Abstract  While nasal cancer is relatively rare among the general population, workers in the nickel refining, leather manufacturing, and furniture building industries exhibit increased incidences of nasal cancer. To investigate the causes of nasal cancer and to design ameliorative strategies, an appropriate animal model for the human upper respiratory regions is required. The present report describes, compares, and assesses the anatomy and physiology of the nasal passages and upper airways of humans, rats, and monkeys for the purpose of determining a relevant animal model in which to investigate potential causes of nasal cancer. Based on the mode of breathing, overall geometry of the nasal passages, relative nasal surface areas, proportions of nasal surfaces lined by various epithelia, mucociliary clearance patterns, and inspiratory airflow routes, the rat, which is very different from humans, is a poor model. In contrast, the monkey exhibits many similarities to humans. Although the monkey does differ from humans in that it exhibits a more rapid respiratory rate, smaller minute and tidal volumes, larger medial turbinate, and a vestibular wing that creates an anterior vortex during inspiration, it offers a more appropriate model for studying the toxic effects of inhaled substances on the nasal passages and extrapolating the findings to humans.

Abstract  Naphthalene, a murine Clara cell cytotoxicant, is metabolized by cytochrome P450 monooxygenases to unstable, chiral epoxide metabolites which can conjugate with glutathione in the presence of glutathione transferases. Analysis of the three diasteriomeric glutathione adducts produced from conjugation of naphthalene oxides was used in these studies to characterize the stereochemistry of naphthalene epoxidation in preparations of nasal mucosa, lung and liver of the mouse, rat, hamster and monkey. The highest rates of naphthalene metabolism were observed in mouse lung and liver microsomal incubations. Rat, hamster and monkey lung microsomal preparations metabolized naphthalene at 12, 37, and 1%, respectively, of the rate observed in mouse lung. The ratio of chiral epoxides produced in microsomal incubations was dependent upon the concentration of naphthalene. At high substrate concentrations (0.25-1.0 mM), the ratio of 1R,2S- to 1S,2R-naphthalene oxide, as assessed by the glutathione adducts generated (adduct 2/adducts 1 + 3), in murine lung microsomal incubations was 10:1 and at low concentrations (0.062 mM and below) varied from 13.8:1 to 30:1. In contrast, the ratio of 1R,2S- to 1S,2R-naphthalene oxide produced in murine liver microsomes varied from 1:1 at high substrate concentrations to 5:1 at low substrate concentrations. The ratio of naphthalene oxides was unaffected by the concentration of glutathione in the incubation. In contrast to the preferential formation of 1R,2S-naphthalene oxide observed in mouse lung microsomal preparations, lung microsomes derived from the rat, hamster and monkey yielded 1R,2S- to 1S,2R-epoxide ratios of 0.48, 0.61 and 0.12, respectively, at 0.5 mM naphthalene.

Abstract  The TLV-TWA 10 ppm (52 mg/m3) and TLV-STEL of 15 ppm (79 mg/m3) are recommended for occupational exposure to naphthalene. These values are intended to minimize the potential for eye and respiratory tract irritation and ocular toxicity that can include cataract formation, optical neuritis, lens opacities, and retinal degeneration. Other adverse effects may include headache, loss of appetite, nausea, and blood dyscrasia, such as hemolytic anemia and hemoglobinuria. Systemic poisoning following dermal contact and absorption of naphthalene warrants a Skin notation. Based on the very limited evidence of carcinogenicity in rodents, pulmonary adenomas in female mice but not in the male mice or in rats of either sex, exposed by inhalation for 2 years, an A4, Not Classifiable as a Human Carcinogen, notation is assigned. Sufficient data were not available to recommend a SEN notation.

Abstract  The Integrated Risk Information System (IRIS) is a database of U.S. Environmental Protection Agency consensus positions on the health effects that may result from chronic exposure to various chemicals found in the environment. The Purpose of this Toxicological Review is to provide scientific support and rationale for the hazard identification and dose-response information in IRIS pertinent to Naphthalene.

