g o v e r n m e n t & policy
CHEMICAL TESTING TAKES TWO PATHS Highproduction-volume chemicals, endocrine disrupters are subjects of overlapping programs
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n this era of environmental concern and public right-to-know, the chemical industry faces many challenges. As the main manufacturer, processor, importer, and user of chemicals, the industry has become the primary focus of the public's concern over possible toxicity from chemicals. Still, efforts to measure the real toxicity of individual chemicals and their impact on the environment have not always been very productive. But now, two major chemical testing programs are gaining momentum and coming together in a unique confluence of industry participation, activist resolve, and government effort. In the two articles that follow, C&EN looks at the status of each effort and details on the issues being debated. The first, written by Senior Editor Jeff Johnson, describes the high-productionvolume (HPV) testing program, which is moving rapidly to do toxicity screening tests on compounds produced or imported in amounts of 1 million lb per year or more. The second article, written by Senior Editor Bette Hileman, reports on the endocrine disrupter testing program, which is looking at the potential toxicity of thousands of compounds to the endocrine systems of humans and wildlife at concentrations in the parts-per-billion range or less. Of the two, the HPV program is the further along and has the most political exposure right now. Although there has long been a testing program under way at the Organization for Economic Cooperation & Development (OECD), the issue became energized last year when Vice President Al Gore called for faster testing of these chemicals. By issuing a challenge to complete this testing in the next five years, Gore has put the program on a fast track, and chemical companies and the Environmental Protection Agency have been struggling to keep up. Amid the activity to find out what tests might already have been done and
what chemicals still have the most tests needing to be done, the large number of animals used for toxicological tests has become an issue. Several meetings have been held at which animal activist groups have called for changing these tests, and it appears that innovative methods that may reduce animal use and speed the process are evolving. But a number of issues are still far from being resolved. Which companies will do all of the tests and how much the tests are going to cost remain questions. How EPA will force companies to do the toxicity tests if they don't want to is another problem. So far, there seems to be a lot of cooperation and planning, but there is long way yet to go. The second testing program is in some disarray. Measuring the minute
WEEELl· effects of thousands of chemicals on endocrine systems is a very daunting task, and EPA is struggling to come up with a viable plan to accomplish it. The issue, like HPV chemicals, has been around for many years, but it was the 1996 publication of the book "Our Stolen Future" by Theo Colborn, Dianne Dumanoski, and John Peterson Myers that really pushed the problem into the public spotlight and forced EPA to take action. The creation of new toxicity tests is also a significant part of the endocrine disrupter problem. Although it is known that chemicals can interfere with endocrine activity and cause deleterious effects, the knowledge of what to test and how to test it is still undeveloped. As a result, plans for prioritizing the more than 80,000 chemicals EPA wants to test are not progressing well, and there is some concern the agency has not even requested sufficient funds to support its own efforts. The chemical industry has been hit on both sides by demands for data and testingfromboth the HPV and endocrine disrupter programs. It appears now that, in the shorter term, HPV testing is going to cost companies in terms of funding tests and meeting regulatory requirements. The impact of the endocrine data program is further away, and if it leads to increased regulation of chemical products, the impact there will be more profound.^
HPV Testing Gets Under Way Jeff Johnson C&EN Washington
C
hemical industry support for a long-stalled program to test the world's most common chemicals may ignite development of a new generation of toxicological tests, say scientists at the Environmental Protection Agency, the Organization for Economic Cooperation & Development (OECD), industry, and academia. Under the high-production-volume (HPV) chemical testing program, some 2,800 chemicals produced or imported in quantities exceeding 1 million lb per year will be subject to a battery of basic screening tests. Modeled on an OECD testing program begun in 1990, the U.S. version calls for the tests to be complete by the end of 2004. The cost of the tests will be borne by industry under an agreement pushed by Vice President Al Gore and negotiated by EPA, the Chem-
