokine levels could synergistically interact with lead-induced elevated TNF levels to further increase airway hypersensi-tivity (Figure 14.1).

In further support of lead's influence on immune deviation, a study has been published in which plasma IgE levels of 2-week-old neonates exposed to lead before and after birth were measured as an index of atopy (Snyder et al. 2000). In this study, neonates exposed to lead either in utero or through lactation had significantly higher plasma IgE levels, as well as lower splenic white blood cell numbers, than age-matched controls. Carefully controlled studies aimed at separating the effects of lead and other heavy metals on disparate T cell subtypes and in tightly controlled exposure windows will be necessary if we are to begin to understand the immunologic dys-regulation at the heart of the processes of asthma sensitization and exacerbation.

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