Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor.

BMS-214662 is a potent and selective inhibitor of farnesyltransferase (FTI). In rodent fibroblasts transformed by oncogenes, BMS-214662 reversed the H-Ras-transformed phenotype but not that of K-Ras or other oncogenes. In soft agar growth assays, BMS-214662 showed good potency in inhibiting H-ras-transformed rodent cells, A2780 human ovarian carcinoma tumor cells, and HCT-116 human colon carcinoma tumor cells. Inhibition of H-Ras processing in HCT-116 human colon tumor cells was more rapid than in H-Ras-transformed rodent fibroblast tumors. BMS-214662 is the most potent apoptotic FTI known and demonstrated broad spectrum yet robust cell-selective cytotoxic activity against a panel of cell lines with diverse histology. The presence of a mutant ras oncogene was not a prerequisite for sensitivity. Athymic and conventional mice were implanted s.c. with different histological types of human and murine tumors, respectively. BMS-214662 was administered both parenterally and p.o. and was active by all these routes. Curative responses were observed in mice bearing staged human tumor xenografts including HCT-116 and HT-29 colon, MiaPaCa pancreatic, Calu-1 lung, and EJ-1 bladder carcinomas. A subline of HCT-116, HCT-116/VM46, resistant to many standard cytotoxic agents by means of a multiple drug resistance mechanism, remained quite susceptible to BMS-214662, and borderline activity was achieved against N-87 human gastric carcinoma. Two murine tumors, Lewis lung carcinoma and M5076 sarcoma, were insensitive to the FTI. In a study performed using Calu-1 tumor-bearing mice, no obvious schedule dependency of BMS-214662 was observed. The FTI, BMS-214662, demonstrated broad spectrum activity against human tumors, but murine tumors were not as sensitive.

Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril.

Vasopeptidase inhibitors are single molecules that inhibit neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) simultaneously. Omapatrilat, the first in this new class of cardiovascular agents, potentiates vasodilatory and cardioprotective peptides and represses angiotensin II. This study compared the effects of omapatrilat with those of a pure ACE inhibitor on cardiac geometry and survival in animals with heart failure. BIO TO-2 cardiomyopathic hamsters (CMHs) in the early stages of dilated heart failure were treated with vehicle or maximal ACE inhibitory doses of captopril (750 micromol/kg/day) or omapatrilat (200 micromol/kg/day). Prolonged vasopeptidase inhibition increased median survival time after the start of treatment by 99 and 31% compared with vehicle and captopril, respectively (median survival times: 146, 221, and 290 days with vehicle, captopril, and omapatrilat, respectively; p < 0.001 for all comparisons). In similar CMHs, captopril or omapatrilat administered for 2 months significantly (p < 0.05) decreased heart weight, pulmonary congestion (lung weight), and left ventricular (LV) chamber volume compared with vehicle. Omapatrilat significantly increased LV mass-to-volume ratio compared with vehicle and captopril. Omapatrilat, but not captopril, significantly increased urinary atrial natriuretic peptide excretion, indicating NEP inhibition. Thus vasopeptidase inhibition with omapatrilat was more effective than ACE inhibition with captopril in preventing changes in LV geometry and premature mortality in hamsters with dilated heart failure.

Chemically-induced nasal carcinogenesis and epithelial cell proliferation: a brief review.

An increased rate of cell proliferation has long been recognized as an important factor in both human and experimental carcinogenesis, and may be a major risk factor for cancer development in a number of tissues. Limited information exists, however, regarding the relevance of increased cell proliferation and nasal cancer. Examples of toxicological studies utilizing nasal cell proliferation data as an important endpoint are briefly reviewed. Data for one of the most extensively studied chemicals, the weakly genotoxic carcinogen formaldehyde, support the contention that the concentration-response relationship for tumor incidence is a function of formaldehyde-induced target cell proliferation, in addition to other factors including target cell population size. The increasing importance of utilizing cell proliferation data in determining dose-response relationships and in biologically-based risk assessment models is discussed.

Hypoxia stimulates human preproendothelin-1 promoter activity in transgenic mice.