ical Manufacturers Association (CMA), and the Environmental Defense Fund (EDF) (C&EN, Nov. 2, 1998, page 19). Although the program requires examination of basic physical and chemical properties of the compounds as well as ecotoxicity and environmental fate, most attention is focusing on a series of human health toxicity screening tests as the program gets under way. The sheer number of chemicals to be run through these tests has caused toxicologists to consider how mammalian toxicity tests can be improved. Consequently, once it begins operating next year, the program is expected to provide an avenue to change testing methods, speed up the testing process, and reduce use of animals. "The issue goes way beyond the HPV program," says Alan M. Goldberg, professor of toxicology at Johns Hopkins University School of Hygiene & Public Health and director of the Center MAY 10,1999 C&EN
23
g o v e r n m e n t & policy for Alternatives to Animal Testing (CAAT). "From an animal welfare perspective, the HPV program could only be called a disaster when it was first announced last year," Goldberg says. He estimates the program would have required nearly 2 million animals to be sacrificed. However, largely because of pressure from the animal-protection movement as well as the realization of the program's dimensions, EPA has gradually changed its test-screening requirements to allow tests to be combined and to rely more on in vitro procedures. Consequently, the number of animals has been reduced from an average high of 430 per chemical to around 100. Most recently, much to the satisfaction of animal rights proponents, EPA disclosed last month that it would conform its genetic toxicity screening requirements to those of OECD, which allow in vitro tests in this category. EPA had stated a preference for in vivo genetic toxicity tests but now will accept in vitro tests, using cultures and mammalian cells. EPA's Charles M. Auer, director of the Chemical Control Division, announced its policy switch at a testing workshop sponsored by the Johns Hopkins' center. And at the two-day workshop, discussions among some 150 toxicologists made clear they hope to use the HPV program as a spur to develop new testing methods. Indeed, the workshop was funded as part of a $320,000 private foundation grant obtained by CAAT, EDF, and the University of Pittsburgh to develop more efficient, less animal-intensive tests through the HPV program. High on the list of tests Goldberg wants most to change are acute toxicity tests that by their nature call for the death of a test animal. Historically, these tests have been expensive and animal intensive, particularly the LD50 test in which dosage is set through the death of half the test animals. Although most of the world's toxicologists have moved away from the LD50, substitutes still use large numbers of animals, Goldberg notes. Instead, he wants to replace the test with methods using cell cultures from animal organs to determine organ-specific acute toxicity levels. 'We are talking basically about acute system failure," he says, "and if you study, for instance, heart failure in a culture, you can determine what level of a chemical is necessary to enter a cell and 24
MAY 10,1999 C&EN
u f
back-calculate the volume distribution to the whole animal and deterHigh-production-volume tests mine the dose without the expense provide basic screening data and death of an animal. "We will still need animal tests Chemical identity for organ-to-organ interactions Name, CAS Registry Number and for impact at low doses, but Physical/chemical properties we can eliminate use of many Melting point animals." Boiling point Vapor pressure Since the HPV testing protocol Partition coefficient and the time frame are already set, Water solubility use of such exotic tests is unlikely. But Goldberg sees a battery of Environmental fate and pathways new testing requirements on the Aerobic biodégradation Abiotic degradation horizon—tests for endocrine dis• Hydrolysis rupting potential, tests of low• Photolysis volume chemicals, and tests for pesticides' impact on children. Fate and environmental distribution assessment Those chemical tests, along Ecotoxicity with the HPV program, he says, Acute toxicity will encourage companies and • Fish, daphnia, algae EPA to more closely consider new Chronic toxicity (when indicated) alternative tests. It may even lead • Daphnia labs to try alternative tests alongMammalian toxicity side traditional toxicity screening Acute toxicity tests used for HPV chemicals and • Oral, inhalation, or dermal thereby begin to develop a dataRepeat dose toxicity base for comparison. • 28-day study or • Combined repeat dose and Chemical industry officials at reproductive toxicity screen the workshop applauded the conGenotoxicity cept but questioned if industry will • Gene mutation be willing to pay more for an al• Chromosomal aberrations ready expensive program. GoldReproductive/developmental toxicity berg says companies in the long • Combined reproductive/developmental toxicity screen or run can save money and time by • Combined repeat dose and reproductive moving to in vitro tests as well as toxicity screen get good publicity by avoiding tests that kill animals. He also says Source: Environmental Protection Agency foundation support may be forthcoming to help fund dual tests. However, developing and validating the rule to include chemical processors these tests will be expensive, and the as well as importers and manufacturers. HPV screening tests alone could cost inTo run all this, EPA is seeking $14 mildustry some $400 million, according to lion and 40 more people next year, up CMA. from $1.25 million this year. Right now, the first step for companies No one knows exactly what the unusual program will cost or how companies after volunteering for a chemical is to will do the testing to comply or even the search out what tests may already have been done, Auer says. The companies exact number of tests to be done. The program is largely voluntary and must present a draft "test plan" to EPA for relies on the companies that make the each chemical they have selected to test at chemicals to select which chemicals the start of the year they will do the tests. Studies by EPA and CMA have found they might test. If companies have not volunteered to test all of the 2,800 chem- that complete data sets exist in the pubicals by December, EPA will issue a rule lic record for only about 6% of the chemrequiring chemical makers to test the icals, but more information may be found in corporate files. In part, the proremaining chemicals. The agency expects problems gain- gram's intention is to drive that search. Mary Jo Miller, a toxicologist with ing "volunteers" for some chemicals, and the anticipated rule will allow use of Exxon Biomedical Sciences Inc., who outside arbitration to apportion cost spoke for CMA at the workshop, urges shares when no company steps up. The companies to cull through their internal net to snare sharers will be widened in databases looking for any data they
might have on HPV chemicals. Since they will design their own test plans, she says, firms can use their own expert judgment to try to convince EPA that certain tests may not be necessary—for instance, when a chemical is an intermediate, exposure is very limited, or the chemical will not enter a particular medium. She also notes that companies can avoid tests by combining chemicals based on similar structure-activity relationships and can use the results from tests on individual chemicals to fill in missing data for the group. For petroleum-related chemicals, she says, one combined category could include 40 or 50 chemicals with "different CAS [Chemical Abstracts Service] numbers but generally the same molecules." She predicts that for the most part companies will form consortia to test chemicals in order to share testing costs and expertise. EPA officials say that, of the 1,100 HPV chemicals select-
ed so far by companies for testing, most will be done by consortia, primarily formed through trade associations. Miller tells C&EN that companies are negotiating now with poten-
Goldberg (left) and Auer
tial test partners, and it is too early to say what tests will be needed or who will do them. However, she expects that companies will increasingly look to a growing number of labs that are now advertising their ability to do HPV tests.
THE
She emphasizes that EPA has told companies to combine as many tests as possible and select shorter duration tests to conserve animals. Auer even warns that EPA will closely examine test plans and quiz companies if more elaborate, animalintensive tests are planned. But Miller notes that companies may choose to do more than screening tests when they lack data on an important chemical and may simply decide "to do the whole barrage of tests and have it done." Similarly, companies may need the data to comply with other regulations or for test demands imposed by other countries, says Herman B. W. M. Koëter, principal administrator for OECD's Environmental Health & Safety Division. "In some parts of the world, industry says, "These are highly used chemicals and they are economically important to us, so lefs spend the money, do the tests, and we are done,'" Koëter says. He
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g o v e r n m e n t & policy notes some of these tests can be very expensive and animal-intensive, costing up to $1 million and using 800 animals for a two-generation reproduction test Koëter's experience with the OECD program—called the Screening Information Data Set (SIDS)—is important because this program is the basis for the U.S. HPV program, and the U.S. data will eventually be housed with the SIDS data in an international database. In its nine-year life, the OECD:run program has completely tested only 161 chemicals and has another 207 chemicals in various stages of investigation. The slow pace, as well as EPA's inability to get the U.S. chemical industry to test these same chemicals under the 1976 Toxic Substances Control Act, was the impetus for the EDF/CMA/EPA program. Koëter's figures show that surprisingly few mammalian toxicity tests have had to be conducted for the first 161 chemicals—a total of 234 tests for the four mammalian toxicity categories. For acute toxicity, only 14 tests were required, and among the 40 chemicals sponsored by U.S. companies, only one acute test was done. Koëter attributes this to history. "In the 1950s, when the chemicals were being developed, if companies wanted some information on toxicity, they used the LD50 test and they stuffed as much as possible into the rats and, if the rats didn't all die, they said, We're done.' It is old-fashioned, but sometimes it gives good information for a screening test." In total, about half of all the tests (114) were done to fill data gaps for the 40 Japanese-industry-sponsored chemicals. Koëter doubts this ratio of toxicity tests will hold in the future as the easyto-do chemicals get picked off. "Companies want to select chemicals where there are lots of data and no problems. We don't want that," he says, but adds that the "political component" in selection is becoming significant. More important, and more controversial, he says, is what happens once the tests are completed and a chemical's risk assessment reveals a potential problem that warrants restricted use, labeling, or reduced exposure to that chemical. So far, Koëter says about 10 to 15 of the 161 chemicals are "baddies." An OECD panel of member countries is in26
