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INTRODUCTION TO DISCUSSION SESSIONS I. ALAR (Daminozide) ALAR is a hydrazine compound that has been used as a plant growth regulator since 1962. The EPA established in 1976 residue tolerances of 1 to 55 ppm on a variety of fruito In 1987, EPA reaffirmed a limit of 20 ppm for app l es. This compound was selected for discussion because: 1. It is typical of cases that appear to have confronted regulators without warning. 2. Data on its health effects are sparse and only exist for exposures to animals. 3. The public (stimulated by the Natural Resources Defense Council) demanded prompt action. 4. Other hydrazine compounds have been found to be carcinogenic. - In its challenge, the NRDC claimed that chemical resictues of ALAR, especially on apples, were causing elevated risks of cancer among children. To emphasize their point, NRDC held news conferences in a-dozen cities and warned that over 5,000 children might die from preschool expos,uLres to ALAR. Ed Brad'ley (on "60 Minutes") stated that ALAR was "the most potent cancer-causing agent in our food supply." As a result, apples disappeared from many grocery shelves and cafeteria lines. Meryl Streep appeared on "Donahue" and the "Today" Show announcing formation of "Mothers and Others for Pesticide Limits." Because of these actions, the apple industry suffered an estimated $100 million loss; some growers were actually forced out of business. Other impacts included the introduction of a bill in the Senate to ban the use of ALAR. And the media praised NRDC for its humanitarian efforts. On the basis of subsequent thorough reviews of the literature and scientific data, these charges were largely refuted. In fact, the National Academy of Sciences (NAS) publication, Issues in Science and Technology, stated that -1-

ALAR poses no health threat. The NAS report, which was based on an examination of 6,000 studies, found "no evidence thatt pesticides or natural toxins in food contribute significantly to cancer risk in the United States." To provide background for a review of this case, you have been provided with selected reports and publications on ALA£:. These include a copy of the NRDC report. Questions thatt you may want to consider in evaluating this issue include: 1. Statistical analyses of the data seem to show an excess of tumors in animals exposed to ALAR. (See paper by Gold, et al.). In light of this, why did EPA reviewers not agree? 2. Is it fair to use data at the 80 ppm level as evidence for the carcinogenicity of UDMH, a metabolite of ALAR? 3. If ALAR and UDMH are assumed to be carcinogenic, what are their potencies? Dr. John Graham will be discussing these and related issues on Friday morning at 9:45. II. Dioxin Dioxin is a byproduct of the manufacture of herbicides. It was first detected in the late 1950s when it was observed as a contaminant that forms during the commercial synthesis of 2,4,5-trichlorophenoxyacetic acid, a compound used as a weed killer and in Agent Orange. Animal studies have stiown that this ubiquitous pollutant is extremely lethal; in fact, it is the most potent carcinogen ever tested. But human effects have been notoriousl,y difficult to confirm -- as exemplified by the decades old controversy over the effects of Agent Orange. This is an interesting issue to review for several reasons: 1. The highly controversial nature of the effects of o this compound. ~ 2. The accusations that industrial groups withheld ~ information that was important to evaluations of its ~ health effects. ~ ~ 3. The success.of bringing disparate groups together ~ to discuss and reach a consensus on the related health ~ effects issues. -2-

