The heavy metal lead is a widely deposited environmental toxicant known to impact numerous physiological systems, including the reproductive, neurological, hepatic, renal, and immune systems. Studies illustrating the capacity of lead to impair immune function and/or host resistance to disease date back to at least the 1960s. However, it has only been in recent years that lead has been recognized among a new category of immunotoxicants-those that dramatically shift immune functional capacity while producing only modest changes to immune cell populations and lymphoid organs. These relatively noncytotoxic immunomodulating chemicals and drugs represent the immunotoxic hazards most difficult to identify and problematic for risk assessment using historic approaches. As a result, such environmental factors are also among the most likely to contribute to chronic immune-related disease at relevant exposure levels. This review considers the animal and human evidence that lead exposure can produce a stark shift in immune functional capacity with a skewing predicted to elevate the risk of atopic and certain autoimmune diseases. At the same time, host defenses against infectious agents and cancer may be reduced. Age-based exposure studies also suggest that levels of blood lead previously thought to be safe, that is, below 10 microg/dl, may be associated with later life immune alterations.

Lead and immune function.

The fundamental characteristic of the adaptive immune system which has evolved in the vertebrates is the ability to recognise, and subsequently destroy, "foreign", and potentially harmful, antigens. The selective advantage which the immune system confers is the capacity to resist infectious, and possibly malignant, disease. It has been apparent for many years that individuals in whom immune function is impaired, due either to a congenital defect or to other factors such as treatment with certain immunosuppressive drugs, exhibit an increased susceptibility to infection and, in some cases, an elevated risk of developing at least some forms of malignancy. There is an increasing awareness from rodent studies that a variety of drugs and environmental chemicals have the potential to unintentionally impair components of the immune system. Risk assessment, based upon data from chemically induced changes in one or more parameters of immune function, is, however, dependent upon a knowledge of the functional reserve of the immune system. One of the objectives of the meeting from which this report derives was to examine what sources of information are available, and what experimental protocols can be employed, to permit accurate evaluation of immunological reserve. Although, under normal circumstances, the immune system selectively and specifically recognises foreign antigen, it is clear that the potential to recognise "self" is present and that in certain circumstances this potential is realised. Antibodies directed against normal tissue antigens have been shown to be associated with, and in some instances the presumptive cause of, "autoimmune" disease. There is a growing list of drugs and chemicals which are capable of eliciting autoantibodies and pathological autoimmune reactions. A second purpose of this meeting and of this report was to review the current state of knowledge regarding drug- and chemical-induced autoimmunity.

Immunotoxicology: suppressive and stimulatory effects of drugs and environmental chemicals on the immune system - A discussion

Evidence implicating oxidative stress in toxicity during lead intoxication in vivo has opened new avenues for investigation of the mechanisms of lead-induced immunosuppression. The current study explores the possibility that lead-induced oxidative stress contributes to the immunosuppression observed during lead poisoning. Fisher 344 rats were exposed to 2,000 ppm lead acetate in their drinking water for 5 weeks. One week following removal of lead from the drinking water, significant reductions in serum levels of IgA, IgM, and IgG were detected. Significant increases in oxidative damage, based on malondialdehyde (MDA) content, were observed in peripheral blood mononuclear cells (PMCs) collected during the same experiments. In addition, MDA content increased in livers from lead-exposed rats. Following 5 weeks of lead exposure, administration of either 5.5 mmol/kg N-acetylcysteine (NAC) or 1 mmol/kg meso-2,3-dimercaptosuccinic acid (DMSA) in the drinking water for 1 week significantly reversed the inhibitory effects of lead on serum immunoglobulin (Ig) levels. Also, all parameters indicative of oxidative stress returned to control levels. These results suggest that oxidative stress contributes to suppressed serum Ig levels during lead intoxication in vivo, and that intervention with either a thiol antioxidant (NAC) or a metal chelator (DMSA) will alleviate this lead-induced suppression by correcting the prooxidant/antioxidant imbalance caused by lead exposure.

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Barry S. Handwerger

Papers

Effect of low-level lead exposure on antibody-dependent and natural killer cell-mediated cytotoxicity