MAY 10,1999 C&EN
vestigating and drawing up management plans for these chemicals, he says. Risk assessment is not required as part of the U.S. HPV program, Auer notes. At this time it is only a screeningtest program, but risk data can be submitted—along with exposure information— in a package with the test data. The basic test data will be included in what Auer calls a "robust summary," a story of a chemical's or chemical category's characteristics explained in a manner understandable to someone
Koëter (left) and Miller
informed on this issue but not necessarily a toxicologist. The summaries will be posted on the Internet by EPA within days of their receipt, he says. The decision to add risk information to the robust summary, Auer says, rests with the data supplier. The summaries will be presented to OECD with or without risk assessments, depending on what EPA has. Koëter predicts OECD will do most of the risk assessments and it will take years after the test data are received before they are complete. He emphasizes that screening data is only the start of the program, and despite any delay, the final result—test data, risk assessment, exposure information—will be a powerful tool, especially considering its international flavor. Eventually, Auer says, EPA will develop risk management plans and exposure assessments, and will make risk judgments on its own, but it will take five to 10 years after the HPV program is wrapped up. Looking at international data storage and retrieval, OECD is preparing an Internet-based system to track chemicals and updated test results for all chemicals in the SIDS program, which is expected to be in operation by year's end, says Leslie Onyon, program administra-
tor in the OECD Environmental Health & Safety Division. Onyon also says OECD may expand a data storage and retrieval system used in the European Union, the International Uniform Chemical Information Database (IUCLID), to store all test data for SIDS/HPV chemicals. The IUCLID system is favored by industry, Onyon notes, and CMA plans to use it to track U.S. industry compliance with the HPV program. However, EPA has leaned toward using its own systems, which would further complicate the data collection and retrieval process. Harmonization of countryspecific information is critical, Onyon says, so it must be collected and presented in a consistent manner and stored in an accessible central system. In the future, Auer envisions an international system in which IUCLID might "sit in the middle" of an Internet data system where a visitor could retrieve international data or be pointed to country-specific information. Onyon says OECD countries are examining such an integrated system but she warns it could be expensive and "mind-bogglingly" complex. For now, simply the flow of test data on 2,800 chemicals into EPA has CMA officials worried that EPA's budget may be insufficient for it to keep up. They are also worried that the robust summaries will become the basis for ad hoc risk assessments and publicity campaigns waged by environmental groups. They are particularly concerned about EDF, whose "Scorecard" web site is currently generating heat for them by providing company-specific emissions data from EPA's Toxics Release Inventory by zip code. Auer sees it another way: 'This concern should encourage companies to provide their own exposure information and conduct their own risk assessments," he tells C&EN. 'They should tell a story about what the data say about the hazards. If problems emerge, it will be good for the makers and users of chemicals to address them. "You must remember," Auer continues, "this is only screening-level data. We still won't know a lot about the chemical. I would hope industry of its own accord would step forward with testing and assessments beyond the SIDS level in recognition of product stewardship."^
Low-Dose Problem Vexes Endocrine Testing Plans Bette Hileman C&EN Washington
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ast July, after two years of hard work, a panel convened by the Environmental Protection Agency came to a consensus on a program to test as many as 87,000 chemicals for their potential to cause endocrine (hormone) disruption. On this panel of 39 industry, academic, government, and public-interest group representatives, many hurdles and disagreements were overcome on the way to that consensus. But now, the program faces new difficulties. Critics say EPA is not putting enough resources into the program to implement it in a timely manner. And the critical issue of whether extremely low doses of chemicals have adverse effects on lab animals remains unresolved, which means it is impossible to know whether these chemicals should
