Click for next page ( 46


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 45
Est~ates of Dietary Oncogenic Risks INTRODUCTION To provide some perspective on the potential impact of alternative policies for setting tolerances, this chapter assesses the estimated dietary oncogenic risks associated with 28 out of 53 pesticides that the EPA has identified as oncogenic or potentially oncogenic. The purposes of this exercise are to gain a sense of the magnitude and distribution of current dietary risks and crops associated with oncogenic pesticides and to establish an estimate from which to measure the direction and magnitude of changes in dietary risk and pesticide use that could result from different policies for setting tolerances for oncogenic pesticide residues in food. All risk estimates in this report are limited to oncogenic risks from residues of currently registered pesticides in or on food. The study focuses on the potential impact of the Delaney Clause on agricultural innovation and the public's dietary oncogenic risk. Oncogenic risks associated with exposure to residues in drinking water or other sources are not included. The risks of other chronic health effects are not examined. The committee has confined its review to risks from herbi- cides, insecticides, and fungicides that the EPA has found to be oncogenic. Plant growth regulators, rodenticides, and other types of pesticides are not considered. A number of analyses were performed on the selected pesticides. The most important analyses are examinations of the distribution of dietary risks by (1) the type of pesticide (insecticide, herbicide, or fungicide), (2) 45

OCR for page 45
46 REGULATING PESTICIDES IN FOOD type of tolerance (processed versus raw food), (3) crop, and (4) the year in which a tolerance was granted. Each analysis is presented as part of the characterization of estimated oncogenic risk. The committee wishes to make clear that emphasis should not be placed on specific risk estimates associated with particular pesticides, groups of tolerances, or food types. The analysis is subject to a wide range of uncertainty, even though based on state-of-the-art data. In developing these estimates, the committee used data that the EPA provided and followed the agency's risk assessment procedures as closely as possible. Basic questions addressed include How many and what percentage of all pesticides used on food are currently thought by the EPA to be oncogens? How is the risk from these pesticides distributed across crops and among types of pesticides? How is the risk distributed by age of tolerance? What portion of risk is associated with section 408 raw agricultural commodity tolerances in contrast to section 409 processed-food toler- ances? Pesticide Use Patterns in the United States The benefits of pesticide use are not examined in rigorous fashion in this report, nor are they considered in the process of making most decisions on tolerances. The committee lacked the time and resources to perform detailed benefit assessments for all oncogenic pesticides. Instead of benefit analyses, use and sales data are given for various pesticides and crops. This information is presented in terms of the number of acres treated with a pesticide, the pounds applied and annual expenditures. The portion of herbicide and fungicide use accounted for by oncogens is described in Tables 3-1 and 3-2. A more detailed analysis of the benefits associated with oncogenic pesticides used on eight selected crops is presented in the next chapter. To appreciate the potential impact of the Delaney Clause, one should note the percentage of all pesticide use that is accounted for by oncogenic herbicides, insecticides, and fungicides. Approximately 480 million pounds of herbicides are used annually in the United States. Of these, about 300 million pounds are agents that the EPA presumes to be oncogenic or for which positive oncogenicity data are currently under review by the agency (see Table 3-1~. These agents account for about 50 to 60 percent of all expenditures on herbicides in U.S. agriculture. In 1985, these expenditures added up to about $1.4 billion of the $2.7 billion spent on all herbicide products. "Not all oncogenic herbicides are

