Document 9mV7yYR1qYv2Q8Mm89DmLED6

FILE NAME: Doubt Science (DBTS) DATE: 2005 DOC#: DBTS016 DOCUMENT DESCRIPTION: Infante Journal Article from IJOEH - Safeguarding Scientific Evaluations by Governmental Agencies SGaofveegrunamrdeinntgalSAcigeennticfiicesE:valuations by Case Study of OSHA and the 1,3-Butadlene Classification PETER F. INFANTE, DDS, DRPH Using the example of the industry pressures on OSHA that preceded the Agency's downgrading the carcino genic potential of butadiene from hum an carcinogen to "possibly carcinogenic to humans" in the face of sci entific evidence, the author warns of the danger to public health of the infringement on governmental agencies' decision making by special-interest groups. Key words: butadiene; carcinogenicity classification; gov ernm ent agencies; OSHA; toxicity classification; indus try influence. INT J O CCU P ENVIRON HEALTH 2005; 11:372-377 Recent reports have raised concern about the ability of governmental and international agen cies to maintain independence from the influ ence of industry when evaluating data related to the carcinogenic risks of chemicals to humans.1-3 Tomatis, a former Director of the International Agency for Research on Cancer (IARC), discusses the strong pres sure that industry attempts to exert on IARC carcinogeneity evaluations because of the effects of these eval uations can have on their profits.2 Huff also has expressed concern about the influence of industry on IARC evaluations in downgrading evi dence of carcinogenicity.1He specifically cites the deci sion regarding 1,3-butadiene (butadiene) arrived at during the February 1998 IARC working group meeting as "the prime example of overt industry influence on the IARC Monographs process." He reports that IARC ini tially voted to list butadiene as a "human carcinogen," The author is Adjunct Professor of Environmental and Occupadonal Health, The George Washington University, School of Public Health and Health Services, Washington, D.C. He was formerly employed by the U. S. Government For three years (1975-1978), he served as an epidemiologist with the National Institute for Occupa tional Safety and Health. For 24 years, he served as a senior health sci entist and Director of the Office of Carcinogen Identification and P W f irarinn (1978-1983) and Director of the Office of Standards Review (1983-2002), Health Standards Program, Occupational Safety and Health Administration. He currently does consulting related to occupational exposures and cancer, but he has not consulted in a case related to butadiene exposure and occupational disease. Address correspondence and reprint requests to: Peter F. Infante, The George Washington University, School of Public Health and Health Services, Washington, DC 20037, U .SA; telephone: (571) 641-3047; e-mail: <pinfante@starpower.net>. but that after one or two working group members left the meeting, the vote was retaken and industry's desired outcome of downgrading the evidence of cancer to "probably carcinogenic"was achieved. He notes that the epidemiology subgroup voted to list butadiene as a "human carcinogen," while the entire working group, influenced by industry and made up of chemists, toxi cologists, and in-vitro experts, subsequently voted to downgrade the evidence of cancer in humans. Sass3 has raised the same issue about industry influ ence on cancer evaluations at the U.S. Environmental Protection Agency (EPA). She reports on the unbal anced industry representation on the EPA Scientific Advisory Board (SAB) panel that reviewed the EPA butadiene-risk assessment. This influence led to an unprecedented investigation by the U.S. General Accounting Office (GAO) of EPA procedures in the selection of SAB panel members. The GAO report con cluded that EPA needed to improve its policies to bal ance the composition of EPA SAB panels to ensure independence from outside influences.4 According to Sass, `T he SAB report, issued in November 1998, rejected EPA staff scientists' recommendations to clas sify butadiene as a human carcinogen, instead recom mending the less-protective classification of `probable human carcinogen.'"3 Subsequent to the GAO report,4 the EPAfollowed staff scientists'opinion and concluded that butadiene was indeed "carcinogenic to humans.''5 The reports cited above raise very important issues about the independence of government and interna tional organizations in carrying out scientific evalua tions. This is not a new problem; however, the magni tude of the current influence of industry and its consultants on governmental deliberations goes well beyond what is healthy for our environment, the gen eral public, and blue-collar workers in particular. The morale of the career civil servants who attempt to func tion in this political environment