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.

No abstract

The involvement of reactive metabolites in cancer and cellular necrosis has been well established. The nucleophile, glutathione, provides a major mechanism of intracellular protection from electrophilic metabolites. Conjugation with glutathione to generate stable, water-soluble metabolites has been utilized to determine the nature and rates of formation of precursor reactive metabolites. In addition, because activities of the glutathione transferases may play a key role in tissue/cellular susceptibilities to electrophilic compounds, measurement of catalytic activities of these proteins can play an important role in discerning the underlying mechanisms of cell-selective toxicities. This unit outlines HPLC methods found to provide good separation of glutathione conjugates and includes two additional procedures that can be utilized in experiments where high throughput assays are needed for measuring transferase activities.

Nitrate is a significant contaminant in Polar snow. Its photolysis in environmental sunlight generates reactive nitrogen, which impacts the oxidative capacity of the atmosphere, influencing the fate and lifetimes of pollutants. The photolysis of nitrate can produce either $\mathrm{NO_2}$ or $\mathrm{NO_2^-}$, with recent experiments suggesting that the process is accelerated at the air-ice interface compared to the bulk solution. In this study, we employed multiscale modeling approaches to investigate the enhanced photoreactivity of nitrate at the ice surface in the presence of two different cations. We characterized the solvation shell of $\mathrm{NO_3^-}$ and explored its pairing with cations in water and ice using {\sl ab initio} molecular dynamics and enhanced sampling. Molecular trajectories were used to calculate light absorption spectra at different solvation conditions and finite temperature. Our analysis revealed that the pairing of nitrate with cations may alter the molar absorption coefficient of nitrate at the air-ice interface affecting the rate of photolysis observed in experiments of ammonium nitrate deposited on snow.