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 47 TABLE 3-1 Agricultural Use Information for Selected Oncogenic Herbicides All Herbicide Pounds Applied Pounds Applied Herbicidea (millions) (%) Alachlor (Lasso) 85 18 Tr~fluralin (Treflan) 39 8 Metolachlor (Dual) 38 8 Glyphosate (Roundup) 8 8 Linuron (Lorox) 7 1.5 Paraquat (Gramoxone) 2.8 1.5 Oryzalin (Surflan) 1.7 0.6 Acifluorfen (Blazer) 1.4 0.3 Subtotal 182.9 38.2 Atrazineb 79 17 2,4-Db 39 8 Total 300.9 63.3 aThe names of the biggest-selling pesticide brands are listed next to the appropriate chemical compounds to serve as examples in this table and in those following. bThese compounds are not on the list of oncogens the EPA made available to the committee (see the discussion of the Waxman list on pp. 5~51). After this correspondence, however, the EPA received data that show positive results for oncogenicity. The EPA has not officially characterized these compounds as oncogenic, but it is significant for the purposes of this report that they induced tumors when tested on animals. Also, the EPA may classify these compounds as oncogenic in the future. These compounds are not included in any risk estimates contained in this report. SOURCE: U.S. Department of Agriculture, 1984, Inputs: Outlook and Situation Report, No. IDS-6, Washington, D.C.: U.S. Government Printing Once; Gianessi, L. P., 1986, A National Pesticide Usage Data Base, Washington, D.C.: Resources for the Future, photocopy; and unpublished data from the EPA for the years 1981 through 1985. considered in the analyses presented in this report. Specifically, data indicating oncogenicity for the herbicides atrazine and 2,4-D were re- ceived by the EPA after the committee's analysis. These pesticides are included here and in Table 3-1 to indicate the potential impact of the Delaney Clause. Atrazine and 2,4-D are not treated as oncogens for any subsequent analysis presented in this study.) In terms of pounds applied, the percentage of oncogenic insecticides is relatively small. This is primarily because two oncogenic synthetic pyrethroid insecticides, permethrin and cypermethrin, are applied at very low rates per acre. The percentage of all acre treatments by oncogenic insecticides is higher, however. (One acre treatment is defined as one acre to which one pesticide has been applied one time.) Presumed oncogens

OCR for page 45
48 REGULATING PESTICIDES IN FOOD TABLE 3-2 Fungicide Use for 10 Major U.S. Food Commodities Fungicide Use Levela Oncogenic Planted Acres Total Total Oncogenic Acre Treated with Treated Fungicide Expendituresb TreatmentsC Fungicidesa Acresa Expendituresa Crop (%) (%) (%) (million) (million) Potatoes 91 80 55 3.2 16.4 Peanuts 83 85 81 6.6 38.3 Apples 53 59 78 3.2 23.5 Tomatoes 52 49 60 2.6 14.6 Plums, prunes 50 49 48 0.1 1.8 Chemes 49 47 80 0.4 3.8 Peaches 38 37 79 1.0 8.2 Almonds 27 26 78 0.7 11.5 All citrus 17 8 72 2.9 29.0 aThis includes organic and inorganic compounds. bThis is the sales value of oncogenic compounds as a percent of total fungicide sales on that crop. It includes expenditures on inorganic compounds such as copper and sulfur. CThis is expressed as the percentage of total fungicide acre treatments on that crop. It includes acre treatments with inorganic compounds. SOURCE: Webb, S.E.H., 1981, Preliminary Data: Pesticide Use on Selected Deciduous Fruits in the United States, 1978, Economic Research Service Staff Report No. AGES810626, Washington, D.C.: U.S. Department of Agriculture; Parks, J. R., 1983, Pesticide Use on Fall Potatoes in the United States, 1979, Economic Research Service Staff Report No. AGES830113, Washington, D.C.: U.S. Department of Agriculture; Ferguson, W. L., 1984, 1979 Pesticide Use on Vegetables in Five Regions, Springfield, Va.: National Technical Information Service; and unpublished data from the EPA for the years 1981 through 1985. make up between 35 and 50 percent of all insecticide acre treatments and expenditures.2 In comparison, fungicides include the highest percentage of oncogenic compounds. Table 3-2 describes fungicide use on 10 major crops. About 90 percent of all agricultural fungicides show positive results in oncogenicity bioassays. These oncogenic fungicides represent from 70 million to 75 million of the 80 million pounds of all fungicides applied annually in the United States.3 Pesticide Use Data Pesticide use patterns in U.S. agriculture and thus pesticide residues in food are changeable. In any growing season, economic factors can alter which pesticides are used on a given crop in a given area. The price