able. As a result, industry fears that the public could become alarmed about the results of an initial false positive. The endocrine disrupter screening and testing program is designed to be tested at very low doses. "Resolution determine whether chemicals mimic, of the low-dose issue is important for interfere with, or otherwise disrupt the solving regulatory and assessment pro- activity of hormones in humans and cesses for these chemicals," says wildlife. It ascertains the effects of Penelope Fenner-Crisp, science coordi- chemicals on estrogen, androgen, and nator for EPA's Office of Prevention, thyroid-related systems. The Endocrine Disrupter Screening & Testing AdvisoPesticides & Toxic Substances. And the high-throughput prescreen- ry Committee (EDSTAC) that devised ing assay procedure, which was to be the program chose these three horused as a first step to prioritize chemicals mones because they are important in and to substitute for several in vitro tests, both humans and wildlife, and because is not working out. If the problems with tests for these systems already exist. this rapid screen cannot be overcome, The 87,000 chemicals to be priorithe endocrine disrupter testing program tized for testing include pesticides, cosis going to be even slower and more ex- metic ingredients, food additives, and pensive than originally anticipated. other chemicals regulated under the Another hurdle is that many of the Toxic Substances Control Act. The testscreens and tests that are to be used in ing system consists of two tiers: Tier 1 the endocrine testing scheme have not screens and Tier 2 tests. Tier 1 is a set of yet been validated. If a chemical seems short-term screens designed to deterto be an endocrine disrupter in an initial mine whether a chemical interacts with screen, validated tests to confirm or ne- estrogen, androgen, or thyroid systems. gate the initial finding are not yet avail- It consists of three in vitro assays and five
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In addition, chemicals for which in vivo assays using rodents, fish, and frogs. The tests are designed to be quick there are already sufficient data would and sensitive enough to detect all estro- bypass Tier 1 and go directly to Tier 2, and a few chemicals with extensive data gen, androgen, and thyroid disrupters. However, the screens will identify would go directly to hazard assessment. some chemicals as endocrine disrupt- About 1,000 chemicals fall into these ers that will turn out to be harmless af- two categories. ter further testing. If Tier 1 screening inBut most chemicals—about 61,000— dicates that a chemical does not interact would undergo Tier 1 screens and those with the endocrine system, no further that are positive in these screens would analysis would be required. None of the need Tier 2 testing Tier 1 screens has been fully validated. as well. Because Chemicals that seem to interact with there is no way to the endocrine system in Tier 1 screens put 61,000 chemiwould be put through Tier 2 testing. This cals through the consists of five assays: a two-generation Tier 1 screens simammalian reproductive toxicity study; multaneously, the an avian reproduction test; a fish life-cycle test; a crustacean life-cycle test; and an amphibian development and reproduction test. If Tier 2 testing shows that a chemical is an endocrine disrupter, it would undergo additional hazard assessment. Because there are so many chemicals to be tested, EDSTAC recommended that a high-speed automated system called highthroughput prescreening replace some of the Tier 1 assays. Rather than preparing and handling samples manually, automated tech- Clockwise from above: Gray, niques and robotics would be used vom Saal, and Sheehan to accelerate the assay process. High-throughput prescreening was to be high-throughput done first on all pesticides and all chemi- prescreen was to cals (about 15,000) with a production vol- be used to prioriume greater than 10,000 lb per year. tize them. But But in the pilot demonstration pro- this may not be gram conducted for EPA by a private con- possible. tractor, the high-throughput system did Under the EDSTAC plan, EPA is to not work and is now being redesigned. pay for standardization and validation of 'The high-throughput screen has tre- the tests, and industry is to pay for the acmendous potential, but not as it's current- tual testing and screening. Nearly all ly formulated," says Paul M. D. Foster, members of EDSTAC contacted by head of endocrine disrupter research at C&EN worry that EPA does not have the Chemical Industry Institute of Toxi- enough resources to get the program off cology (CUT), Research Triangle Park, the ground. The law mandates that the N.C. "But I think there are ways to do it," program be "operational" by September he says. If high-throughput prescreening 1999 and that some results be reported to cannot be made to work satisfactorily, the Congress by September 2000. Gary E. whole testing program will be more ex- Timm, senior technical adviser in EPA's pensive because all of it will be done man- Office of Prevention, Pesticides & Toxic ually rather than partly with robotics. Substances, estimates that the whole testBefore any chemicals are tested they ing program will cost EPA about $50 milwould go through an initial sorting. Poly- lion. Costs for standardizing and validatmers with number-average molecular ing the Tier 1 screens are in the $15 milweights greater than 1,000 daltons (about lion to $25 million range. However, EPA 25,000 chemicals) would be put in one has only $4 million for the program in fiscategory and their testing would be de- cal 1999 and has requested $7.7 million ferred until a much later time when their for next year. components would be reviewed. 'This will not pay for all of the bioas28