Significant elevations in endothelin (ET)-1 levels accompany many diseases, but the underlying regulatory mechanisms are unclear. To investigate the in vivo regulation of human preproendothelin-1 (PPET-1), we examined the activity of the PPET-1 promoter in transgenic mice exposed to hypoxia. Mice expressing one of three PPET-1 promoter-luciferase (PPET-1/LUC) reporter transgenes (approximately 2.5 kb, 138 bp, or none of the 5'-flanking sequences of the PPET-1 gene) were generated. LUC expression was reduced in mice with a truncated 138-bp PPET-1 promoter. Exposure of mice bearing the 2.5-kb PPET-1/LUC transgene to hypoxia (10% O2 for 24 h) increased LUC expression sixfold in pulmonary tissue but only twofold in other tissues. In situ hybridization revealed the strongest transgene expression in the pulmonary vasculature and bronchiolar epithelium. These data are consistent with the hypothesis that hypoxic induction of the PPET-1 gene leads to increased pulmonary production of ET-1 in diseases associated with low O2 tension.

Utilization of electron probe microanalysis in gadolinium-treated mice.

Gadolinium is used as a contrast media for magnetic resonance imaging and, experimentally, to block Kupffer cell phagocytosis. In this study, we utilize electron probe microanalysis to determine the subcellular localization of gadolinium chloride (GdCl3) administered to mice in a short-term toxicology study. Male CD-1 mice were administered 0.0, 2.5, or 8.0 mg/kg GdCl3 iv for 14 consecutive weekdays. Liver-associated enzymes were significantly elevated in high-dose animals only and correlated histologically with multifocal, hepatocellular degeneration associated with a neutrophilic infiltrate. Morphological investigations were performed on high-dose animals. Hepatocytes and Kupffer cells had morphologic features of cellular injury consisting of swollen mitochondria and vesiculated profiles of endoplasmic reticulum. Hepatocytes, Kupffer cells, bile canaliculi, and neutrophils in the liver contained discrete aggregates of electron-dense granular material, as did pulmonary interstitial macrophages, splenic macrophages, and mesangial cells of the renal glomerulus. The intracellular granular material in the liver, lung, spleen, and kidney was confirmed as gadolinium by qualitative electron probe microanalysis. These results document both hepatic and extra-hepatic accumulation of gadolinium in cells of the mononuclear phagocytic system and highlight the importance of electron probe microanalysis in toxicologic assessment.

Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations of cells.

Formaldehyde induces nonlinear, concentration-related increases in nasal epithelial cell proliferation and squamous cell carcinomas (SCC) in rats. A formaldehyde carcinogenicity study was conducted in which a major end point was correlation of cell proliferation indices with sites of formaldehyde-induced SCC. A poor correlation in certain sites led to incorporation of the number of cells in each site into the correlation. Rats were exposed (6h/day, 5 days/week) to formaldehyde (0, 0.7, 2, 6, 10 or 15 ppm) for up to 24 months with interim sacrifice time points at 3, 6, 12, and 18 mo. A unit length labeling index (ULLI; S-phase nuclei/mm basement membrane) was determined for specific nasal regions in addition to a population-weighted ULLI (PWULLI). The PWULLI was defined as the product of regional ULLI and total number of nasal epithelial cells in the respective site. Nasal SCC sites of origin were mapped. Formaldehyde induced SCC in a highly nonlinear fashion, with no observed effect at the level of 2 ppm, a minimal response at 6 ppm, and a sharp increase at 10 and 15 ppm. The tumor incidence was 1, 22, and 47% at 6, 10 and 15 ppm, respectively. ULLI was significantly (P<0.05) increased at 10 and 15 ppm but not at the lower concentrations. There was a good correlation between PWULLI and regional tumor incidence (R(2) = 0.88), while the correlation of regional SCC with ULLI was relatively poor (R(2) = 0.46). We conclude that target cell population size and sustained increases of cell proliferation in these populations, determined by differences in regional airflow-driven formaldehyde binding to DNA dose to these sites, coupled with the known nonlinear kinetics of formaldehyde binding to DNA, can together account for the nonlinearity and site specificity of formaldehyde-induced nasal SCC in rats.

Comparative cardioprotective effects of cromakalim and diltiazem in ischemic hypertrophied rat hearts.