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 49 of the crop might be up or down, affecting how much growers are willing to spend for a certain amount of pest control. Weather and soil conditions can preclude or command certain treatments. The presence or absence of a given pest affects pesticide use. The emergence of pest resistance to previously applied pesticides can lead to rapid shifts in pesticide use patterns. Government acreage reduction programs and other policies alter crop- and land-use patterns, which thereby affect pesticide use. Pesticide use patterns also vary widely across major crops. Nearly all cultivated cropland in the United States is treated annually with at least one herbicide. About 15 percent of these acres receive a treatment with a fungicide. Some crops do not depend greatly on any pesticide. This is particularly true of improved pasture and hay, small grains, and some orchard crops. Virtually all perishable fresh fruits and vegetables, on the other hand, depend heavily on pesticides. Some are treated a dozen or more times each year with six or more different active ingredients. Farmers spent about $5 billion on pesticides in 1984. These costs represent a little more than 21 percent of farm expenditures for manufac- tured products such as seed, fertilizer, electricity, fuels, and oils. Pesti- cides accounted for only 4 percent of all production costs, however. Hired-labor costs were twice as much as pesticide costs; interest on debt and depreciation costs were five times as much.4 Problems in Estimating Current Risk The analytical methods involved in estimating oncogenic risks from pesticide residues in food presume resolution of complex technical and policy issues. The risk assessment methodology currently used by the EPA is guided by a set of standard procedures. These procedures are modified on an ad hoc basis when the situation warrants. In each analysis, the committee adopted what it understood to be the EPA's current methodology. The committee recognizes, however, that many key ele- ments of the agency's risk assessment procedures are under review.5 Choosing one set of assumptions can have profound implications for the resulting estimates. For example, depending on how the agency establishes average expected residue levels in food, the calculation of exposure to pesticide residues in a given foodstuff can yield risk estimates that vary by orders of magnitude. Assumptions of how and when to aggregate risks from a pesticide used on a variety of crops will also influence risk estimates. A pesticide's oncogenicity potency factor, called a Q star or Q* (see the boxed article "The 'Q Star' " on pp. 54-55), can also vary by orders of magnitude. This variation depends on such factors as whether a surface area or body weight correction is made in extrapo-

OCR for page 45
50 REGULATING PESTICIDES IN FOOD rating risks from rodents to humans, whether malignant and benign tumors are combined, and what extrapolation model is used. The EPA generally follows a conservative policy in estimating risk. The agency tries to make necessary assumptions in a way that minimizes the chance of underestimating risks. The result is that these risk estimates probably overstate true oncogenic risk. The substitution of more refined information on exposure to residues, or the potency of the oncogen at low doses, could alter risk estimates substantially. This report only notes the importance of these assumptions and underlying issues; it does not offer guidance on how to solve the problems associated with them. The EPA provided all the data used to establish the committee's estimates of current dietary risk. The committee made no adjustments in the EPA's data. In certain cases, the committee used the data in new analyses to understand the theoretical impact of different regulatory standards and methods of calculating risks and benefits. Although estimated oncogenic risks generally are presented in a quan- titative fashion, a wide margin of uncertainty surrounds nearly all of the numbers. With this in mind, the reader should focus on general patterns of risk distribution and how key parameters change when policy alterna- tives are assessed in Chapter 4, not on specific point estimates of risk. DESCRIPTION OF THE DATA BASE AND THE ANALYTICAL METHOD An estimate of a chemical's oncogenic potential generally is derived from the results of chronic feeding bioassays, which typically involve rats or mice. The committee was not charged with the task, nor did it have the expertise or resources, to review the EPA's toxicological data for the purpose of making case-by-case determinations of oncogenic potential. For this analysis, the committee adopted the list of 53 pesticides that the EPA preliminarily has determined to have oncogenic potential. The EPA transmitted this list to Congressman Henry Waxman on October 21, 1985. The pesticides on the list are presented in Table 3-3. As the EPA receives and analyzes additional oncogenicity data, some active ingredients on the list may be removed and others added. The committee did not guess how many currently untested pesticides will be oncogenic. Although more oncogenic pesticides will be found, the committee cannot say which ones or how many. In this report, pesticides that the EPA has characterized as suspect oncogens are treated as oncogens, even though a final judgment on oncogenicity may not have been reached on the basis of available data. This approach parallels EPA policy. Once the EPA determines that a pesticide has oncogenic potential, even on a preliminary basis, the