MAY 10,1999 C&EN
mm say standardization, validation, and further assay development required to make the program work," says Peter L. deFur, associate affiliate professor of biology at Virginia Commonwealth University, Richmond. 'We have two issues here," says Sandra L. Tirey, coleader of the public health team at the Chemical Manufacturers Association. "One is that EPA should have enough resources to do all the validation and standardization. Another is we want to make sure that if high-throughput prescreening or Tier 1 screens are begun, that all the tests are available for people to pursue," she adds. If Tier 1 screens indicate a problem with a chemical, and Tier 2 is not ready, "we're left twisting in the wind with no way to pursue additional work on a positive," she explains. She worries that EPA will put preliminary results on the Internet before a chemical has gone through the full battery of tests, and the public will become unnecessarily alarmed. Angelina Duggan, a development and regulatory affairs manager for FMC Corp., Chicago, says the great need for research and validation of tests shows that regulatory policies have gotten way out in front of the science on endocrine disrupters. 'With so little funding, the entire program could sit on the shelf," warns Ted Schettler, science director for the Science & Environmental Health Network, Boston. "If EPA doesn't come up with the money to go through the standardization and validation phase, the program is not going to get done," he adds. However, EPA's Timm claims the 2000 budget is adequate. "It's not clear that money is going to be the rate-limiting step for the year 2000," he says, "but clearly we'll need a substantial increase in funding for the year 2001." Money can be saved by coordinating endocrine testing with high-production-volume chemical tests, he adds. Timm also says EPA does not have to run the high-throughput prescreen until the other tests are ready. The agency has the discretion to delay putting test results on the Internet "until it is confident the data are meaningful," he explains. One of the serious questions plaguing the testing program right now is whether chemicals can have adverse effects in an-
Dynamit Nobel imals—and by implication, in humans— at very low doses. Resolving this issue has several practical outcomes. First, if scientists do come to a consensus that these chemicals indeed have effects at very low doses, the chemicals would have to be tested perhaps at six doses rather than the usual three, says Timm. Eventually, the two highest doses might be eliminated, but still four doses would be required, he says. This would make the testing program more expensive. A broad range of doses would be necessary because some chemicals appear to have dose-response curves shaped like an inverted U. In other words, they cause adverse effects at very low levels, then the effects increase with increasing dose, but at higher levels the effects begin to drop off. DeFur believes that quite a few chemicals have such dose-response curves. "I don't think it's a question of whether or not these things occur," he says. "It's when you find them, what do you do with the data?" Another outcome of confirming lowdose effects is that many chemicals that have been tested with standard toxicological methods would have to be retested because they may have effects at very low doses that were missed in the original assays. And for those chemicals that turn out to have adverse effects at levels way below current tolerances, the tolerances would have to be lowered, deFur says. A third consequence would be that the uses of some chemicals might be phased out, deFur adds. If populations are exposed to a chemical that causes adverse effects at environmental levels of exposure, it might eventually be banned. Several researchers are finding adverse effects in lab animals from quite low doses of a number of chemicals. L. Earl Gray, a reproductive toxicologist at EPA's Health Effects Research Laboratory, Research Triangle Park, found that when the pesticide vinclozolin is administered to pregnant mice at low doses, it causes adverse effects in the reproductive tracts of the male offspring. In lab studies on rodents, Kenneth B. Delclos, pharmacologist at the Food & Drug Administration's National Center forToxicological Research (NCTR), Jefferson, Ark., demonstrated that low levels of nonylphenol increased offspring prostate weight. Frederick S. vom Saal, a developmental biologist at the University of Missouri, Columbia, found that when low doses of methoxychlor are administered to pregnant mice, the male offspring have enlarged prostates.