Abstract  The lung, which is in intimate contact with the external environment, is exposed to a number of toxicants both by virtue of its large surface area and because it receives 100% of the cardiac output. Lung diseases are a major disease entity in the U.S. population ranking third in terms of morbidity and mortality. Despite the importance of these diseases, key issues remain to be resolved regarding the interactions of chemicals with lung tissue and the factors that are critical determinants of chemical-induced lung injury. The importance of cytochrome P450 monooxygenase dependent metabolism in chemical-induced lung injury in animal models was established over 25 years ago with the furan, 4-ipomeanol. Since then, the significance of biotransformation and the reasons for the high degree of pulmonary selectivity for a myriad of different chemicals has been well documented, mainly in rodent models. However, with many of these chemicals there are substantial differences in the susceptibility of rats vs. mice. Even within the same species, varied levels of the respiratory tract respond differently. Thus, key pieces of data are still missing when evaluating the applicability of data generated in rodents to primates, and as a result of this, there are substantial uncertainties within the regulatory community with regards to assessing the risks to humans for exposure to some of these chemicals. For example, all of the available data suggest that the levels of cytochrome P450 monooxygenases in rodent lungs are 10-100 times greater than those measured in the lungs of nonhuman primates or in man. At first glance, this suggests that a significant margin of safety exists when evaluating the applicability of rodent studies in the human, but the issues are more complex. The intent of this review is to outline some of the work conducted on the site and species selective toxicity and metabolism of the volatile lung toxic aromatic hydrocarbon, naphthalene. We argue that a complete understanding of the cellular and biochemical mechanisms by which this and other lung toxic compounds generate their effects in rodent models with subsequent measurement of these cellular and biochemical events in primate and human tissues in vitro will provide a far better basis for judging whether the results of studies done in rodent models are applicable to humans.

Abstract  Current OSHA standards for naphthalene exposure are set at 10 ppm (time-weighted average) with a standard threshold exposure concentration of 15 ppm. While several studies have thoroughly delineated the time course and dose response of injury by naphthalene administered ip, the pattern and severity of injury by inhalation exposure are unknown. These studies compare the regiospecific and dose-dependent cytotoxicity of naphthalene after inhalation exposure. Mice and rats were exposed for 4 h to naphthalene vapor at concentrations of 0-110 ppm. In rats, no injury was observed in the lung epithelium at exposure concentrations up to 100 ppm. Exposures as low as 2 ppm produced proximal airway injury in mice, with increased severity in a concentration-dependent fashion up to 75 ppm. Terminal airways of exposed mice exhibited little or no injury at low concentrations (1-3 ppm). Exposures of 8.5 ppm or higher were required to produce injury to Clara cells in the terminal airways. In contrast, administration of naphthalene (300 mg/kg) extended the injury pattern toward the lobar bronchus. We conclude (1) the pattern of injury to naphthalene is highly dependent on the route of exposure, (2) lung injury to inhaled naphthalene is species dependent, and (3) Clara cells of mouse airways are exquisitely sensitive to inhaled naphthalene at concentrations well below the current OSHA standard for human exposure.

Abstract  ConocoPhillips Company is involved with an industry group that has sponsored an acute inhalation study in rats involving naphthalene. As a sponsor, ConocoPhillips has been provided with a preliminary draft of the pathology report. ConocoPhillips is submitting this draft study report in accordance with Section 8(e) of the Toxic Substances Control Act (TSCA) because it includes findings that EPA may consider reportable. Toxicological endpoints observed in this study are not new; however, the naphthalene concentrations and duration of exposure in this study may be considered a new finding. ConocoPhillips is submitting a preliminary rough draft of data on the acute effects of naphthalene vapors on nasal epithelial cells in rats. Two strains of rats, Fischer 344 (F344) and Sprague Dawley, were exposed to naphthalene vapors at the following target concentrations: 0, 0.1, 0.3, 1, 10 and 30 ppm for a single six hour period. A total of 30 animals of each sex per strain were exposed. The day following exposure, the animals were killed and nasal respiratory tissues were removed, processed with hematoxylin and eosin stains, and subsequently evaluated by light microscopy. Necrosis related to exposure to naphthalene was seen predominately in the olfactory epithelium. According to the preliminary pathology report, minimal effects were first observed in all groups exposed to a naphthalene vapor concentration of 1 ppm. Clear and strong pathological changes were observed in all groups exposed to vapor concentrations of 10 ppm and 30 ppm.