Previous studies have indicated that alterations in cardiac ATP-sensitive potassium channels (KATP) can occur with cardiac hypertrophy. The goal of this study was to determine the effect of cardiac hypertrophy in spontaneously hypertensive rats (SHR) on the response to the cardioprotective agents diltiazem and cromakalim. Isolated rat hearts from 14-wk-old SHR, normotensive heterozygote Wistar-Kyoto (WKY), and Sprague-Dawley (SD) strains were subjected to 25 min of global ischemia and 30 min of reperfusion in the presence of vehicle (3-30 microM cromakalim or 0.1-1.0 microM diltiazem). SHR had heart weight-to-body weight ratios 40-50% greater than age-matched SD or WKY. Both diltiazem and cromakalim increased reperfusion contractile function in a concentration-dependent manner in SD rats as previously reported. Cromakalim and diltiazem caused similar improvements in reperfusion function in WKY rats and SHR. Cumulative lactate dehydrogenase (LDH) release during reperfusion was similar for vehicle-treated SD, WKY, or SHR hearts. LDH release was significantly attenuated by cromakalim and dilitiazem at all concentrations tested in SD and WKY hearts, whereas LDH release was not attenuated in SHR hearts by any concentration of cromakalim or diltiazem tested. Morphological assessment of hearts by light microscopy indicated that the severity and distribution of myocardial lesions were not affected by cromakalim in SHR hearts, compared with vehicle-treated SHR, supporting the LDH data. These results suggest that in SHR hearts, cromakalim and dilitiazan may exert much of their cardioprotective effects on the population of myocytes that are not irreversibly damaged.

Amelioration of ischemia/reperfusion injury in isolated rats hearts by the ATP-sensitive potassium channel opener BMS-180448.

OBJECTIVE: Aims of this study were: (1) Evaluate by morphology and specific physiological and biochemical parameters, the protective effects of the cardioselective ATP-sensitive potassium channel opener BMS-180448 on ischemic/reperfused isolated rat heart, and (2) Determine the earliest time point ischemia-induced myocardial injury is observed by light microscopy. METHODS: Hearts from Sprague-Dawley rats were perfused on a Langendorff apparatus. After equilibration, hearts were treated with BMS-180448 (10 micro M) or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. Four hearts/group were collected following 10, 18, or 25 min of ischemia. A nonischemic control group was also evaluated. Following 25 min of ischemia, another set of hearts was reperfused with oxygenated Krebs-Hensleit solution and allowed to recover for 30 min. Light and electron microscopic changes of the myocardium were semi-quantitatively evaluated together with physiological (i.e., heart rate, left ventricular diastolic pressure, time to contracture formation) and biochemical (i.e., lactate dehydrogenase, LDH, release) endpoints. RESULTS: Cardioprotective effects of BMS-180448 following ischemia/reperfusion consisted of a reduced rate of contracture formation, reduced LDH release, and enhanced recovery of contractile function during reperfusion (P < 0.05). Light microscopic evidence of myocardial damage was detected following 18 min of ischemia. Morphological changes in ischemic/reperfused hearts included interstitial edema, myofiber degeneration, and hypercontraction band formation. Ultrastructurally, swollen myofibrils, swollen mitochondria with disrupted cristae and electron-dense deposits, myofibrillar lysis, and contraction bands, were observed. Light and electron microscopic severity scores were significantly less (P < 0.05) in BMS-180448-treated hearts at the 25 min ischemic time point and in reperfused hearts, as compared to similarly-treated vehicle hearts. CONCLUSIONS: BMS-180448 ameliorates morphological evidence of ischemia/reperfusion myocardial damage in the isolated rat heart model, in agreement with physiological and biochemical parameters.

Comparison of acute hepatocellular proliferating cell nuclear antigen labeling indices and growth fractions, p34cdc2 kinases, and serum enzymes in carbon tetrachloride-treated rats.

