By Thaddeus Schug
April 2011
NIEHS/NTP scientists joined forces with leaders in the field of green chemistry in what may turn out to be a groundbreaking meeting, “Green Chemistry and Environmental Health Sciences — Designing Endocrine Disruption Out of the Next Generation of Materials,” held March 21-23 in Sausalito, Calif.
The challenges facing scientists trying to design such new materials are daunting. Say a chemist has developed a compound that he or she believes could be a replacement for bisphenol A (BPA). How will the scientist determine if the molecule is safer to human health and the environment? What testing will need to be done and what will guide scientists through this process?
The goals of the meeting in Sausalito were ambitious — to develop a consensus statement on the principles that guide the science needed to assess risks of potential endocrine disruptors, and to develop a reliable and rational testing protocol to aid chemists as they develop and bring the next generation of chemicals into the marketplace.
The intersection of green chemistry and environmental health science
Karen O’Brien, Ph.D., from Advancing Green Chemistry (AGC) and Pete Myers, Ph.D., of Environmental Health Sciences (EHS), welcomed participants to the event, which brought together an equal mix of biologists and chemists. Representatives from NIEHS and NTP included Division of Extramural Research and Training (DERT) program administrator Jerry Heindel, Ph.D., and Kristina Thayer, Ph.D., director of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR).
Following a social ice-breaking exercise on the evening of March 21, the first full day of the meeting opened with presentations from Terry Collins, Ph.D., the Teresa Heinz Professor of Green Chemistry at Carnegie Mellon University, and John Warner, Ph.D., president and founder of the Warner Babcock Institute for Green Chemistry.
Both Collins and Warner stressed the need for fundamental changes in the way that scientists design new chemicals and the process of bringing them into the marketplace. “We must also pay close attention to the environmental impact and the effects on human health posed by these chemicals, and for those reasons chemists need to work hand-in-hand with biologists,” said Warner. He also stressed that chemists generally have no background in toxicology, but that they need to be able to test the chemicals being developed for endocrine activity and to do it early on in the product development process.
Designing a chemical screening protocol
The remainder of the day was divided into discussion sessions covering each phase of a newly developed screening model, designed by a science advisory board formed by meeting organizers that met monthly, via teleconference, for six months prior to the workshop. The protocol is geared towards identifying a wide-range of endocrine-active chemicals, such as atrazine, BPA, brominated flame retardants, organotins, perchlorates, and phthalates. The Board conducted interviews with scientists with expertise in specific areas of toxicology, endocrine disruption, and assay development.
The testing paradigm proposed involves a five-tiered approach, starting with the fastest and cheapest assays and working through more specialized tests to determine whether a new chemical has endocrine disrupting characteristics. The initial two phases rely on predictive computer modeling and high-throughput screening to quickly weed out problem chemicals. These tests are followed by more specific in vitro cell-based screening assays with a mind to refining, reducing, and replacing animal testing as much as possible.
The final two phases involve use of fish, amphibian, and mammalian in vivo modeling systems. Overall, the protocol is intended to help green chemists establish a high degree of confidence that the replacements they are developing are unlikely to be harmful to humans or the environment.
The next steps
The meeting wrapped up with discussion on how to proceed with development of the testing protocol as well as plans for implementation. The advisory board plans to use input from the meeting to develop and publish a white paper outlining guidelines that chemists can use to assess the quality of protocols and tests used to assess endocrine disruption.
(Thaddeus Schug, Ph.D., is a postdoctoral research fellow currently on detail as a program analyst in the NIEHS Division of Extramural Research and Training. He was part of the NIEHS/NTP delegation and a presenter at the meeting.)
