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Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways. Because asthma may represent manifestations of chronic inflammation of the airways, the levels of histamine and six prostanoid mediators were measured in airway fluids obtained by bronchoalveolar lavage (BAL) of 12 normal, 11 allergic rhinitic, and 15 asymptomatic, allergic asthmatic subjects. Simultaneous profiling of prostanoid mediators in individual samples was performed using gas chromatography-mass spectrometry. Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects (p less than 0.01), with concentrations in airway fluids of asthmatic subjects after correction for dilution of 3.8, 0.5, and 1.4 nanomolar, respectively. Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects (p less than 0.01), distinguishing the subjects with lower airway disease from those with another atopic condition. Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects. We conclude that elevated levels of multiple mediators with potent bronchoconstricting activity are present in the airways of subjects with mild asthma, indicating that even mild disease is associated with evidence of airway inflammation. The interactions of bronchoconstricting mediators and airway inflammation may play important roles in the pathogenesis of asthma.

Aryl hydrocarbon hydroxylase was measured in cultured human lymphocytes induced with benzathracene and in pulmonary alveolar macrophages induced in situ in cigarette smokers. Considered separately, neither lymphocyte AHH nor macrophage AHH levels were distinctly different in either noncancer or lung cancer patients. Considered simultaneously, lymphocyte and macrophage AHH levels are quite different in noncancer and lung cancer patients. The lung cancer patient group was seen to contain a significantly higher percentage of persons with high levels of AHH than did an age-matched group of noncancer patients, (P less than 0.001), when more than one tissue was assayed to determine the individual's enzyme levels.

A component capable of binding benzo(a)pyrene was measured in plasma from cigarette smokers and nonsmokers. This plasma fraction was found to have a high specificity of binding to benzo(a)pyrene, bound benzanthracene competitively with benzo(a)pyrene, and was positively correlated (r = 0.861, p less than 0.001) with the capacity of the individual subject's lymphocytes to be induced for AHH activity in culture. An inverse correlation (r = -0.957, p less than 0.001) between the presence of the plasma component in lung cancer patients and the capacity of lung cancer patients' lymphocytes to be induced in culture is unexplained at this time. A benzo(a)pyrene-binding fraction was not found in induced or uninduced cultured lymphocytes from smokers or nonsmokers, or in homogenates of lung excisional tissue from smokers with or without primary lung cancer.

In this paper we will attempt to provide some explanations for the organ selectivity of four different pneumotoxicants (monocrotaline, naphtalene, 3-methylindole, and 4-ipomeanol)

Severe acidosis associated with acetazolamide therapy is rare. We report the first case in which plasma and whole blood acetazolamide concentrations were measured. A 61 year-old patient receiving oral acetazolamide for treatment of glaucoma presented with a 7 day history of declining mental status. The patient was lethargic and oriented only to name. The respiratory rate was 36 per minute in a Kussmaul pattern with arterial blood gases revealing a pH of 7.23, pO2 68 mmHg, paCO2 14 mmHg and bicarbonate 6 mEq/L. Serum creatinine was 3.1 mg%, Cl 126 mEq/L, and anion gap 15. Urine pH was 6.0. Infection and other causes of acidosis and bicarbonate loss were excluded, and he was discharged with normal mental status and improving acid-base balance 18 days after admission. Acetazolamide concentrations four days after the last dose were 26.38 mcg/ml and 38.84 mcg/ml in serum and whole blood, respectively. The serum half-life was 34 hours, compared to a range of 1.5 to 6 hours in subjects with normal renal function. Monitoring acetazolamide concentrations may be useful in adjusting dosage and preventing toxicity in patients with decreased renal function.

5S ond study consisted of 70 golden syrian hamsters: 54 experimental and 16 control animals. The implantation of the thread in the trachea induced a regenerative basal cell hyperplasia of the epithelium. We Ibund squamous metaplasia and progressive intraepithelial neoplasia (lEN) prior to the development of squamous cell carcinoma (CA). In the experimental guinea pigs, only one invasive CA was found at 265 days postoperation. In the experimental hamsters, the first CA was seen at 55 days postoperation, and 65% of the animals sacrificed between 120 and 250 days developed CA. Most of the hamsters with CA also developed spindle cell tumors in the tracheal stroma. The control hamsters and guinea pigs did not develop lEN, and the mature respiratory epithelium was reconstituted. We conclude that this method reliably produces localized, readily accessible preneoplastic and neoplastic lesions in the trachea of hamsters and, to a lesser extent, in that of guinea pigs. This model of squamous cell bronchogenic carcinoma should prove useful in the study of tumor ultrastructure, the immunologic response to cancer, and the relationship of diet to cancer.

Especially during the past two decades, there has been a growing awareness that exposure of individuals to exogenous environmental agents is responsible for various kinds of cancer. Chemical carcinogenesis in man was first documented in 1775 by the British physician Percival Pott, who attributed the high incidence of scrotal cancer in London chimney sweeps to their chronic exposure to soot and coal tars[l]. In the two hundred years following that initial observation, at least 1000 chemicals have been shown to induce cancer in a wide variety of tissues [2]. As our civilization has become industralized, our food, air, and water have undergone increased contamination with a number of cancer producing chemicals. It is currently estimated that approximately 75 to 85 percent of human cancer may be directly associated with exposure to these environmental carcinogens [3].

4-Ipomeanol (IPO) is the first agent to undergo preclinical development at the National Cancer Institute (NCI) based principally on a specific biochemical-biological rationale for clinical investigation as an antineoplastic agent targeted against lung cancer. This disease-specific development of IPO was initially stimulated by observations that the compound was activated by metabolism, preferentially within the mammalian lung, specifically within bronchiolar Clara cells, and that its predominant toxicity was to the lung in most species. IPO is inactive or only minimally active against most conventional antitumor test systems. However, some human lung cancer cell lines, as well as a variety of fresh human lung tumor biopsy specimens, have been shown to be capable of mediating the in situ biotransformation of IPO to a potentially cytotoxic intermediate. In this report, the biochemistry, metabolism, preclinical pharmacology, and toxicology of IPO are reviewed and the clinical development plans for this unique and challenging new agent are presented.

THE ENVIRONMENT AND THE LUNG 39$ achieved by prior culture for five days in DMEM + 0.5% FCS) and fibroblast cell counts determined after one, two, and four days. DMEM + 0.5% FCS ± asbestos incubated for four hours as controls. Supernatants from unexposed PAM had no influence on fibroblast replication rate. In contrast, supernatants from PAM exposed to asbestos significantly increased the rate of fibroblasts doubling; the doubling time decreasing five-fold from a control of 310±21 hours to 54±4 hours, P

Both short-term and long-term xenograft models may be useful in conjunction with an in vitro based disease-oriented drug screening program. Shortterm models may be most valuable in making initial assessments of the potential in vitro drug screening leads for in vivo use. We have previously shown that a substantial number of such leads may be subject to metabolic inactivation (1) and that this may be associated with a lack of therapeutic activity and a relative lack of toxicity in vivo. Certainly, rapid excretion or other pharmacologic factors may also render compounds inactive in vivo. Short-term as says may be very useful for identifying such compounds and thus setting priorities for further testing of in vitro drug leads in more rigorous longer-term models. Rational application of these longer-term models with particular attention to modeling of in situ vascular barriers, tumor microenvironment, and the natural history of the target diseases may facilitate identification and development of new drugs with significant clinical activity against the common adult solid tumors.