4.The far-reaching implications of the consensus reached in this particular case. In the absence of definitive human data, the EPA assumed that there is no safe level for dioxin, that is, that the dose - effect relationship was linear. Following this approach, EPA set an acceptable intake level of 0.006 picograms per kilogram of body weight per day. Following a non•-:Einear approach, Canada and several of the European countries, set limits that were 170 to 1700 times higher than that recommended by EPA. At a meeting at the Banbury Center at the Cold Spring Harbor Laboratory, 38 researchers and regulators from the U. S. and Europe recently reached agreement on the health effects of dioxin. Specifically, they agreed that, before dioxjln ca' can cause its myriad toxic effects, be they cancer or birth defects, it must first bind to and activate a receptor. The importance of this azreement is that, if receptor bindi.na- is an essential first step before any toxic effects can occur, then that implies that there is a "safe" dose or pPB.c:t.ical."threshold" below which no toxic effects occur. This also indicates that the linear non-threshold model does not aLpply. An additional implication of the acceptance of this approach is that there could be significant changes in current assessments of the risks of many other chemical compoundsin common use today. You have been provided with several background papers on this subject. Dr. Linda Birnbaum will be here on Friday morning'at 11:15 to discuss this issue in greater detail. Questions that you may want to consider in discussing this topic include: 1. How valid is the assumption that the necessity for receptor binding,assures that a chemical compound has a threshold for toxic effects? 2. If there is a threshold for dioxin, what is it? Are,there sufficient data available to determine whether dioxin intake of the U.S. population is below this threshold? 3. How many other toxic compounds must first bind to an activate a receptor? That is, how far reaching are the implications of the findings with respect to dioxin? -3-

III. Lead Lead is of concern both in the occupational and ambient environment. Major sources of intake for the general public include the ingestion of lead from drinking water that has either flowed through lead pipe or pipe in whic]1 lead was used as a solder; eating from lead glazed dishes; consuming vegetables grown in lead contaminated soil; and eating food that has been contaminated by lead that has leached from crystal and plastic food bags. A major source of lead among children is through the consumption of lead-based paint in houses. Although it has been.illegal for more than 50 years to use lead paint in houses, it is estimated that over 40 million homes in the L.S. still contain hazardous quantities of leaded paint. A second major source of lead intake by the general pubiliic is.through inhalation of lead oxide from automobile exhausts and from suspended soil dust. Of the lead in gaso].ine,'approximately 75% is released with the exhaust gases. Of this, about 35% is emitted as a submicrometer- sized aerosol; about 40% is emitted as >10 micrometer sized parti.cles. In 1970, about 190,000 metric tons of lead were released into the atmosphere in the U.S. through the combustion of gasoline. Through prohibition of the use of lead in gasoline, this had been reduced to about 100,000 metric tons in 1979. Today, releases from this source amour.Lt to less than 5,000 metric tons (Figure 1). Lead is considered to be an interesting issue to review for several reasons: 1. There is a multitude of sources through which the population can be exposed. As a result, assessment of exposures is difficult; measurements of doses, whenever practical, is clearly a superior method for estimating potential'health effects. 2. Lead appears to have a range of health effects; these include neurobehavioral effects in children and blood pressure effects in adults. No single mechanism appears sufficient to account for these effects. 3. Conventional animal toxicological studies of lead appear to provide little information about serious human chronic health issues. You'have been provided with a selection of background reports on this topic. Dr. Howard Hu will be here Friday afternoon at 1:15 to discuss this subject in detail. Questions that you may want to consider include:

1. Are there good methods for estimating doses occurring as a result of exposures to lead? In this regard, how useful are measurements of lead levels in blood or in urine? 2. Since each health effect thought to result from exposures to lead may have a different causitive mechanism, might there be a different relation between dose and effect for each? What is the likelihood that any'of the observed health effects from lead will show a linear non-threshold relationship to dose? 3. Whereas lead acetate has been shown to be carcinogenic in animals, this is not the chemical form to which humans are commonly exposed. The carcinogenicity of organic compounds is dependent on the specific chemical compound. Should the same be assumed for lead? 4. Two of the health effects of lead are thought to be a reduction in IQ and an increase in blood pres,sure. In this regard, what are the public health implications of a 4 point reduction in IQ or a 3 point increase in blood pressure? 150 SOURCE CATEGORY ® TRM1SPOftTAnoN ® !N®USTRtAL PROCESS€S ® ~~ N soua w,~ 0 , ,,,. , ........- ,,,,,,,.,,,,- --------- ~ , ; ;, - _-__ _ _ _--„ ~ --- -.-------- ---------- ~__ _~~ , 1979 1980 1981 1982- 1983 1984 1985 1986 1987 1988 Figure 1 Airborne Emissions of Lead in the United States -- 1979 - 1988