At a small lab in a nondescript building outside UC Davis, research assistants stuff cigarettes into a chambered wheel that emits puffs as it turns. With one crank of the wheel, 10 little puffs of smoke escape. It's odd to catch a whiff of burning tobacco in this institutional setting where all smoking is banned, but certainly no odder than watching a machine smoke the equivalent of two cartons of cigarettes a day.

The smoke-filled air is headed -- in concentrations that would be familiar to airline stewardesses and bartenders of yore -- into the rooms of a breed of mice known for their special ability to develop lung tumors. The experiment is designed to simulate the effects of smoking on mice, "which mice are too smart to do," says Hanspeter Witschi, associate director of the Institute for Toxicology and Environmental Health. "In early experiments scientists blew smoke into their cages, but the animals would hold their breath."

This machine -- and the research it's used for -- helps Witschi observe the effects of secondhand smoke in laboratory animals and, by association, in people. It's an area of study that has piqued the attention of public health officials, occupational health and safety agencies and legislators for more than three decades. In 1992 the federal Environmental Protection Agency, using epidemiological studies, declared secondhand smoke to be a human carcinogen. Nevertheless, questions remain: At what concentrations does secondhand smoke cause cancer? Over what period of time? And more importantly, can drugs or diet make a difference in preventing cancer?

In research published in the May issue of the journal Carcinogenesis, Witschi answers this latter question in the affirmative. His lab found a diet of dexamethasone, a corticosteroid used to treat asthma, and myoinositol, a substance found in cereal bran, to be effective in preventing lung cancer in male mice exposed to heavy tobacco smoke. It is, Witschi believes, the first animal model study to test substances that might prevent smoking-induced lung cancer.

"We tested several compounds that had previously been shown to prevent cancer, but these studies were done on mice injected with tobacco carcinogens," says Witschi. "These agents didn't work in mice who had inhaled smoke, a model that has much more in common with how humans develop lung cancer."

Witschi, himself a reformed smoker, has spent 20 years tracking acute pulmonary disease. A medical doctor and professor of toxicology, he studies adenocarcinoma of the lung, the most common tumor found in smokers.

Research Cigarettes. Photo courtesy of Synthesis Magazine.

This was not always the case; before the advent of filtered nicotine sticks, squamous cell carcinoma was the most common lung cancer. Then in the 1970s, the National Cancer Institute funded a number of studies aimed at developing safer cigarettes. Eventually, scientists recommended filtered cigarettes as a way of lessening the risk of cancer by reducing intake of tar.

It did nothing to make lung cancer rates decline, says Witschi. Instead, smokers developed a different but equally dangerous form of lung cancer.

Why? "Cigarette smoking is an expression of nicotine addiction, and while filters take out most of the tar, they also take out much of the nicotine," he says. "So smokers had to inhale more deeply and smoke more cigarettes to get their nicotine fix. In the process they got more volatile carcinogens and nitrosamines into their lungs."

Not that it makes much difference to the smokers who develop lung cancer. Regardless of what tissue it originates in, lung cancer is tough to treat, partly because it's often diagnosed late and partly because it's an aggressive disease. About 150,000 Americans a year die of lung cancer, 90 percent of them current or former smokers. Average survival time after diagnosis is less than a year.

Witschi's work began as a study of how secondhand smoke (which researchers prefer to call environmental tobacco smoke) affects lung development. He started out by trying to produce lung cancer in mice in a laboratory setting by exposing them to a mixture of mainstream smoke -- smoke exhaled by the smoker -- and sidestream smoke that drifts off the end of a cigarette.

"Trying to pinpoint which of the 4,000 compounds in cigarettes cause cancer is, to me, hopeless," says Witschi. "Humans don't consume those compounds separately. They consume them in cigarette smoke."

In his Toxic Pollutants Health Research lab, mice were exposed to secondhand smoke six hours a day, five days a week for five months -- "roughly the way workers in industry would encounter secondhand smoke," says Witschi.

Researchers used unlabeled research cigarettes from the Tobacco Research Institute in Lexington, Kentucky.

"They contain no additives," says Witschi. "A friend who tried one said they had no flavor. So the cigarettes are not pleasant for smokers but give us the unflavored smoke we need."

The experimental mice were kept in a smoking environment for five months, then placed in clean air for four more months. The clean air interval was designed to mimic what happens to people who smoke but then quit. As expected, the mice developed multiple lung tumors. Voila! The cause-and-effect link between secondhand smoke and lung cancer was established.

Next, with a grant from the National Institute of Environmental Health Sciences, Witschi fed the mice substances that other researchers thought prevented cancer. These included a phytonutrient found in citrus peels, a selenium compound, aspirin, green tea and two kinds of isothiocynates (an antioxidant nutrient) found in cabbage and watercress.

Once fortified, the mice were then exposed to heavy tobacco smoke and then clean air. Researchers would expect 89 percent of the mice to develop lung cancer, with an average of 2.4 tumors per animal. None of the other compounds made a dent in this statistic. But one regimen, a combination of dexamethasone and myoinositol, caused tumor incidence to drop to 62 percent and to one tumor per animal.

Dexamethasone and myoinositol were also effective in reducing tumors in mice who were fed the substances after they had been exposed to smoke for several months and then exposed to clean air -- a model for people who quit smoking.

What this holds for the future is anyone's guess. Besides cereal, myoinositol is found in beans and rice. Dexamethasone is currently prescribed for people with asthma and rheumatoid arthritis. Theoretically, someone could get these substances from their diet and a quick trip to the doctor's office. But the dosages and duration of the regimen are questions that still need to be answered in studies that involve humans. Witschi is working with a researcher at the University of Minnesota to make that happen.

Research assistant Kristy Cheng prepares special research cigarettes for use. Photo courtesy of Synthesis Magazine

"We've had a lot of disappointments in the field of chemoprevention for lung cancer," Witschi notes. "In the late 1970s they initially thought beta carotene reduced the risk of lung cancer in smokers. But when they tested it further, they found it actually increased the risk of lung cancer."

Finding an effective anti-cancer regimen would be especially useful for people who are at high risk of developing cancer. "Even the heaviest smokers don't all get lung cancer. A smaller number, perhaps 20 percent of smokers, are genetically inclined to get the disease," Witschi adds.

The newly smoke-free would also benefit. Statistically, the risk of lung cancer increases in smokers the first three years after quitting, after which it levels out, eventually becoming the same as if the person had never smoked. Most researchers explain this blip by pointing out that many smokers quit once they have developed chronic fatigue and a nagging cough -- signs they've already got the disease. No treatment exists to reduce the risk of lung cancer in smokers most vulnerable to it.

"Our observation that myoinositol and dexamethasone were highly effective in mice who had 'quit' smoking may be of practical significance," Witschi says. "Chemoprevention administered at this moment might reduce this temporary increase in risk."

Nothing, of course, compares to the premier chemoprevention strategy of not smoking in the first place, but for the estimated 40 million Americans who have quit smoking, Witschi's research is good news, indeed.

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