A representative diagram of the draft screening protocol unveiled at the meeting. The protocol is designed in a tiered approach, with rapid and cost effective screens conducted in the early phases and more extensive testing toward the end. (Slide courtesy of Pete Myers)
Left to right, Collins, Heindel, and Warner mix ingredients for a batch of salmon tartare. The cooking exercise was used as an ice-breaking event to demonstrate how environmental health scientists and chemists can work together to solve complex issues. (Photo courtesy of Pete Myers)
Laura Vandenberg, Ph.D., left, contributes to the discussion on assay development, as Tom Zoeller, Ph.D., center, and Wim Thielemans, Ph.D., look on. Vandenberg, a postdoctoral fellow at Tufts University, studies the developmental effects of endocrine disrupting chemicals. (Photo courtesy of Pete Myers)
Left to right, Bruce Blumberg, Ph.D., Thayer, and Andreas Kortenkamp, Ph.D., served as panel members for a discussion on
in vitro screening assays. (Photo courtesy of Pete Myers)
A group photo of the meeting attendees. The meeting was held at the Cavallo Point Lodge, which sits adjacent to the Golden Gate Bridge. (Photo courtesy of Pete Myers)
NIEHS grantees Andrea Gore, Ph.D., left, and Frederick vom Saal, Ph.D., were among panel members for the discussion on
in vivo assays. Both Gore and vom Saal are members of the project’s scientific advisory board. (Photo courtesy of Pete Myers)
Greening up drug production includes changing chemists, too.
Tuesday, May 31st, 2011Henderson,RK, J-G Concepcion, DJC Constable, SR Alston, GGA Inglis,G Fisher, J Sherwood, SP Binks and AD Curzons. 2011. Expanding GSK’s solvent selection guide – embedding sustainability into solvent selection starting at medicinal chemistry. Green Chemistry http://dx.doi.org/10.1039/c0gc00918k.
The large drug company GlaxoSmithKline (GSK) is reducing the use of problematic solvents in drug production in a unique way. They are changing the behavior of medicinal chemists – the researchers who develop new drugs.
An article in the journal Green Chemistry describes the company’s efforts to target the chemists by updating a popular green solvent guide and having the solvents easily available. The researchers’ choice of solvents is usually copied for industrial production of the drug. A change to a less harmful solvent has an enormous impact in creating a cleaner and safer pharmaceutical industry.
Organic chlorinated solvents are used in large quantities to produce pharmaceutical drugs. To produce 1 kilogram (kg) (2.2 pounds) of active drug, an average of 46 kg (100 pounds) of raw materials are used. Of these raw materials, an average 56 percent – or 26 kg (47 pounds) – are solvents.
Historically, medicinal chemists had a single focus: to develop new drug molecules in the shortest time possible. Solvent choice was purely based on familiarity with the chemical’s properties. Time to explore other, cleaner, solvents was not available as it slowed down new developments. The current focus on sustainability and safety is changing this single focus approach.
GSK’s approach is based on a solvent selection guide published in 1998. The guide ranks common solvents based on their environmental, health and safety issues. A 2003 update includes life cycle assessments – the environmental effects from production and disposal.
This latest edition extends the list of solvents to 110 from 47. It also provides more details in the assessments and presents a quick and comprehensive selection reference guide to steer scientists away from the most problematic solvents.
The complete solvent selection guide scores each solvent from 1 to 10 – one is bad, 10 is good – for eight categories. The categories include: waste treatment after use, environmental impact, human exposure and health effects, flammability, stability, life cycle impact from production, legislative limitations on its use and melting and boiling point.
Color coding makes it easier to understand. The combination of all data on one poster allows direct comparison. In addition, an electronic version includes links to documents with further information.
The guide alone was not enough to boost the use of greener solvents, so the company combined it with other methods to promote them. The greener solvents were readily available in the stockroom, the solvent selection guides were posted, and the benefits of less hazardous solvents were highlighted.
Chemists at GSK choose the greener solvent if they were aware of it. For example, the greener solvent 2-methyltetrahydrofuran is replacing other more problematic solvents. It was used in 16 percent of studies in 2007-2009 instead of 3.5 percent in 2005-2006.
The authors conclude that real changes can be made by improving availability of information, guidance and the actual solvents. The solvent selection guide described is a powerful tool. It is publically available, so it can be used by the whole scientific community and competing companies.
Even though reducing overall use of solvents should be the ultimate aim, this approach constitutes an important step in the right direction to a truly sustainable chemical and pharmaceutical industry, according to the study’s researchers.
Tags: GREEN CHEMISTRY, pharmaceutical
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