CRITICAL FACTORS IN ASSESSING RISK FROM EXPOSURE TO NASAL CARCINOGENS

Anatomical, physiological, biochemical and molecular factors that cont ribute to chemical-induced nasal carcinogenesis are either largely div ergent between test species and humans, or we know very little of them . These factors, let alone the uncertainty associated with our knowled ge gap, present a risk assessor with the formidable task of making jud gments about risks to human health from exposure to chemicals that hav e been identified in rodent studies to be nasal carcinogens. This pape r summarizes some of the critical attributes of the hazard identificat ion and dose-response aspects of risk assessments for. nasal carcinoge ns that must be accounted for by risk assessors in order to make infor med decisions. Data on two example compounds, dimethyl sulfate and hex amethylphosphoramide, are discussed to illustrate the diversity of inf ormation that can be used to develop informed hypotheses about mode of action and decisions on appropriate dosimeters for interspecies extra polation. Default approaches to interspecies dosimetry extrapolation a re described briefly and are followed by a discussion of a generalized physiologically based pharmacokinetic model that, unlike default appr oaches, is flexible and capable of incorporating many of the critical species-specific factors. Recent advancements in interspecies nasal do simetry modeling are remarkable. However, it is concluded that without the development of research programs aimed at understanding carcinoge nic susceptibility factors in human and rodent nasal tissues, developm ent of plausible modes of action will lag behind the advancements made in dosimetry modeling. (C) 1997 Elsevier Science B.V.