is also an important and often overlooked casualty in these situations. INDUSTRY'S INFLUENCE ON OSHA'S CA N CER EVALUATION FOR BUTADIENE To further illuminate the issue, I review an example of industry influence on the cancer evaluation made by the Occupational Safety and Health Administration 372 (OSHA) in the preamble to its Final Standard for Occu pational Exposure to 1,3-Butadiene.6As part of a nego tiation to complete the standard and to avoid a legal challenge by industry as well as delay in the approval of the standard during the Office of Management and Budget (OMB) review process, OSHA changed its inter pretation of the evidence related to the carcinogenic effects of butadiene to humans, Specifically,just prior to publication of its final standard, OSHA changed its con clusion that "butadiene causes an increased risk of death from cancers of the lymphohematopoietic system" in humans and instead stated that butadiene was a "probable human carcinogen." This is an impor tant if subtle modification. The classification of a sub stance as a "known carcinogen" means that there is suf ficient evidence to conclude that it causes cancer in people. Classification of a substance as a "probable car cinogen" or a "suspect carcinogen means that data linking the substance to cancer in humans are weaker and thus subject to more uncertainty and debate.. This changed classification in the preamble to the final stan dard did not result in any change to the regulatory pro visions of the standard. It does, however, raise the issue of governmental responsibility to communicate the full extent of a hazard to workers, to the public, and to employers, who may not have been part of the "negoti ated interpretation" of the cancer hazard. The down playing of the cancer hazard may also unnecessarily impede compensation to workers who develop lympho hematopoietic cancer as a result of butadiene exposure. DEVELOPMENT OF THE OSHA STANDARD FOR 1,3-BUTADIENE The OSHA Butadiene Proposal (1990) In 1990, the Occupational Safety and Health Adminis tration (OSHA) proposed to lower the workplace per missible exposure limit (PEL) for butadiene from a time-weighted average (TWA) of 1,000 ppm to 2 ppm. The proposal also included a short-term exposure limit (STEL) of 10 ppm, to be measured over a 15-minute sampling period. Ancillary provisions related to expo sure monitoring, medical surveillance, worker training and education, personal protective equipment, etc., also were included. This proposal was based on evi dence that butadiene induced cancer in experimental animals and also was associated with an increased risk of death from cancer of the lymphohematopoietic system, which had been demonstrated in five epidemi ologic studies of workers.7For its preliminary quantita tive cancer risk assessment, OSHA used data from the National Toxicology Program (NTP), namely, the "NTP I" study, as it was referred to by OSHA. This study demonstrated that inhalational exposure of mice to butadiene at levels that were both above and below the OSHA PEL of 1,000 ppm induced cancers of the lung, heart, liver, mammary gland, ovary, and forestomach, as well as lymphomas.8 For its "best"estimate of the quantitative cancer risk to humans, OSHA relied on data showing the induction of heart hemangiosarcoma in female mice from the NTP I study. Modeling the dose response from this butadieneinduced tumor site indicated an excess risk of 147 cancer deaths per 1,000 workers exposed over an occupational lifetime to the 1,000 ppm butadiene PEL. Expressed in another way, 14.7% of the workforce exposed to the PEL would be estimated to die from cancer. The excess life time occupational cancer risk estimated by OSHA to result from exposure to the "proposed"PEL of 2 ppm was five extra cancer deaths per 1,000 workers. OSHA considers a risk of one extra cancer death per 1000 workers over an occupational lifetime of 45 years to be a significant risk to worker health. OSHA has not characterized the significance of risk below this level because it has had difficulty in reducing exposures to get below the "significant risk" level due to problems of "economic feasibility" with the health standards it had promulgated since the Supreme Court s decision on benzene.9 All of the health standards promulgated by OSHA since the 1980 Supreme Court decision on ben zene have resulted in significant (one or more per 1,000 workers' occupational lifetime) risks of cancer remaining from exposures to the new permissible levels, even though the risks have been greatly reduced by the promulgation of the new standards.11 OSHA held public hearings on the 1990 proposal in January and February 1991. The post-hearing com ment period closed in February 1992. Subsequently, the standard lay dormant at OSHA as the