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: Southwest metropolitan Mexico City children are repeatedly exposed to high levels of a complex mixture of air pollutants, including ozone, particulate matter, aldehydes, metals, and nitrogen oxides. We explored nasal cell 8-hydroxy-2'-deoxyguanosine (8-OHdG), a major mutagenic lesion producing G-->T transversion mutations, using an immunohistochemical method, and DNA single strand breaks (ssb) using the single cell gel electrophoresis assay as biomarkers of oxidant exposure. Nasal biopsies from the posterior inferior turbinate were examined in children in grades one through five, including 12 controls from a low-polluted coastal town and 87 Mexico City children. Each biopsy was divided for the 8-OHdG and DNA ssb assays. There was an age-dependent increase in the percentage of nasal cells with DNA tails > 10 microm in Mexico City children: 19 +/- 9% for control cells, and 43 +/- 4, 50 +/- 16, 56 +/- 17, 60 +/- 17 and 73 +/- 14%, respectively, for first through fifth graders (p < 0.05). Nasal ssb were significantly higher in fifth graders than in first graders (p < 0.05). Higher levels (2.3- to 3-fold) of specific nuclear staining for 8-OHdG were observed in exposed children as compared to controls (p < 0.05). These results suggest that DNA damage is present in nasal epithelial cells in Mexico City children. Persistent oxidative DNA damage may ultimately result in a selective growth of pr eneoplastic nasal initiated cells in this population and the potential for nasal neoplasms may increase with age. The combination of 8-OHdG and DNA ssb should be useful for monitoring oxidative damage in people exposed to polluted atmospheres.Environmental Health Perspectives 06/1999; 107(6):469-74. · 7.03 Impact Factor
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ABSTRACT: Physiologically based pharmacokinetic (PBPK) models require estimates of catalytic rate constants controlling the metabolism of xenobiotics. Usually, these constants are derived from whole tissue homogenates wherein cellular architecture and enzyme compartmentation are destroyed. Since the nasal cavity epithelium is composed of a heterogeneous cell population measurement of xenobiotic metabolizing enzymes using homogenates could yield artifactual results. In this article a method for measuring rates of metabolism of vinyl acetate, a metabolism-dependent carcinogen, is presented that uses whole-tissue samples and PBPK modeling techniques to estimate metabolic kinetic parameters in tissue compartments. The kinetic parameter estimates were compared to those derived from homogenate experiments using two methods of tissue normalization. When the in vitro gas uptake constants were compared to homogenate-derived values, using a normalization procedure that does not account for tissue architecture, there was poor agreement. Homogenate-derived values from rat nasal tissue were 3- to 23-fold higher than those derived using the in vitro gas uptake method. When the normalization procedure for the rat homogenate-derived values took into account tissue architecture, a good agreement was observed. Carboxylesterase activity in homogenates of human nasal tissues was undetectable. Using the in vitro gas uptake technique, however, carboxylesterase activity was detected. Rat respiratory carboxylesterase and aldehyde dehydrogenase activities were about three and two times higher than those of humans, respectively. Activities of the rat olfactory enzymes were about equivalent to those of humans. K(m) values did not differ between species. The results suggest that the in vitro gas uptake technique is useful for deriving enzyme kinetic constants where effects of tissue architecture are preserved. Furthermore, the results suggest that caution should be exercised when scaling homogenate-derived values to whole-organ estimates, especially in organs of cellular heterogeneity.Toxicological Sciences 01/1999; 46(2):235-46. · 4.48 Impact Factor
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ABSTRACT: Experimental observations and theoretical considerations indicate a dose threshold for most chemically induced noncancer toxic effects below which the increased risk of toxicity is zero. Thus, the historical approach for minimizing risk from toxic chemicals has been to experimentally determine a no-observed-adverse-effect-level (NOAEL) and then to apply safety or uncertainty factors to estimate a dose not expected to produce that toxic effect in humans. In contrast, for radiation and chemically induced cancer, it has been assumed that all agents operate by a genotoxic mode of action and that some risk can be assigned to even vanishingly small doses. Accordingly, risk assessments for carcinogens have commonly been based on the assumption that the tumor dose-response curve at low doses is linear and passes through the origin. Mode of action is defined as a fundamental obligatory step in the induction of toxicity or cancer. It is now clear that tumor induction can arise in a variety of ways including not only a DNA-reactive genotoxic mode of action, but also non-DNA-reactive nongenotoxic-cytotoxic and nongenotoxic-mitogenic modes of action. Initial risk assessment approaches that recognized this distinction identified a chemical carcinogen as either genotoxic or nongenotoxic, with no middle ground. The realization that there is a continuum whereby different chemicals can act by a combination of modes of action and the recent explosion of research into molecular mechanisms of carcinogenesis indicate that all relevant information should be integrated into the risk assessment process on a case by case basis. A comprehensive approach to risk assessment demands that default assumptions be replaced with an integrated understanding of the rate-limiting steps in the induction of toxicity or cancer along with quantitative measures of the shapes of those dose-response curves. The examples of more contemporary risk assessments are presented for chloroform and vinyl acetate.Regulatory Toxicology and Pharmacology 03/1999; 29(1):23-36. · 2.14 Impact Factor