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Keystone lecture explores the challenges of mixtures research

By Melissa Kerr
September 2010

Biochemist Andreas Kortenkamp, Ph.D., spoke as a part of the Keystone Science Lecture Seminar Series during his visit to NIEHS June 23. Kortenkamp's presentation, titled "Mixtures: The Future of Toxicology Research, Testing and Risk Assessment," explored the different approaches and many challenges involved in mixtures research. The presentation was hosted by NIEHS Health Scientist Administrator Jerry Heindel, Ph.D.

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Looking to future directions in extramural program research

Biochemist Andreas Kortenkamp, Ph.D.
Kortenkamp is well known for his seminal paper in the mixtures field, "Something from 'nothing'"( - which demonstrated the significant mixture effects of eight weak estrogenic chemicals combined at concentrations below the level of no observed effect concentrations. (Photo courtesy of Steve McCaw)

Arun Pandiri, Ph.D.
Kortenkamp's talk attracted scientists from throughout NIEHS, such as Intramural Research Training Award (IRTA) Fellow Arun Pandiri, Ph.D., who works in the Investigative Pathology Group. (Photo courtesy of Steve McCaw)

Left to right, Erik Tokar, Ph.D., Todd Jusko, Ph.D., intern Arielle Sloan, and Staff Scientist Retha Newbold
Also intrigued by the talk were, left to right, NTP IRTA Fellow Erik Tokar, Ph.D., Epidemiology Branch IRTA Fellow Todd Jusko, Ph.D., Summers of Discovery intern Arielle Sloan, and NTP Staff Scientist Retha Newbold. (Photo courtesy of Steve McCaw)

Jerry Heindel, Ph.D., and Andreas Kortenkamp, Ph.D.
As Heindel, left, demonstrated, one purpose of the Keystone Lecture Series is to offer administrators insight into future directions for the extramural grants portfolio by hosting guest speakers who are experts in fields of interest. (Photo courtesy of Steve McCaw)

Kortenkamp ( Exit NIEHS has a worldwide reputation as an expert and pioneer within the field of chemical mixture research. His recent research follows endocrine disrupting compounds in the environment and the possibility that these chemicals contribute to the rising incidence of breast and testicular cancer. Kortenkamp is a professor and the head of the Centre of Toxicology in the School of Pharmacy at the University of London. He is also head of the mixtures consortium at the European Union.

As Heindel explained in his introduction, NIEHS scientists recently gathered to discuss future directions for NIEHS-supported research in chemical mixtures and to "figure out what we [at NIEHS] can really do to move forward in this field and have a big impact." In the at-capacity audience were scientists from throughout the Institute with interests in mixtures research, including several members of intramural and extramural programs, as well as the National Toxicology Program, including Chief of the NTP Biomolecular Screening Branch, Ray Tice, Ph.D., and NTP Associate Director John Bucher, Ph.D.

Defining "mixtures" and designing studies of their effects

Kortenkamp began his lecture by specifying his definition of mixtures in relation to the thousands of chemicals in the environment that may end up in human tissue. "How can we deal with co-exposure to a large number of chemicals and how can we assess their effects?" he asked. As he described the ways a scientist could assess a particular mixture, Kortenkamp said he prefers a component-based analysis. A central concern in current mixture research is assessing whether a group of chemicals act in an additive fashion or antagonistically.

Delving into the history of multiple-chemical studies, Kortenkamp identified inconsistencies in past investigations. In general, he explained, human toxicology studies were inadequately designed and the combination effects indeterminate, whereas ecotoxicology studies were more adequately designed and the combination effects were evident. A large part of the problem, he said, was a tendency to not use a hypothesis.

The critical need for prioritizing and grouping chemicals

The current problem lies, according to Kortenkamp, in prioritizing and grouping chemicals. As yet, guidelines for grouping criteria are unclear. The U.S. Environmental Protection Agency groups chemicals according to similarity of mechanisms, while Kortenkamp argues that chemicals should be grouped by common adverse outcomes. Referring to endocrine disruption as an example, he said, "It doesn't matter very much by which detailed molecular mechanism androgen action in fetal life was disturbed, because the outcome will be similar."

According to Kortenkamp, there is an unfortunate trend among scientists to stick with one major chemical component despite the thousands of other possibilities in the environment. For example, many toxicologists have considered that pp'DDE, the main metabolite of the parent compound pp'DDT, is linked to breast cancer. However, Kortenkamp said his research indicates that it contributes very little. He said that seven chemicals explained more than 90 percent of expected combination effects in his experiments, and pp'DDE was very far down the list, compared to several others that have not been as well researched.

As he looked to the future of chemical mixtures research, Kortenkamp said he hopes to see a decline in the trend of researching "your favorite chemical." He would like to see the development of a more useful way for defining a mixture of concern. He also said that exploring what he calls the dirty dozen chemicals should be a high priority, as should investigating fractionations of compounds and focusing on additional endpoints.

(Melissa Kerr studies chemistry at North Carolina Central University. She is currently an intern in the NIEHS Office of Communications and Public Liaison.)

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