We evaluated various biomarkers associated with cell proliferation immediately following insult with the classic hepatotoxicant carbon tetrachloride (CCl4). Rats were administered a single necrogenic dose of CCl4 and euthanized at either t = 4, 8, 12, 16, or 24 hr postdose. Parameters evaluated included the following: immunohistochemical detection of hepatocellular proliferating cell nuclear antigen labeling indices (PCNA-LIs; percentage of cells in S phase) and growth fractions (PCNA-GFs; percentage of cells in the cell cycle); PCNA and the cyclin-dependent kinase p34cdc2 (CDK) protein in S-9 fractions by Western blot and enzyme-linked immunosorbent assay (ELISA); and liver-related serum enzymes. An increase in PCNA-GF was observed at t = 4 hr, concomitant with elevations in CDK and PCNA protein (Western blot). PCNA-LIs were increased by t = 24 hr, as were CDK and PCNA by ELISA. Sorbitol dehydrogenase was the most sensitive enzyme, with increases observed at t = 4 hr. Our results indicate that PCNA-GF, CDK, and PCNA levels reflect hepatocellular regeneration as early as 4 hr following CCl4 insult. We conclude that these assays are early and sensitive indicators of acute hepatotoxicity that may be advantageous to evaluate in the early stages of exploratory studies.

Cell proliferation and formaldehyde-induced respiratory carcinogenesis.

Formaldehyde is a nasal carcinogen in the rat but the cancer risk this chemical poses for humans remains to be determined. Formaldehyde induces nonlinear, concentration-dependent increases in nasal epithelial cell proliferation and DNA-protein cross-link formation following short-term exposure. Presented in this review are results from a mechanistically based formaldehyde inhalation study in which an important endpoint was the measurement of cell proliferation indices in target sites for nasal tumor induction. Male Fischer 344 rats were exposed to 0, 0.7, 2, 6, 10, or 15 ppm formaldehyde for up to 2 years (6 hr/day, 5 day/week). Statistically significant increases in cell proliferation were confined to the 10 and 15 ppm groups, which remained elevated throughout the study. The concentration-dependent increases in cell proliferation correlated strongly with the tumor response curve, supporting the proposal that sustained increases in cell proliferation are an important component of formaldehyde carcinogenesis. The nonlinearity observed in formaldehyde-induced rodent nasal cancer is consistent with a high-concentration effect of regenerative cell proliferation of the target organ coupled with the genotoxic effects of formaldehyde. Cell kinetic data from these studies provide important information that may be utilized in the assessment of risk for humans exposed to formaldehyde.

Cell proliferation and nasal carcinogenesis.

The nasal passages of rodents provide valuable opportunities for research on relationships between cell proliferation and cancer. The nose, which has multiple functions, possesses a diverse range of tissue types, each with its own morphologic, physiologic, and metabolic characteristics and site-specific cell turnover rates. Moreover, for inhaled materials deposited in the nose, complex regional uptake or deposition patterns can result in site-specific responses, including cancer. Presented here are important criteria necessary for undertaking cell proliferation studies in the nasal passages. The current literature concerning nasal toxicity and the toxicant-induced proliferative response are also reviewed. Rodent nasal epithelium provides a fruitful area for research on the role of cell proliferation in carcinogenesis.

Regional increases in rat nasal epithelial cell proliferation following acute and subchronic inhalation of formaldehyde.

Short-term studies (9 days) in the rat have demonstrated that formaldehyde-induced nasal epithelial lesions are associated with increases in surface epithelial cell proliferation rates. The present studies were designed, in part, to investigate cell proliferation rates in the nasal epithelium of rats exposed to formaldehyde for a longer duration in order to determine if correlations exist between (1) the concentration-response in cell proliferation rate with the previously published formaldehyde bioassay tumor response; (2) sites of increased cell proliferation and the regions of the nasal passages that exhibit formaldehyde-induced cytotoxicity; and (3) sites of increased cell proliferation and the regions of the rat nasal passages previously determined to be most susceptible to neoplasia (i.e., the lateral meatus and nasal septum of the anterior nasal passages). Another important endpoint of this study was to provide data for a comparison of formaldehyde-induced responses in rats with previous findings in rhesus monkeys. Fischer-344 rats were exposed to 0, 0.7, 2, 6, 10, or 15 ppm formaldehyde for up to 6 weeks and pulse labeled with tritiated thymidine prior to each scheduled termination. Exposure to formaldehyde at 6 ppm or higher induced site-specific lesions in the nasal respiratory epithelium and was associated with increases in cell proliferation rate which remained statistically elevated throughout the 6 weeks. While a direct correlation between sites susceptible to formaldehyde-induced nasal cancer and increased cell proliferation was not evident, results from the present studies did demonstrate a clear correlation between sites of cellular injury and increases in cell proliferation and a concentration-dependent response which correlated with the previously published formaldehyde bioassay tumor response. Furthermore, this work demonstrated that formaldehyde-induced responses in rats exposed to 6 ppm were morphologically similar to those reported in the rhesus monkey; however, the distribution of lesions between the two species differed significantly.

