Heavy exposure to solvent linked to cancer.

The chemical solvent trichloroethylene has a bad reputation these days. The popular nonfiction book A Civil Action (1995, Jonathan Harr, Random House) and its movie version relate how residents of a Massachusetts town came to blame a set of leukemia cases on trichloroethylene and other chemicals in the town's water supply.

In Europe, scientists know trichloroethylene well. During studies of various cancers, they have analyzed patients' exposure to the solvent. While the work hasn't yet produced hard proof that the chemical causes malignancies, German researchers now report strong evidence linking excessive trichloroethylene exposure to cancer via a specific gene mutation.

For decades, metal-processing workers in Germany used trichloroethylene as a degreaser--breathing its fumes in poorly ventilated rooms, washing floors with it, even scrubbing their hands and arms with the chemical. To gauge the cancer risk these practices imparted, scientists scrutinized a gene called yon Hippel-Lindau (VHL), which normally suppresses the disease.

Mutations in this gene cropped up in 33 of 44 kidney cancer patients who had been exposed to trichloroethylene in the workplace, researchers report in the May 19 JOURNAL OF THE NATIONAL CANCER INSTITUTE. In general, about half of kidney cancer patients have a mutated VHL, says coauthor Hiltrud Brauch of the Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart.

The intensity of exposure to trichloroethylene varied among the former factory workers, and those getting heavier doses of the solvent over many years were more likely to have multiple VHL mutations. Of the 17 cancer patients with the greatest solvent exposures, 11 had two or more mutations in VHL.

The VHL gene is a string of hundreds of nucleotides, the components of DNA. At nucleotide 454, the scientists identified a potential weak link in the molecular chain. In 13 of the trichloroethylene-exposed cancer patients, a defect showed up at this precise location. In contrast, none of 107 people with kidney cancer who had not been exposed to trichloroethylene and none of 97 healthy volunteers had a mutation at nucleotide 454. Of 14 patients with multiple VHL mutations, 9 had a defect at the 454 spot.

"I think this is a very important, exciting study," says W. Marston Linehan, a urologist at the National Cancer Institute in Bethesda, Md. While researchers suspected a link between trichloroethylene and kidney cancer, "there was no molecular basis for it until this study," he says.

However, the study data don't establish whether such a mutation is merely a marker of trichloroethylene overexposure or instead a risk factor for kidney cancer, says toxicologist Laura C. Green of Cambridge Environmental, a consulting firm in Massachusetts. Further tests on animals may clarify this point, she says.

Also, the study concentrates on gross overexposure to the chemical and so contributes little to the debate behind A Civil Action. The German workers encountered trichloroethylene doses that "are thousands of times greater" than the amounts people typically come across in contaminated air or drinking water, Green says.

The researchers have produced "a good paper," says toxicologist Steven R. Tannenbaum of the Massachusetts Institute of Technology. However, he cautions that the work on VHL mutations, and particularly the 454 nucleotide site, is far from conclusive. He notes that the majority of the heavily exposed workers with kidney cancer had an intact 454 site.

The cancer tracked in this study, clear-cell renal carcinoma, accounts for roughly 85 percent of kidney cancer cases, Linehan says. Kidney cancer itself ranks 13th in frequency among malignancies in the United States. It is diagnosed in roughly 27,000 people annually and accounts for about 12,000 deaths every year.