Immunomodulation or immunotoxicity occurs when environmental factors (such as stress, health status, and chemical exposure) change the homeostatic processes that regulate the immune system in susceptible populations. The consequences of immunotoxicity can be highly divergent and depend on the environmental factor, the duration and timing of the exposure, the overall health status of the exposed person, and the route of exposure. Immunotoxicity may occur from direct effects on immune cells or from indirect effects on various cell components, such as altered endocrine function. It may also occur at an anatomic site that is distant from the point of entry. Indeed, the systemic nature of the immune system may mean that an exposure at one site causes damaged or modified cells to move to another location in the body where they may mediate the effects of the toxicant.

Adverse health effects associated with immunotoxicity may include higher infection rate; alterations in lymphocyte cell populations; hyperactivity of immune cells, such as increased respiratory activity (increased production of reactive oxygen and reactive nitrogen species) and cytokine production; autoimmunity; altered immune-cell trafficking throughout the body; increased allergy or atopy; and susceptibility to cancer. Research to determine the immunotoxicity of an agent focuses on those and other responses. EPA has developed a health-effects test guideline for immunotoxicity (EPA 1998a).

In the case of formaldehyde, as has been discussed elsewhere in the present report, most of or all the direct effects occur at the point of entry in the upper respiratory tract. Immune cells in the bronchial and nasal associated lymphoid tissue (BALT and NALT) are most likely proximal targets of formaldehyde. Understanding the potential immunotoxicity of formaldehyde is therefore of critical importance.

Adverse effects of formaldehyde on BALT and NALT may be manifested systemically because these lymphoid cells migrate to the lymph nodes, spleen, liver, peripheral blood, and other immune tissues. Specifically, most BALT and NALT cells belong to the arm of the immune system referred to as the innate immune system. The role of the innate immune cells is to recognize and respond to tissue damage, apoptotic cells, and evolutionarily conserved protein and glycoprotein patterns expressed on bacteria, viruses, parasites, and other pathogens. The consequences of innate immune-cell recognition of pathogen-associated molecular patterns (PAMPs) are to increase production of reactive oxygen species, to engulf the particles expressing PAMPs, and to migrate systemically where the potential infectious agent is presented to the adaptive arm of the immune system. The role of the adaptive arm of the immune system is to produce cytokines, which activate antibody production, increase inflammation, and recruit lymphocytes to the site of infection.