Critical factors in assessing risk from exposure to nasal carcinogens.
ABSTRACT 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.
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ABSTRACT: Three-dimensional mini organ cultures of human inferior nasal turbinate epithelia have proved to be a useful tool in genotoxicology studies. They allow repetitive or chronic exposure of cells to xenobiotics in a well-preserved organ-specific mucosal architecture for an extended period of time. It is the aim of the present study to concurrently monitor cumulative genotoxic and apoptotic effects of sodium dichromate, N-nitrosodiethylamine (NDEA) and N-methyl-N-nitro-N-nitroso-guanidine (MNNG). Mini organs were raised by separating fresh specimens of human inferior nasal turbinates (n=11) into 1 mm3 sized pieces and culturing them on multiwell plates with bronchial epithelial basal medium for 6 days. Aliquots of the mini organs were subsequently exposed to sodium dichromate (1.0 mM, 1h), NDEA (50 mM, 1h) or MNNG (0.07 mM, 1h) on days 7, 9 and 11 versus a single exposure on day 11 only. DNA fragmentation and apoptotic events were assessed on day 11 using the alkaline single cell microgel electrophoresis assay (comet assay) and the annexin V-affinity assay. Significant DNA fragmentation could be demonstrated after a single exposure of the mini organs to sodium dichromate. Following three subsequent incubations, there was a further increase in the genetic damage observed, accompanied by an increase in the rate of apoptotic cells. In contrast, after single and triple incubation with NDEA there was neither an increase in genetic damage nor in the fraction of apoptotic cells detectable. Repetitive exposure to MNNG resulted in an accumulation of DNA damage without an observable increase in apoptosis. The results verify the need to assess apoptosis in genotoxicology research and to investigate cumulative effects of xenobiotics. Three-dimensional mini organ cultures of human upper aerodigestive tract epithelia have shown to be well-suited for improving the ability to distinguish between cumulative genotoxic and apoptotic effects.Toxicology Letters 04/2007; 169(2):152-61. · 3.15 Impact Factor
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ABSTRACT: Air pollution is a serious health problem in major cities in Mexico. The concentrations of monitored criteria pollutants have been above the US National Ambient Air Quality Standards for the last decade. To determine whether the number of primary malignant nasal and paranasal neoplasms has increased, we surveyed 256 such cases admitted to a major adult oncology hospital located in metropolitan Mexico City (MMC) for the period from 1976-1997 and to a tertiary hospital in Monterrey, an industrial city, for the period from 1993-1998. The clinical histories and histopathologic material were reviewed, and a brief clinical summary was written for each case. In the MMC hospital the number of newly diagnosed nasal and paranasal neoplasms per year for the period from 1976-1986 averaged 5.1, whereas for the next 11 years it increased to 12.5. The maximal increase was observed in 1995-1997, with an average of 20.3 new cases per year (P = 0.0006). The predominant neoplasms in these series were non-Hodgkin's lymphoma, squamous cell carcinoma, melanoma, adenocarcinoma, Schneiderian carcinoma, and nasopharyngeal carcinoma. In the Monterrey hospital a 2-fold increase in the numbers of newly diagnosed nasal and paranasal neoplasms was recorded between 1993 and 1998. The predominant MMC neoplasm in this series, namely nasal T-cell/natural killer cell non-Hodgkin's lymphoma, is potentially Epstein-Barr virus related. Nasal and paranasal malignant neoplasms are generally rare. Environmental causative factors include exposure in industries such as nickel refining, leather, and wood furniture manufacturing. Although epidemiologic studies have not addressed the relationship between outdoor air pollution and sinonasal malignant neoplasms, there is strong evidence for the nasal and paranasal carcinogenic effect of occupational aerosol complex chemical mixtures. General practitioners and ear, nose, and throat physicians working in highly polluted cities should be aware of the clinical presentations of these patients. Identification of this apparent increase in sinonasal malignant neoplasms in two urban Mexican polluted cities warrants further mechanistic and epidemiologic studies.Otolaryngology Head and Neck Surgery 05/2000; 122(4):499-508. · 1.73 Impact Factor
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ABSTRACT: The respiratory tract is frequently identified as a site of toxicity for inhaled xenobiotic chemicals. Usually, these observations come from controlled animal studies. For these studies to be of quantitative value to human health risk assessment, species-specific factors governing dosimetry of inhaled substances must be taken into account. Toxicokinetics of vapours in the respiratory tract are defined by absorption, distribution, metabolism, and excretion, as they are in other tissues; however, these concepts take on new dimensions when considering respiratory tract toxicants, especially those that elicit portal of entry effects by directly interacting with the tissue lining the respiratory tract. Species-specific factors related to anatomy, physiology and biochemistry govern inter-species extrapolation of toxicokinetics. This article discusses critical factors of respiratory tract kinetics that should be considered when developing physiological-based toxicokinetic (PBTK) models for inhaled vapours. Important considerations such as impact of regional airflow-delivery, water solubility, reactivity, and rates of local biotransformation on respiratory tract tissue dosimetry are highlighted. These factors can be accounted for only to a limited extent when using default approaches to extrapolate dosimetry of inhaled substances across species. On the other hand, PBTK modeling has the flexibility to accommodate many of the critical determinants of respiratory tract toxicity. PBTK models can also help identify the most critical toxicokinetic data necessary to replace defaults. PBTK approaches have led to more informed estimates of human target tissue dose, and therefore human health risk, especially where these risk assessments have been based on extrapolation of animal dosimetry studies. Experience derived from the development of more intensive case studies have, in turn, enabled simplified approaches to the use of PBTK modeling for respiratory tract toxicants. Whether simplified or highly complex, PBTK modeling approaches are proven to be of great utility to risk assesors interested in applying quantitative information to informed risk assessment evaluations.Toxicology Letters 03/2003; 138(1-2):103-17. · 3.15 Impact Factor