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REVIEW: ASSESSING THE POTENTIAL TO INDUCE RESPIRATORY HYPERSENSITIVITY
Citation:
HOLSAPPLE, M., D. JONES, T. KAWABATA, I. KIMBER, K. SARLO, M. K. SELGRADE, J. SHAH, AND M. WOOLHISER. REVIEW: ASSESSING THE POTENTIAL TO INDUCE RESPIRATORY HYPERSENSITIVITY. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 91(1):4-13, (2006).
Impact/Purpose:
To present findings from a workshop designed to understand the basis for immune-mediated damage to the lung in order to characterize hypersensitivity
Description:
The respiratory tract has been long recognized as an important target organ in the safety assessment of drugs and chemicals, as well as protein- or peptide-based products. Indeed, acute and repeat dose inhalation studies have been an important part of guideline studies throughout the world for many years. A number of factors have recently contributed to an increase in the attention focused on the respiratory tract as a target organ for safety assessment. For example there has been an increase in asthma among the general population from the mid-1960s to the mid-1990s prompting investigations into cause and prevention (Devereux, et.al. 2003). One study indicated that occupational asthma has surpassed traditional dust disorders to become the most commonly reported occupational lung disease (Petsonk, 2002). Clinical investigators estimate that up to 20% of adult onset asthma is caused by occupational factors and that roughly 90% of these cases involve immunological mechanisms (Mapp, 2005). There is also growing interest in the lung as a route for drug delivery. Another consideration is that our knowledge of the biology of the lung as it relates to the cellular and molecular bases for responses to damage is increasing. Moreover, it is known that damage to the respiratory tract can be triggered either by nonspecific irritation or by specific immune-mediated mechanisms, and it is acknowledged that traditional inhalation studies are not designed to address fully the impact of the latter. Finally, it is recognized that different types of immune-mediated responses (Janeway et al., 2005) can be triggered by different classes of compounds, and that some immune reactions in the lung are life threatening. For example, Type I or immediate hypersensitivity responses can trigger asthma, anaphylaxis and/or anaphylactic shock (cardiopulmonary collapse). As such, it is important to understand as fully as possible the basis for the immune-mediated damage to the lung in order to characterize adequately the risks of individual chemicals or proteins.
It is against this background that the Immunotoxicology Technical Committee (ITC) of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized two activities centered on the state-of-the-science of methods in immune-mediated respiratory hypersensitivity (RH) testing. First, an expert roundtable discussion was convened in May, 2003, and attracted ~40 participants from the U.S. and Europe representing primarily industry (50%) and government (35%). Second, a 2-day international workshop was organized in June, 2004, and attracted ~75 participants again representing mostly industry (45%) and government (38%). The format for this workshop comprised a combination of plenary lectures, after which a series of predetermined questions were addressed. The plenary lectures were intended to provide a foundation of appropriate background information, and emphasized the state-of-the-science associated with the clinical aspects of respiratory hypersensitivity, and with a variety of animal models used to determine the potential of chemicals or proteins to cause immunological sensitization of the respiratory tract. The questions were intended to provide a framework for discussion by the participants, and are presented in Table 1.
At the outset of the workshop, the participants formulated the following working definition of respiratory hypersensitivity (i.e., Question #1 from Table 1) a hypersensitivity response in the respiratory tract precipitated by a specific immune response, mediated by multiple mechanisms, including IgE antibody. The participants acknowledged that this definition was limited to the discussions and summaries related to the workshop and recognized that there are other types of immune-mediated hypersensitivity that can occur in the lung that are independent of IgE. The workshop was structured to address various classes of compounds and the subsequent sections of this review will consider chemical-specific, protein- / peptide-specific and drug-specific aspects of respiratory hypersensitivity.
Subsequent to the 2004 workshop, a group of participants, representing both government and industry, have continued to consider the conclusions and recommendations that represent the substance of this review article. The specific objective of this review is to address the current state-of-the-science associated with respiratory hypersensitivity, as defined above, and in the context of the following questions:
" What are the appropriate methods for identifying and characterizing respiratory hypersensitivity hazards and risks?
" What are the key data gaps and related research needs with respect to respiratory hypersensitivity testing?