Abstract  CYP2A13, a human cytochrome P450 enzyme expressed mainly in the respiratory tract, is believed to play an important role in the initiation of smoking-induced lung cancer. CYP2A13.1 has high efficiency in the metabolic activation of a major tobacco-specific carcinogenic nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). CYP2A13*2, a variant allele, was previously found to be associated with decreased incidence of lung adenocarcinoma in smokers. The aim of the present study was to determine whether the CYP2A13.2 protein has decreased enzyme activity and/or expression levels in the lung, compared with CYP2A13.1. CYP2A13.2 has two sequence variations from CYP2A13.1: R25Q and R257C. We compared the activities of heterologously expressed CYP2A13.1 and CYP2A13.2 toward several known CYP2A13.1 substrates: NNK, N-nitrosomethylphenylamine, N,N-dimethylaniline, 2'-methoxyacetophenone, and hexamethylphosphoramide. Our results indicated that CYP2A13.2 was 20 to 40% less active than CYP2A13.1 with the substrates tested. We also determined the levels of the CYP2A13*2 mRNA, relative to the level of the CYP2A13*1 mRNA, in the lung tissue from *1/*2 heterozygotes. We found that the CYP2A13*2 allele was associated with a level of allelic expression similar to 40% lower than that of the CYP2A13*1 allele. Sequence analysis of the promoter region of the CYP2A13*2 allele identified a 26-nucleotide deletion. Functional analysis of a 2-kilobase pair CYP2A13-luciferase promoter construct indicated that the 26-nucleotide deletion causes decreases in CYP2A13 promoter activity in the A549 human lung cell line. These findings suggest that the reported association of the CYP2A13*2 allele with decreased incidences of lung adenocarcinoma in smokers can be at least partly explained by a decrease in CYP2A13 function.

Abstract  SUMMARY: Statistical inference about the parameter values of complex models, such as the ones routinely developed in systems biology, is efficiently performed through Bayesian numerical techniques. In that framework, prior information and multiple levels of uncertainty can be seamlessly integrated. GNU MCSim was precisely developed to achieve those aims, in a general non-linear differential context. Starting with version 5.3.0, GNU MCSim reads in and simulates Systems Biology Markup Language models. Markov chain Monte Carlo simulations can be used to generate samples from the joint posterior distribution of the model parameters, given a dataset and prior distributions. Hierarchical statistical models can be used. Optimal design of experiments can also be investigated. AVAILABILITY AND IMPLEMENTATION: The GNU GPL source is available at (http://savannah.gnu.org/projects/mcsim). A distribution package is at (http://www.gnu.org/software/mcsim). GNU MCSim is written in standard C and runs on any platform supporting a C compiler. Supplementary Material is available online at (http://www.gnu.org/software/mcsim).

