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Hodgson E. Modern toxicology [2004].pdf
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340 IMMUNOTOXICITY

The guinea pig intratracheal test has been used to establish the relative potency of different detergent enzymes and establish safe occupational exposure levels. As the name implies, guinea pigs are sensitized by intratracheal exposure and induction of cytophilic antibodies are assessed. Dose responses obtained for new enzymes are compared to a reference enzyme for which safe exposure levels have been established. The relative potency of the new enzyme to this reference is used to establish a safe exposure level for the new enzyme.

Exposure to certain low (<3000) molecular weight compounds (haptens) has also been associated with the development of occupational asthma. Highly reactive compounds such as the diisocyanates or acid anhydrides have the capacity to react with protein and induce an immune response. Toluene diisocyanate (TDI) and trimellitic anhydride are the compounds that have been most extensively studied in this regard. There is a great deal of interest in developing a test to screen chemicals for this type of effect in order to avoid induction of immune responses that could lead to occupational asthma. Although specific IgE antibodies have been detected in some individuals with TDI asthma, it has not been uniformly present and some of these individuals exhibit the late phase but not the immediate response. Hence, unlike proteins, there is less certainty about the mechanisms underlying respiratory allergic responses to low molecular weight compounds.

Structure activity approaches similar to those described for contact sensitizers have been developed, but this approach has limitations because the database of known respiratory sensitizers is small compared to contact sensitizers and the underlying mechanisms are less well defined. At the other extreme guinea pigs have been exposed by inhalation for a number of days, rested, and then challenged at a later date by inhalation with subsequent monitoring of respiratory responses. Although this approach has produced a good model of TDI asthma, it is too cumbersome and expensive for routine testing. Because the capacity to interact with protein is a pre-requisiteto allergenicity, it has been suggested that testing for protein reactivity in vitro could provide an initial screening test for chemicals. Also, because it appears that respiratory sensitizers are a subset of chemicals that produce positive results in a contact sensitivity test, it has been suggested that the LLNA test be used as the first tier in screening chemicals for this effect. The problem then becomes separating chemicals that are strictly contact sensitizers from those that have the capacity to cause respiratory sensitization. Efforts have been made to determine whether differences in responses to dermal application of these chemicals could provide a means for making this distinction. One proposal is to assess total serum IgE following dermal exposure, assuming that respiratory sensitizers would produce a bigger IgE signal. Another approach has been to assess cytokine profiles in the draining lymph node following dermal exposure. Different subsets of T helper (Th) cells, have been associated with type I immediate (Th2) and type IV delayed (Th1) responses. These different populations of T cells are distinguished by different cytokine profile and efforts are underway to use these differing profiles to distinguish respiratory from contact sensitizers. However, there is as yet nowell-validated,well-acceptedtest to assess low molecular weight chemicals for the capacity to induce respiratory allergy. This remains a subject of intense research.

19.5.3Adjuvants

An adjuvant is a compound administered in conjunction with an antigen that nonspecifically enhances the immune response to that antigen. Adjuvants are used in