Toxic and neoplastic responses in the nasal passages: future research needs.

It is evident that much remains to be learned about the nasal passages and their responses to toxic materials. For the nose of both laboratory animals and humans, information is needed in the areas of anatomy, physiology, biochemistry, neurobiology, physiopathology, and oncology. This article briefly discussed toxic and neoplastic responses of the nasal passages, and identified a number of issues and questions that provide potentially valuable areas for further research. It was stated that: (1) Histopathologic examination of the nose could profit from the development of a good all-purpose fixative. (2) A consistent and appropriate classification of nasal passageways, epithelia, and other structures is needed to avoid further confusion. (3) A workable scheme for lesion mapping is needed for routine description of lesion distribution in the nasal passages in rodent toxicology studies. (4) Quantitative data are needed concerning regional substrate specificities and kinetics of nasal enzymes in animals and humans for a wide range of enzymes responsible for metabolism of xenobiotics. Moreover, the following questions should be addressed in the future: (1) What is the nature of the progenitor cells in the olfactory epithelium, basal cells alone, or basal and ductular cells? (2) What determines the resistance of regenerated rat olfactory epithelium to subsequent methyl bromide exposure? (3) Can this resistance phenomenon be demonstrated with other olfactory toxicants and in other species? (4) What influence do cage contaminant gases have on olfactory research in laboratories using rodents? The authors also believe that, despite the fact that nasal airflow has been a subject of investigation for many years, much remains to be learned about this complex process. It is expected that the application of computer technology to mathematical modeling of nasal airflow and regional gas uptake will yield significant new information for the understanding of mechanisms responsible for the distribution of upper respiratory tract lesions in animals and humans. The combination of models of regional uptake, wall flux rates, critical biochemical events, nasal blood flow, and other features of nasal physiology, and integration of these models with lower respiratory tract models, will provide valuable tools for investigations of nasal pathology and toxicology. It was also stressed that the effects of toxicants on olfactory function in humans deserve more attention since, in some past studies, it was suggested that the protection afforded by current TLVs against olfactory toxicity may be marginal. A simple and sensitive olfactometric test of general application for toxicology testing in animals remains to be validated.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal molds: relevance to formaldehyde toxicity.

For highly water soluble and reactive gases, such as formaldehyde, the reported distribution of nasal lesions in rats and rhesus monkeys following inhalation exposure may be attributable, at least in part, to regional gas uptake patterns that are a consequence of nasal airflow characteristics. Inspiratory nasal airflow was studied at flow rates across the physiologic range using a unidirectional dynamically similar water-dye siphon system in clear acrylic molds of the nasal airways of F344 rats and rhesus monkeys. In both species there were complex and inspiratory flow streams, exhibiting regions of simple laminar, complex secondary (vortices, eddies, swirling), and turbulent flows, with only minor effects of the volumetric flow rates studied on these flow patterns. There was a precise association between points of dye intake at the nostril with complex but generally coherent streaklines throughout the nose, indicating the potential for sensitive dependence of nasal airflow on nostril geometry. On the basis of these studies, a classification for the major airways (meatuses) in the nasal passages of rats and rhesus monkeys was proposed. The spiral shape of the anterior nasal airway of the rat was considered to play an important role in local mixing of inspired airstreams. In the rhesus monkey, the complex geometry of the nasal vestibule contributed to the formation of secondary flows and turbulence in the anterior nose, which represents a potentially important difference between rheusus monkeys and humans. There was a good correlation between routes of flow, regional secondary flows, turbulence, and impaction of airstreams on the airway wall, with the reported distribution of formaldehyde-induced nasal lesions in rats and rhesus monkeys. These studies support the proposal that nasal airflow patterns play an important role in the distribution of lesions induced by formaldehyde.

Examination of potential mechanisms of carcinogenicity of 1,4-dioxane in rat nasal epithelial cells and hepatocytes.