Abstract  Human P450 2A13 is the most efficient enzyme for catalyzing the metabolism of nicotine and metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). It is conceivable that P450 2A13 also metabolizes chemicals in air pollutants because this enzyme is highly expressed in the respiratory tract. In this study, we investigated the possibility that P450 2A13 can metabolize naphthalene, styrene, and toluene, which are included in air pollutants as well as tobacco smoke, although they were known to be metabolized by P450 1A2 or 2E1. We found that P450 2A13 catalyzed 1- and 2-naphthol formations from naphthalene with higher intrinsic clearances ( kcat/ Km) (3.1- and 2.2-fold, respectively) than P450 1A2 and also more efficiently catalyzed the styrene 7,8-oxide formation from styrene and the benzylalcohol formation from toluene than P450 2E1. The overlapping substrate specificity of P450 2A13 with P450 2E1 was supported by the finding that P450 2A13 catalyzed chlorzoxazone 6-hydroxylation (8-fold higher value of kcat/ Km) and p-nitrophenol 2-hydroxylation (19-fold higher value of kcat/ Km), which are marker activities of P450 2E1. Thus, we found that P450 2A13 metabolizes diverse environmental chemicals and has overlapping substrate specificities of P450 1A2 and 2E1, suggesting that P450 2A13 plays important roles in the local metabolism of environmental chemicals in the respiratory tract related to toxicity or carcinogenicity.

Abstract  Naphthalene is metabolized by several cytochrome P-450 (CYP) monooxygenases to 1,2-epoxynaphthalene. However, the subsequent interactions of the epoxide with macromolecules in the cells, and the significance of these interactions to cellular injury, are not well characterized. Additionally, CYP1A1, which can metabolize naphthalene to 1,2-epoxynaphthalene, may be induced by a number of xenobiotics. Yet, the in situ interaction between naphthalene and CYP1A1 alone, without the influence of other xenobiotic metabolizing enzymes, has not been examined. Using a model eukaryotic expression system capable of over-expressing recombinant CYP1A1, we found that naphthalene was toxic to cells expressing CYP1A1 in a dose- (LC50: 0.3 mM) and time-dependent (LT50: 12 h) manner. Naphthalene treatment of CYP1A1-expressing cells resulted in a 47% decrease in cellular glutathione (GSH) levels. Pretreatment with ethyl ester GSH, a GSH analog, protected CYP1A1-expressing cells such that viability was 30% greater than for cells treated with naphthalene alone. Cytotoxicity was strongly correlated (r2: 0.96) with covalent binding of cellular proteins. Alkaline permethylation techniques showed that cysteinyl-SH groups of cellular proteins are a nucleophilic target of the epoxide metabolite. These results suggest that, in the absence of other pathways, naphthalene is modified by CYP1A1 to 1,2-epoxynaphthalene, which subsequently binds cellular sulfhydryl groups on proteins and GSH.

Abstract  The distribution of the various epithelial types lining the nasal cavity in normal 7 and 16 weeks old male Fischer-344 rats and male B6C3F1 mice has been mapped at the light microscopic level. Photographs of transverse sections of the nose were analysed using a Zeiss Videoplan computerized image analysis system programmed for measurement and evaluation of count, area, perimeter and length. In rats, the volumes of the nasal cavity at 7 and 16 weeks are 156 and 257 mm3 respectively; while in mice the nasal cavity volume is essentially the same (32 . 5 and 31 . 5 mm3) at the same two ages. Total surface areas of the nasal cavity in rats at 7 and 16 weeks are 799 and 1344 mm2 respectively; and in mice 278 and 289 mm2. The percentages of the nasal cavity surface lined by squamous, respiratory and olfactory epithelium are similar at both ages in both species. Applications and significance of these data are discussed.

Abstract  Summary. Hydrocarbons used as solvents in industry are thought to have effects on respiratory system. However, its effect on tracheal morphology and function is poorly investigated. Therefore the present study attempted to investigate the rat tracheal structure following different types and concentrations of hydrocarbon exposure. To do this, 65 Swiss albino rats were divided into 6 groups. While control group animals were undergone no treatment, 5 experimental group animals received different types of hydrocarbons saturated in air, such as 1,2-dibromoethane, 1,1,1-trichloroethylene, naphthalene, carbontetrachloride and carbonsulphide at 1, 3 and 6 hour intervals in isolated chambers. Control group consisted of 5 rats whereas the experimental groups contained 60 rats (12 for each group). Tracheal tissue samples were collected from the control and experimental group animals, and were processed for light microscopy. Tracheal morphology underwent distinct alterations after 1,3, and 6 hours of hydrocarbon exposure. Common tracheal features for all experimental groups were a thinner epithelial layer along with occasional exfoliation, hyparemic and dilated vasculature with intraluminal haemorage, and inflammatory cell infiltration into the underlying connective tissue. Tracheal glands taking place in the lamina propria seemed to be increased following several hydrocarbon exposure. In conclusion, it may he postulated that the hydrocarbons used in the present study cause irreversible tracheal alterations. Therefore one must take extreme caution when these toxic compounds are used.