Bush and Clinton administrations had little interest in complet ing the butadiene standard. Development of the OSHA Final Butadiene Standard (1996) In light of all of the effort that had gone toward the development of the butadiene proposal, and the recog nition that a new standard was needed to protect exposed workers from a significant risk of developing cancer, an OSHA career civil servant raised the possibil ity of bringing together representatives of the manufac turers and users of butadiene as well as the unions that represented workers involved in its manufacturing in order to determine whether a mutually agreed upon standard could be negotiated. These entities met and produced an outline for a voluntary agreement for pro visions of a standard to be included in the OSHA Final Standard. In March 1996, OSHA published the agree ment and reopened the butadiene record for 30 days to allow the public to comment on the joint recommenda tions. The recommendations addressed the PEL and a number o ancillary provisions such as exposure moni toring and goals, medical surveillance, hazard coimmi- VOL11/NQ4, OCT/DEC2005 www.IJoeh.com Safeguarding Evaluations 373 nication, and respiratory protection. OSHA Health Standards staff was charged with completing the docu mentation of the health hazards related to butadiene as well as the quantitative risk assessment in order to deter mine the significance of the risk of exposure to butadi ene and the significance of the reduction in risk that could be achieved by the new standard. The OSHA Office of Regulatory Analysis was responsible for calculating the health benefit, in terms of cancer deaths avoided, to be derived from the new butadiene standard through use of OSHA's preferred quantitative risk-assessment analysis results. OSHA's Disconnect between Its Evaluation of the Epidemiologic D ata and Its Conclusion about Evidence of Causality OSHA had strong confidence that epidemiologic stud ies had demonstrated that butadiene caused lymphohematopoietic cancers in workers. To come to this con clusion, it had examined the results of six epidemiologic studies, or groups of studies, of exposed workers. The first of these was a series of studies of workers employed in the styrene-butadiene rubber (SBR) industry, conducted by the University of North Carolina. These studies, not designed to evaluate buta diene per se, demonstrated an elevated risk of lymphohematopoietic malignancies in this industry. I h e ele vated risk for these malignancies, however, could not be linked solely to butadiene, as benzene and other sol vents were also present in the workplace. In the second group of studies, OSHA examined the mortality experience among workers employed in a Texaco butadiene-manufacturing facility located in Texas. Divine updated this study population through 1985 and found a statistically significant excess of mor tality from lymphosarcoma and reticulosarcoma com bined.6 The sub-cohort of these workers employed before 1946 (wartime workers) demonstrated a statisti cally significant excess of death from the same cancers and, according to OSHA, the risk was even higher than that for the total group. OSHAfound these findings con sistent with those from an earlier study of these workers by Downs. OSHA characterized the findings from this study population as providing several notable results. OSHA determined that the statistically significandy ele vated risk of death from lymphosarcoma was consistent with the excess of lymphomas seen in the mouse stud ies.6 OSHA also noted that the relative risks for these cancers were the highest in the groups of workers that had experienced the heaviest exposures to butadiene. Finally, OSHA determined that the observation of the significandy elevated rate of malignancy in workers employed for less than ten years was a "notable result." OSHA also evaluated the National Institute fo r Occupational Safety and Health (NIOSH) cohort of workers employed at adjacent SBR facilities located in Texas. For plant A, OSHA found that while the overall mortality was significandy decreased, e.g., the stan dardized mortality ratio, or SMR, was equal to 80, the risks for lymphopoietic cancers (SMR = 155), lym phosarcoma and reticulum-cell sarcoma (SMR = 181), and leukemia (SMR = 203) were all elevated, although none of these results was statistically significant. The subgroup of workers who had begun employment in the war years, however, did demonstrate borderline sig nificandy elevated rates of death for these cancers, e.g., lymphohematopoietic cancer (SMR = 212) and leukemia (SMR = 278). Because the highest rates of mortality for these malignancies occurred among workers whose exposures had begun during World War II, when exposures were thought to have been the high