DNA damage in the nasal passageway: a literature review.

The purpose of this review is to provide a compilation of work examining DNA damage in the nasal cavity. There are numerous methods to identify and quantify damage to DNA and the diversity of methods and toxicologic endpoints is illustrated by the range of studies presented here. There are a large number of independent studies measuring endpoints in the upper respiratory tract; however, with regard to toxicant induced DNA damage in the nasal passageway, the effects of two compounds, 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and formaldehyde (HCHO), appear to have been extensively characterized. The body of work on NNK and formaldehyde have provided insights into molecular mechanisms of DNA damage and repair and induced cell replication and its relationship to nasal cancer. With new technologies and molecular techniques, the sensitivity to enable evaluations of the minute quantities of nasal tissue available in test species and human biopsy impact the study of the nasal-toxicant interactions. As methods used to characterize DNA damage increase in sensitivity, the importance of both exogenous and endogenous sources of DNA damage, steady-state levels of cellular damage, repair, and resulting mutations, low-dose exposure assessments and inter-species extrapolation will become increasingly complex. Additional studies of DNA damage in the nasal passage will undoubtedly challenge future estimations of risk and impact what are perceived to be acceptable levels of exposure to known and predicted carcinogens. The aim of this paper is to provide to the interested scientist literature relevant to the effects of agents on nasal DNA, so that areas of insufficient information can be identified and used to further develop and expand the knowledge base for nasal DNA toxicant interactions.

Critical factors in assessing risk from exposure to nasal carcinogens.

Anatomical, physiological, biochemical and molecular factors that contribute to chemical-induced nasal carcinogenesis are either largely divergent between test species and humans, or we know very little of them. These factors, let alone the uncertainty associated with our knowledge gap, present a risk assessor with the formidable task of making judgments about risks to human health from exposure to chemicals that have been identified in rodent studies to be nasal carcinogens. This paper summarizes some of the critical attributes of the hazard identification and dose-response aspects of risk assessments for nasal carcinogens that must be accounted for by risk assessors in order to make informed decisions. Data on two example compounds, dimethyl sulfate and hexamethylphosphoramide, are discussed to illustrate the diversity of information that can be used to develop informed hypotheses about mode of action and decisions on appropriate dosimeters for interspecies extrapolation. Default approaches to interspecies dosimetry extrapolation are described briefly and are followed by a discussion of a generalized physiologically based pharmacokinetic model that, unlike default approaches, is flexible and capable of incorporating many of the critical species-specific factors. Recent advancements in interspecies nasal dosimetry modeling are remarkable. However, it is concluded that without the development of research programs aimed at understanding carcinogenic susceptibility factors in human and rodent nasal tissues, development of plausible modes of action will lag behind the advancements made in dosimetry modeling.

Mitogenic responses of rat nasal epithelium to hexamethylphosphoramide inhalation exposure.

Hexamethylphosphoramide (HMPA) is a rat nasal carcinogen that induces squamous cell carcinomas in the anterior portions of the nasal cavity following chronic inhalation exposures as low as 50 ppb. These tumors may arise as a result of P-450-mediated release of formaldehyde (HCHO), a known rat nasal carcinogen. The goal of this research was to investigate early responses of the nasal epithelium to inhaled HMPA. Rats were exposed nose-only to approximately 3 ppm HMPA for 6 h, and killed 18, 48, 96 or 144 h post-exposure. In a separate study, rats were exposed nose-only for 6 h for 1, 2, 3, or 5 consecutive days and killed 18 or 96 h post-exposure. With both single and repeated doses of HMPA, there was no evidence of cytotoxicity in the anterior nose. Olfactory degeneration and necrosis of the dorsal meatus, Bowman's glands and tips of the ethmoid turbinates increased in severity with repeated exposures to HMPA. Cell proliferation was assessed in levels of nasal tissue that included regions of squamous, respiratory, transitional and olfactory epithelium. Regional induction of cell proliferation was measured by BrdU incorporation, and reported as the number of labeled cells/mm basement membrane. At 18 h after a single exposure, there was an increase in cell proliferation in squamous epithelium, which returned to control levels within 48 h. A transitory increase in cell proliferation was observed regions of respiratory and transitional epithelium, although the response of each tissue, in terms of magnitude and peak time of response post-exposure, also differed. Along the dorsal meatus in Level 9, olfactory labeling initially decreased, returned to control levels by 96 h, but again declined at 144 h post-exposure. In repeat dose studies, the squamous epithelium response was variable 18 h post-exposure. For respiratory and transitional epithelium, increased cell proliferation 18 h post-exposure was correlated with increased dose (exposure) of HMPA. Cell proliferation responses following two or more exposures returned to near control levels within 96 h post-exposure. In conclusion, HMPA induced cell proliferation, but not cytotoxicity, in the anterior nose at approximately 3 ppm. These data suggest that HMPA induces proliferative, perhaps mitogenic, responses in the nasal epithelium, and this response may facilitate the fixation of low level genetic damage induced by liberated HCHO.

A comparative study of antipyrine pharmacokinetics in saliva and plasma using a colourimetric method of antipyrine analysis.

1. Half-life, apparent volume of distribution and metabolic clearance rate for antipyrine elimination were reliably estimated from either plasma or saliva samples. 2. Pharmacokinetic analysis of antipyrine from saliva utilizing a simple and sensitive colourimetric technique provided a convenient method for assessing the activity of hepatic microsomal drug-metabolizing enzymes.