Abstract  Zusammenfassung Bei zwei Frühgeborenen und einem Neugeborenen wurden akute hämolytische Innenkörperanämien beobachtet, die durch Inhalation eines naphthalinhaltigen Sekretolytikums (Vaporin®) hervorgerufen wurden. Bei einem der Frühgeborenen waren wegen einer aus anderen Gründen vorausgegangenen Austauschtransfusion praktisch nur Erwachsenen-Erythrozyten im Kreislauf vorhanden; auch diese reagierten bemerkenswerterweise mit Innenkörperbildung. Summary Severe acute haemolytic anaemia, with Heinz-inclusion bodies, occurred in two premature and one full-term newborn infants after the inhalation of naphthalene vapours contained in “Vaporin”®, an anti-cough vaporizer previously recommended for use especially in infants and young children. One of the premature infants, having had an exchange transfusion, had practically only adult R.B.C. But these, too, reacted surprisingly by forming inclusion bodies. Resumen Anemia hemolítica aguda por inhalación de naftalina en dos prematuros y un recién nacido En dos prematuros y un recién nacido se observaron anemias hemolíticas por cuerpos de Heinz, que fueron provocadas por inhalación de un secretolítico que contenía naftalina (Vaporin®). En uno de los prematuros existían en la circulación prácticamente sólo eritrocitos de adultos por causa de una transfusión de intercambio precedente por otros motivos; es digno de anotar, que también éstos reaccionaron con la formación de cuerpos de Heinz.

Abstract  This report, entitled, A Review of the Reference Dose and Reference Concentration Processes, summarizes the review and deliberations of the Risk Assessment Forum's RfD/RfC Technical Panel and its recommendations for improvements in the process of deriving reference values, including setting less than lifetime as well as chronic reference values. It discusses revisions to the overall framework for the derivation of reference values that broaden and expand the information considered in setting reference values. The document is a review, not guidance, and it evaluates the state-of-the-art for hazard characterization with a focus on protection of potentially sensitive subpopulations. The report makes a number of recommendations that should be considered in the implementation of changes in the current process and/or development of needed guidance. The Technical Panel views the RfD/RfC process as one that should be continually evolving as new information becomes available and as new scientific and risk assessment approaches are developed. This does not mean that current RfDs or RfCs are invalid, but these new scientific issues should be included in the process of re-evaluating current reference values. As a follow-up to the recommendation for deriving less-than-lifetime reference values, the report includes a review of current testing guideline protocols to determine what data are collected that could be used in setting these reference values. The Technical Panel has provided specific recommendations for deriving reference values and the development of guidance in some cases and more general conclusions and recommendations in others. Case studies are included to illustrate the recommendations of the Technical Panel.

Abstract  This table only includes occupational exposure limits (OELs) for substances listed in the OSHA Z-1 Table. OELs for hundreds of additional substances have been adopted by Cal/OSHA, NIOSH, and ACGIH. These organizations periodically make revisions to their OELs and so they should be consulted directly for their most current values and substances, as well as special notations such as for skin absorption. The TLVs® and BEIs® are copyrighted by ACGIH® and are not publicly available. However, they can be purchased in their entirety on the ACGIH® website. Permission must be requested from ACGIH® to reproduce the TLVs® and BEIs®.