est, OSHA thought these findings were noteworthy. OSHA concluded that the NIOSH study "by itself did not demonstrate that occupational exposure to butadi ene causes cancer. It is reasonable to interpret this state ment to mean that along with other evidence, this study provided supportive evidence to an overall evaluation that butadiene does cause cancer in humans. The fourth and fifth studies evaluated by OSHA, sponsored by the International Institute of Synthetic Rubber Producers (IISRP), were the cohort study of SBRworkers conducted by Matanoski et al., followed to 1982, and the case-control study for lymphohe matopoietic cancers nested within this cohort, con ducted by Santos-Burgoa and Matanoski. Regarding the cohort study, OSHA agreed with the conclusions of the authors that the risk of death from lymphohe matopoietic cancers seemed to be higher in the SBR industry than in the general population and seemed to be associated with three different work areas in the plants. In the nested case-control study, OSHA noted that the odds ratio (OR) for leukemia was 6.8 and sta tistically significant and was even higher in the matched-pair analysis, OR = 9.35 (95% Cl = 1.10 42 23) Butadiene exposure above the group mean also was associated with an OR of 2.30 for all lymphohe matopoietic cancers. OSHA entertained several lines of criticism from the IISRP about the study and ultimately rejected them. It is ironic that IISRP sponsored the study, approved the study design and method, and then disagreed with the findings at OSHA hearings. The sixth epidemiologic study of butadiene-exposed workers evaluated by OSHA was that of Delzell et al This study, also sponsored by the IISRP, included work ers from seven of the eight plants previously studied by Matanoski et al. and the two plants studied previously by NIOSH as mentioned above. According to OSHA, "one of the most important findings of the research of Delzell et al. was strong and consistent evidence that employment in the SBRindustry produced an excess of leukemia." OSHA noted that both white and black hourly workers with 10+ years of employment and 20+ years of latency had significantly elevated mortality 374 Infante w w w .ljoeh.com INT J OCCUP ENVIRON HEALTH ratios for leukemia, SMRs = 192 and 436, respectively. It further stated that the study demonstrated a doseresponse relationship between cumulative butadiene exposure and relative risk of leukemia. In its Summary and Conclusions of the epidemio logic evidence, OSHA listed "seven criteria" that it said could be used to judge the presence of a causal rela tionship between occupational exposure to butadiene and cancer of the lymphohematopoietic system. The "seven criteria" that OSHA listed were taken from a paper by Sir Austin Bradford Hill13: temporal relation ship; consistency; strength of association; doseresponse relationship; specificity of association; biolog ical plausibility; and coherence. (It is important to note that Hill never called them "criteria" but rather referred to them as "things to consider.") In the pre amble to the Final Butadiene Standard, OSHA indi cated that the epidemiologic, animal, and mechanistic data met all of its "criteria for a causal relationship." The preamble to the OSHA standard clearly shows that the OSHA staff evaluating the data believed that expo sure to butadiene in the workplace caused lymphohe matopoietic cancer in humans (Table V-4, titled "Evi dence That 1,3-Butadiene is a Human Carcinogen"). Yet, in a following section of the preamble on bonemarrow effects, OSHA stated that "epidemiologic stud ies of the styrene-butadiene rubber (SBR) industry suggest that workers exposed to BD are at an increased risk of developing leukemia, or lymphoma, two forms of hematologic malignancy." Finally, in the "Signifi cance of Risk" section, it states "OSHA has concluded that butadiene is a probable human carcinogen."6 The latter characterization of butadiene's cancer risk to humans misrepresents OSHA's evaluation of the epi demiologic data and is a reflection of a negotiation with the butadiene industry on the final standard. The D ata Relied Upon by OSHA for Its Quantitative Risk Assessment Between the time of OSHA's proposal in 1990 and March 1996, a second butadiene-inhalation study of cancer in animals was conducted by the NTP,14,1B and updated results from a number of epidemiologic stud ies were introduced into the record. In the NTP II study, the animals were exposed to butadiene levels closer to those prevailing in the workplace. The span of exposure levels was 0, 6.25, 20, 62.5, 200 and 625 ppm for six hours/day, five days/week for up to 105 weeks. This study again demonstrated the induction of tumors at essentially the same sites shown in the earlier NTP study, including