Several long-term studies with 1,4-dioxane (dioxane) have shown it to induce liver tumors in mice, and nasal and liver tumors in rats when administered in amounts from 0.5 to 1.8% in the drinking water (Argus et al. 1965; Kociba et al. 1974; National Cancer Institute, 1978). In order to examine potential mechanisms of action, chemically-induced DNA repair (as an indicator of DNA reactivity) and cell proliferation (as an indicator of promotional activity) were examined in nasal turbinate epithelial cells and hepatocytes of male Fischer-344 rats treated with dioxane. Neither dioxane nor 1,4-dioxane-2-one, one of the proposed metabolites, exhibited activity in the in vitro primary rat hepatocyte DNA repair assay, even from cells that had been isolated from animals given either 1 or 2% dioxane in the drinking water for 1 week to induce enzymes that might be responsible for producing genotoxic metabolites. No activity was seen in the in vivo hepatocyte DNA repair assay in animals given a single dose of up to 1000 mg/kg dioxane or up to 2% dioxane in the drinking water for 1 week. Treatment of rats with 1.0% dioxane in the drinking water for 5 days yielded no increase in liver/body weight nor induction of palmitoyl CoA oxidase, indicating that dioxane does not fit into the class of peroxisomal proliferating carcinogens. The percentage of cells in DNA synthesis phase (S-phase) was determined by administration of 3H-thymidine and subsequent quantitative histoautoradiography. The hepatic labeling index (LI) did not increase at either 24 or 48 h following a single dose of 1000 mg/kg dioxane.(ABSTRACT TRUNCATED AT 250 WORDS)

Proliferative and neoplastic lesions in the rodent nasal cavity.

Proliferative lesions in the rodent nasal cavity are reviewed; attempt was made to compare species affected, sex differences, strain differences, route of administration and tumor types occurring both spontaneously and after induction by different chemicals. This review is not meant to be all inclusive but to be representative of observed trends. Our general conclusions in this paper are that: 1) spontaneous nasal tumors in rodents are very rare; 2) spontaneous nasal tumors in rats are most often squamous cell tumors, whereas hemangiomas or respiratory adenomas predominate in mice and squamous cell tumors are rare; 3) rats are usually more susceptible to the induction of epithelial tumors of the nasal cavity than mice; 4) chemically-induced hemangiomas and hemangiosarcomas of the nasal cavity have only been reported in mice; 5) tumors of the olfactory epithelium are almost uniformly malignant and invasive, while nonsquamous tumors of the respiratory epithelium are typically less invasive; 6) chemically-induced tumors of the olfactory region, either mesenchymal or epithelial, do not always require an inhalation route of exposure but may occur by systemic targeting of this region; and 7) chemicals inducing tumors in the olfactory region often produce a variety of tumor morphologies in this location as well as squamous and polypoid tumors of the transitional region. More work will be needed to illucidate the mechanisms of nasal carcinogenesis and to further refine the current tumor classification system.

Airflow, gas deposition, and lesion distribution in the nasal passages.

The nasal passages of laboratory animals and man are complex, and lesions induced in the delicate nasal lining by inhaled air pollutants vary considerably in location and nature. The distribution of nasal lesions is generally a consequence of regional deposition of the inhaled material, local tissue susceptibility, or a combination of these factors. Nasal uptake and regional deposition are are influenced by numerous factors including the physical and chemical properties of the inhaled material, such as water solubility and reactivity; airborne concentration and length of exposure; the presence of other air contaminants such as particulate matter; nasal metabolism, and blood and mucus flow. For certain highly water-soluble or reactive gases, nasal airflow patterns play a major role in determining lesion distribution. Studies of nasal airflow in rats and monkeys, using casting and molding techniques combined with a water-dye model, indicate that nasal airflow patterns are responsible for characteristic differences in the distribution of nasal lesions induced by formaldehyde in these species. Local tissue susceptibility is also a complex issue that may be a consequence of many factors, including physiologic and metabolic characteristics of the diverse cell populations that comprise each of the major epithelial types lining the airways. Identification of the principal factors that influence the distribution and nature of nasal lesions is important when attempting the difficult process of determining potential human risks using data derived from laboratory animals. Toxicologic pathologists can contribute to this process by carefully identifying the site and nature of nasal lesions induced by inhaled materials.