Science / Medicine : Tie Between Chemicals and Disease May Be Near

Times Staff Writer

One of the banes of environmental medicine is the inability of science to establish a precise link between a hazardous chemical and human disease. But that may soon change, according to a team of researchers led by a UC Berkeley professor of industrial hygiene.

In a recently published report, Stephen M. Rappaport and his collaborators say they have come up with an experimental way to trace human genetic mutations in white blood cells back to a single chemical.

The ability to do such "fingerprinting" is the first time that scientists have been able to identify the precise chemical interaction between DNA molecules in human blood and a hazardous material.

If refined, the technique, which was performed on the blood samples of 50 workers at a West Coast plastics factory, could lead to more definitive ways to sort out often-baffling human health claims as a result of exposure to suspected carcinogens and other toxic chemicals.

Until now, it has been nearly impossible to irrefutably link human health problems with specific chemicals either in the workplace or in the general environment. The case against asbestos, for instance, was established only after decades of following the health of tens of thousands of shipyard workers. As they inexorably succumbed to unusual cancers and respiratory diseases, it became painfully clear that asbestos is a deadly environmental hazard.

Thus, a technique that can fingerprint a specific chemical that causes genetic mutations would go a long way in expeditiously settling such scientific uncertainties.

This ability to link a single chemical with a specific DNA mutation had not been demonstrated in humans until now, Rappaport said in a recent interview. "We're at the cutting edge of this whole question of environmental cancers."

"We're looking at an important event--the interaction between genetic material and a potentially cancerous substance," said the associate professor of industrial hygiene at the School of Public Health. "In fact, we may be viewing the chemical reaction that initiates cancer."

The prevailing theory on environmentally induced cancers holds that it is reactions in the genetic code, such as seen by Rappaport's technique, that may supply the impetus for abnormal growths.

A full report on the work was published in the August issue of the journal Carcinogenesis. Rappaport and his collaborators discussed their work last year in Helsinki, Finland, at an international symposium on cancer epidemiology sponsored by the World Health Organization.

The original technique, called the "32P-post labeling," was developed by Baylor University chemist Kurt Randerath in 1981.

As adapted by Rappaport and his collaborators, the analytic process, while quite cumbersome and time-consuming, represents a significant improvement over the original process.

The technique begins with the extraction of a blood sample and then the isolation of the white blood cells in each sample. Next, various enzymes are added to separate the four bases of the DNA.

Using radioactive phosphate, a sophisticated analytical machine called a thin-layer chromatograph and old-fashioned photography, researchers can then document even extremely small molecular reactions in the genetic code.

If a chemical has altered the DNA, it will produce a reaction called an "adduct," which is a specific product of DNA and the chemical in question--the so-called fingerprint.

"Measuring the DNA damage brings us 100 steps closer to putting cancer and the environment together," Rappaport said.

But one shortcoming of the technique is that it works only when scientists know what specific chemical to look for. And that is one reason why previous attempts to use the technique in humans have led to unclear results.

Randerath, for instance, has used it to look for genetic damage caused by cigarette smoke, but the many toxic substances in tobacco made it impossible to link a specific chemical to a particular adducts, according to Rappaport. All that showed up was the presence of overlapping classes of chemicals, but not a single, specific agent--thus yielding a less-than-precise reading.

The same problem has plagued other researchers who have sought to make the link between DNA damage and exhausts from industrial foundries.

Until now, environmental physicians typically confront a group of sick people without knowing for sure what caused the diseases and illnesses. "What we didn't know is what happened in those people's lives that contributed to that disease. What's been unclear is the exposure," Rappaport said.

But by providing the fingerprint of a specific, suspected chemical, the technique could become an invaluable tool in solving environmental pollution cases.

"It's kind of like putting a puzzle together," Rappaport explained.

His on-going research involves 50 workers at an unnamed West Coast fiberglass factory where the ambient air measures high in styrene, a common synthetic chemical used in the manufacture of reinforced plastics such as cups, bathtubs, boats, computer consoles and cars.

Because of privacy considerations, Rappaport said he cannot disclose the name of the factory or the names of the workers who volunteered for the study.

He did note that the presence of adducts in some of the 50 workers is "worrisome." But he quickly added that if any clinical significance of that finding exists, it is "10 or 20 years down the road."

As a pure research project, Rappaport emphasized, his study is not intended to yield medical conclusions.

He said the participants will be notified, perhaps by the end of November, of their levels of adducts, if any. The information will also be accompanied by an explanation that medical science at this point is unclear as to what the adducts mean, if anything.

For now, Rappaport said, all that is proved by the presence of adducts is that the individual workers have been exposed to styrene--not a surprising finding in and of itself.

Curiously, not all the workers had styrene oxide adducts in their blood--even though many of them probably have been exposed to roughly the same amount of styrene. One explanation for this phenomenon might be individual susceptibility; another could be shortcomings in the post-labeling technique, Rappaport said. The researchers are also trying to refine the method, he said.

And before the technique can become a clinical diagnostic tool, Rappaport noted, it must be tested in studies involving larger numbers of people than the 50 in the current study.

But if such a technique can be perfected, it could become an handy tool with which to monitor exposure to hazardous chemicals in the workplace, according to Rappaport.

There has been much debate in recent years over whether styrene is a cancer-causing substance. Results of animal experiments have been equivocal. Several large human epidemiological studies--in England and the United States--have not found a link.

Still, styrene is under suspicion. Just last year, the World Health Organization upgraded the chemical from a "not classifiable" status to a "possible" carcinogen. One reason for this is that laboratory experiments have shown that styrene oxide--the metabolite of styrene--is carcinogenic among rodents.

CHEMICAL FINGERPRINTS

Through a technique called '32P-post labeling,' researchers at UC-Berkeley were able to detect that the hazardous chemical styrene had altered the DNA of some factory workers.

The technique begins with the extraction of a blood sample and the isolation of white blood cells. Next, various enzymes are added to separate the four bases of the DNA.

Using radioactive phosphate, a sophisticated analytical machine called a thin-layer chromatograph and old-fashioned photography, researchers were then able to notice small molecular reactions in the genetic code.

Chemical alteration of DNA produces reactions called adducts--labelled here 1 through 5. The presence of the adducts is the 'fingerprint' that proves the worker was exposed to styrene.

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