lung tumors from exposure to 6.25 ppm butadiene--a level 160 times lower than the OSHA exposure limit permitted at the time. In its Final Butadiene Standard, OSHA set limits of 1 ppm for the eight-hour TWA and 5 ppm for the STEL,6along with the ancillary provisions that are usu ally included in OSHA standards. In the preamble to its final standard, OSHA stated that the estimated cancer risks to workers based on NIOSH analyses of animal cancer data in the NTP II study ranged from 0.9 to 30 excess cancer deaths per 1,000 workers over an occu pational lifetime. Risk assessments from other entities also were cited. Based on results from the NTP II study, OSHA also calculated its own cancer risk estimates for butadiene in relation to a PEL of 1 ppm. Based on male mouse data, the excess cancer risks to humans were 1.3 per 1,000 using lymphomas as the cancer effect and 6.4 per 1,000 using the lung cancer response. Based on female mouse data, the estimated excess cancer risks were 6.0 per 1,000 using lymphomas as the cancer effect and 8.1 per 1,000 using lung cancer as the site. OSHA also evaluated the quantitative risk of cancer to workers exposed to butadiene based on the updated epidemiologic data.6For this evaluation, it relied on the risk assessment performed by NIOSH that was based on the cohort study of workers exposed to butadiene in the synthetic rubber industry by Delzell et al,, as submitted to the International Institute of Synthetic Rubber Pro ducers on October 2, 1995. Utilizing the relative-risk model that best fit the data reported by Delzell et al.,12 NIOSH calculated the maximum likelihood estimate (MLE) of risk associated with occupational lifetime exposure to 1 ppm butadiene to be eight extra leukemia deaths per 1,000 workers. OSHA concluded that the risk of leukemia demonstrated by the Delzell et al.12study was concordant with the quantitative risk esti mates based on the animal cancer studies mentioned above. At this point in its evaluation of occupational cancer risk related to butadiene exposure, OSHA departed from its past policy of relying on epidemio logic data when dose-response information was avail able from both toxicologic and epidemiologic stud ies.16'17 Instead, OSHA relied upon animal cancer data to estimate quantitative cancer risks to workers exposed to butadiene. OSHA's choice of cancer risk from animal studies instead of leukemia risk from epidemiologic studies to express its quantitative risk assessment misin forms workers about the severity of the cancer hazard from exposure to butadiene by understating the risk. OSHA's Benefits Analysis In each standard promulgated by OSHA, it is required that the Agency provide an estimate of the benefits of the standard. Since the Supreme Court decision on benzene,16 when issuing health standards, OSHA has traditionally used its quantitative risk assessments to determine the benefits of the standard. In other words, it estimates the number of lives that might be saved, or illnesses prevented, by any change in practice that would be required by the standard. In its preliminary quantitative risk estimate of cancer deaths related to the proposed 2 ppm TWA for butadiene,7 OSHA esti- VOL 11/NO 4, OCT/DEC 2005 www.IJoeh.com Safeguarding Evaluations 375 misleading the public erodes trust in the Agency and government in general. The Persistent Attempt of Butadiene Industry Representatives to Influence Cancer Evaluations of National and International Governmental Agencies The involvement of the butadiene industry in the car cinogenicity evaluations of its product by various gov ernmental and international agencies appears to repre sent a consistent effort to minimize the knowledge of its cancer-causing properties in humans. As mentioned above, IARC also changed its evaluation that butadiene was a "human carcinogen" to one that concluded that butadiene was "probably carcinogenic to humans." This change in evaluation allegedly occurred after overnight lobbying by industry and IARC staff.1Thus, the industry was successful in influencing both IARC and OSHA. The butadiene industry's efforts to minimize knowl edge of the carcinogenic potential of butadiene failed to change the views of either the EPA or the NTP. The EPA Butadiene Scientific Advisory Board panel, with much industry representation, rejected EPA staff scien tists' conclusion that butadiene is a human carcinogen and instead recommended a weaker cancer classifica tion.3The selection process for the EPA Butadiene SAB panel, however, was criticized by the GAO as needing to be changed to achieve balance in the composition of members, in order to ensure independence from out side influences. In the end, EPA maintained its `car cinogenic to humans" classification for butadiene. In 1997, the NTP, through