Despite these findings, the low-dose debate is becoming centered around the research on one chemical, bisphenol-A This high-volume substance with worldwide production of about 100,000 tons per year is used to make polycarbonate plastic and resins. At least four labs have reported conflicting results concerning the possible endocrine effects of bisphenol-A on developing rodents. Vom Saal found that when pregnant mice are given a daily dose of 2 \ig of bisphenol-A per kg of body weight during pregnancy, the male offspring have prostates 35% larger than controls and the female offspring have abnormalities in their reproductive tracts. John Ashby of Zeneca Central Toxicology Laboratory in the U.K more or less repeated vom Saal's work and found no effect of bisphenol-A on the prostate weight of the male offspring. However, Ashby sacrificed the animals at a much later age (nine-and-a-half months) than vom Saal did (three months), and Ashby's control animals and dosed animals both had enlarged prostates. Like men, mice get enlarged prostates as they age, usually starting at about nine months, so natural enlargement could have been masking effects of bisphenol-A A study sponsored by the Society of the Plastics Industry, Washington, D.C., found that low doses of bisphenol-A had no effects on male mice exposed in utero. In this study, the female offspring were not examined. Many toxicologists are skeptical of these results, because the study's positive controls did not show any effect with the strong estrogen diethylstilbestrol. "Just from an experimental design point of view, any toxicologist would be very wary of ever relying on a study where the positive control had failed to show an effect," says John Young, a toxicologist at Hampshire Research Institute, Alexandria, Va. Frank Welsch, a researcher at CUT, looked for effects of bisphenol-A on two groups of male rats in utero. In the first group, bisphenol-A caused no effect; in the second, there was a statistically significant increase in prostate weight. Joseph K. Haseman, a statistician at the National Institute of Environmental Health Sciences, reanalyzed Welsch's raw data and concluded that the overall study indicates "an increase in prostate weight with bisphenol-A treatment." Some researchers argue that enough work has been done to try to find consistent effects from low doses of bisphenol-A and that the issue should be abandoned.
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But Daniel M. Sheehan, director of the Endocrine Disrupter Knowledge Base Program at NCTR, says it would be "a disservice to science" not to try to do new and better controlled experiments and figure out what is happening with bisphenol-A "I know it is complicated," he says. "Anything in science that is important is like this. If we assert that we cannot adequately control our experiments, that is wrong." The bottom line from all of this research and argument is that the toxicology of bisphenol-A is not resolved. According to industry spokesmen, if scientists eventually reach a consensus that bisphenol-A has no adverse effects at low doses, the entire low-dose issue will become much less important for other chemicals as well. Such a consensus would "sort of push the low-dose issue further to the side," CMA's Tirey says. It would leave low-dose effects "in the theoretically possible, but not-shown category," she explains. EPA's Timm plans to convene a panel in the fall to examine the entire low-dose issue.
