http://news.bmn.com/news/story?day=020502&story=1

30 April 2002 22:00 EST

by Apoorva Mandavilli, BioMedNet News

Too many toxicologists rely on a stale paradigm to evaluate carcinogens, today complained one of the foremost environmental toxicologists in the US. Modern "biologically-based" concepts are not only more accurate, they also offer faster and less expensive screening, says Christopher Portier, director of the Environmental Toxicology Program at the US National Institute of Environmental Health Sciences in North Carolina.

"If we're honest with ourselves as scientists, we're looking at more complicated data structures than we've ever looked at before," noted Portier. "Toxicology has changed [and] we have to do a better job."

For decades, toxicologists have simply collected data by examining tumors, or tumor-related deaths, in animal models, he says. Speaking this afternoon towards the end of a two-day symposium on carcinogenesis bioassays at the New York Academy of Sciences, Portier bemoaned this form of linear analysis with one endpoint.

Instead, toxicologists must take into account precursor lesions, dietary and weight changes, tumor location, biological structures and various biochemical changes, Portier urged.

Complex analysis, "where there is no single endpoint," uses more of such data and allows testing across sex, species and genetic subtypes, Portier told BioMedNet News. "The idea is to simply expand the paradigm."

The existing paradigm is based on "concepts that are 50-plus years old," noted J. Carl Barrett, director of NIH's Center for Cancer Research. In that oversimplified model of cancer, he said, there are two main steps: the initiating event, and the subsequent environmental promotion of cancer.

But the environment "can work in very dramatic and very subtle ways," Barrett noted. The focus has thus far been on the more dramatic effects but "we could be missing subtle effects by taking a simple approach."

For example, a small change in the level of an enzyme could translate into a 10-fold difference in cancer risk, Barrett said. "It's time to revise what we use in toxicology and ask if we can do it better," he noted. "I certainly hope this is the approach of the future."

Some of the tools needed for complex analysis are already in place. Researchers now use microarrays to determine a tumor's subtype, and proteomics to understand its microenvironment.

The National Toxicology Program is also developing basic physiological constants for animal models, including data on cardiac output, weight by age and tissue size.

But switching to the new system will still be a formidable challenge, Portier admitted. The analyses are much more difficult computationally and mathematically.

Biologists will need to work closely with statisticians and make a commitment to approaching data in a nontraditional way, he added.

"If I had to say where this was going," Portier said, "I'd say we need a database-based analysis rather than a dataset-based analysis."

One such public database, now in its conceptual stages at the NIH's Center for Toxicogenomics, will include raw toxicological, biological, gene and protein expression data relevant to environmental toxicology.

Once all the tools are in place, Portier said, researchers may have to tailor existing study designs to fit the new format. They will also have to convince regulatory agencies, like the US Food and Drug Administration (FDA), to accept the analyses in lieu of animal data.

The FDA has at least one reason to favor the scheme, Portier says. While animal-based bioassays take a minimum of five years and several million dollars, databases promise a quick, inexpensive way to screen carcinogens.

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