the Federal Register, solicited public input into its cancer classification for butadiene as a substance "known to be a human carcino gen."Subsequently, the NTP evaluated all comments and concluded that butadiene was a human carcinogen. This evaluation included a final review by the NTP Board of Scientific Counselors, a non-governmental scientific review body. In May 1998, the Chemical Manufacturers Association (CMA) wrote to the Director of the NTP m response to its final notice about its cancer classification of butadiene. The CMA, representing the major domes tic producers, users, and importers of butadiene, requested that the NTP not list butadiene as a "known carcinogen." The CMA supported its position in part by citing the IARC's February 1998 butadiene evaluation and the EPA SAB panel's butadiene evaluation men tioned above.24The NTP rejected the CMA arguments. While it is beneficial for science to have critical review of scientific study results, it is not beneficial to public health to have industries and their consultants apply political pressure on national and international governmental agencies in order to downgrade evi dence of cancer risks during reviews of scientific evi dence related to the toxicity of the chemicals that they manufacture and sell. References Huff T IARC Monographs, industry influence, and upgrading, ' downgrading, and under-grading chemicals: a personal point of view. Int J Occup Environ Health. 2002; 8:249-70. I. Tomatis L. The IARC Monographs ProKuam: changmg aUitudes towards pubUc health. Int J Occup Environ Health, 2002,8.144- i SassJB. Industry efforts to weaken the EPiVs classification of the carcinogenicity of butadiene. In tJ Occup Environ Health. 2005, 1 U . f S n e r a l Accounting Office. EPA's Scientific Addsory Board Panels. Improved Policies and Procedures N e e d e d ^ Ensure Independence and Balance. Washington, DC. GAO, 2001 (Report No. GAO-01-536). . ,,, , 5. U.S. Environmental Protection Agency. National Center for Environmental Assessment, Office of Research and Deve op- ment Integrated Risk Information System, Health Assessment offi1,3-Butadiene. October 2002. EPA/600/P/P-98/001F. 6. Occupational Safety and Health Administratnm O o a p a j m J Exposure to 1,3-Butadiene, Final Rule. Fed Reg. 1996,61.56746 7. Occupational Safety and Health Administn Exposure to 1,3-Butadiene, Proposed Rule and Notice of Hear mg Fed Reg. 1990;55:32735-826. 8 H uff JE, Melnick RL, Solleveld HA, et al. Multiple organ car cinogenicity of 1,3-butadiene in B6C3F mice after 60 weeks o inhalation exposure. Science. 1985;227:548-9. 9. Industrial Union Dept., AI'L-CIO v. American Petroleum Inst. 1980, 10. Infante PF. Cancer and blue-collar workers: Who cares? New Solutions. 1995;5:52-7. , . , II. Occupational Safety and Health Administration. OctupaUonal Exposure to Methylene Chloride: Final Rule. Fed Reg. 1997, 12. D ektnR sC thiakum arN , Hovinga M, et al. ^follow-up study of synthetic rubber workers. Toxicology. 1996.113:182-9.. 13. Hill AB. The environment and disease: association or causauon. Proc R Soc Med. 1965;58:295-300. . f,, 14 Melnick RL, HuffJ, Chou BJ, Muller RA. Carcinogenicity of 1,3- butadiene in C57BL/6 X C3H FI mice at low exposure concen trations. Cancer Res. 1990;50:6592-9. , , ,, 15. Nadonal Toxicology Program. 9th Report on Carcinogens. , Butadiene, CAS NO. 106-99-0. 2000; Department of Health and Human Services, Public Health Service National Inst.tute of Environmental Health Sciences, National Toxicology Program Research Triangle Park, NC. Contract No. NOl-ES-85421 16. OafupadonaJ1S-ifety and Health * f * g * ^ : s Z t w Exposure to Benzene, Final Rule. Fed Reg. 1987,52.344bU-b/ts. 17. Occupational Safely and Health AdministraUom tRxapauonal 18. P u E a w 9L5" stF'c o n g re stslffi^ O c c u p a tio n a l Safety 19. Otxi^adonal^afety^and H ea l* ^ m i n i s t r a t i o n ^ Exposure to Formaldehyde: Final Rule. Fed Reg. 1 , 20. Occupational Safety and Health Administration. Occupational Exposure to Ethylene Oxide, Final Standard, Fed g. . eo.i 1414-38 21. Vladeck DC. Unreasonable delav unreasonable interventuin: the battle to force regulation of ^ e n e oxide G ern^ town Public Law Research Paper No. 634865. <http.//ssm . 22. Sxupati'onaKSafety and Health Admintitration^Occupational Exposure to Hexavalent Chromium; Proposed Rule. Fed Reg. 2004;69:59306-474. , . . . -. 23 Infante P. Change in the Agency s interpretation of the ep dentiologic evidence in the preamble to the final standard rndi- L m g that 1,3-butadiene is a human carcinogen, Memorandum 24 Price CM ^V i Preridenh CHEMSTAR. Proposed cancer classi fication of 1,3-butadiene. Letter to Olden K, Director, NaUonal Toxicology Program. May 18,1998. 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