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 5 ~ pesticide is treated as an oncogen for regulatory purposes.6 For consis- tency in the following chapters, the committee treats all chemicals on the Waxman list as oncogenic compounds. In such cases the EPA usually does not approve new food tolerances for these pesticides until a thorough risk/benefit assessment of all current uses is completed The Universe of Oncogenic Pesticides In Chapter 2, the committee discussed some of the uncertainties surrounding the determination of a pesticide's potential to induce cancer. Of the 289 pesticides identified for this study as the universe of pesticides used on foods, the EPA found 53 active ingredients oncogenic or potentially oncogenic. This figure represents about 18 percent of all pesticides used on foods. Unfortunately, the data supporting many of these pesticides are incomplete. For some, particularly certain insecti- cides, most registered uses on foods have been canceled. The committee did not assess the quality or completeness of the oncogenicity data supporting these 289 pesticides. The EPA's registration standards program is designed for this purpose, however. Data supporting 115 pesticides registered for use on foods, most of which were registered before 1980, have been assessed under the program. (New active ingre- dient registrations generally require two valid oncogenicity studies and are rarely subject to a registration standard.) Of the 115 older pesticides, only 23 percent fully satisfied the oncogenicity data requirement; 41 percent had some oncogenicity data on file but did not fully satisfy the EPA's current oncogenicity data requirements; and 36 percent had no adequate oncogenicity data on file. Oncogenic risk is estimated by multiplying human exposure to pesti- cides by the Q*. The agency supplied the committee with potency factors for 30 of the 53 oncogenic pesticides currently used on food. The committee used 28 of these potency factors in generating the estimates of oncogenic risk. The number and percentage of oncogenic pesticides with available potency factors are shown in Table 3-4. Two chemicals for which the EPA has calculated potency factors, daminozide and asulam, are excluded from the committee's analysis. Daminozide, a plant growth regulator, is not characterized as a herbicide, insecticide, or fungicide; asulam has no food tolerances. The Q~'s and the food consumption and tolerance information in the EPA's Tolerance Assessment System (TAS) form the principal components of the risk calculations in this report. Table 3-4 illustrates that the committee derived its risk estimates from a roughly equivalent percentage of currently used oncogenic insecticides, fungicides, and herbicides. The portion of oncogenic active ingredients analyzed ranges from 63 percent for insecticides to 79 percent for

OCR for page 45
52 REGULATING PESTICIDES IN FOOD TABLE 3-3 Potentially Oncogenic Pesticides Identified by the EPA Year First Volume of Use Active Ingredient Tolerance (pounds active Major Crop (common/trade name) Granted Type ingredient/year)a Uses Acephateb (Orthene) 1972 Insecticide 1,900,000 Citrus Acifluorfen (Blazer) 1980 Herbicide 1,400,000 Soybeans Alachlorb (Lasso) 1969 Herbicide 85,000,000 Corn, soybeans Amitraz (Beam) 1968 Insecticide 50,000 Cattle Arsenic acid NA Herbicide NA Cotton Asulam 1975 Herbicide NA Sugar cane Azinphos-methylb 1956 Insecticide 2,500,000 Peaches, pome (Guthion) fruits Benomylb (Benlate) 1972 Fungicide 2,000,000 Citrus, rice, soybeans, stone fruits Calcium arsenate NA Insecticide NA Stone fruits Captafolb (Difolatan) 1959 Fungicide 6,000,000 Apples, cherries, tomatoes Captanb 1955 Fungicide 10,000,000 Almonds, apples, peaches, seeds Chlordimeformb 1968 Insecticide NA Cotton (Galecron) Chlorobenzilate 1956 Insecticide/ 1,500,000 Citrus acaricide Chlorothalonilb 1961 Fungicide 6,000,000 Fruits, peanuts, (Bravo) vegetables Copper arsenate 1971 Insecticide NA Vegetable crops Cypermethrinb 1984 Insecticide 600,000 Cotton (Ammo, Cymbush) ~ , , . Cyromazine~ 1984 Insecticide NA Poultry (Larvadex) Daminozide (Alar) 1967 Growth 875,000 Apples, peanuts regulator Diallate 1969 Herbicide 500,000 Sugar beets Diclofop methylb 1980 Herbicide 1,200,000 Soybeans (Hoelon) Dicofol (Kelthane) 1955 Insecticide/ 2,500,000 Citrus, cotton acaricide Ethalfluralinb 1982 Herbicide NA Soybeans (Sonalan) Ethylene oxide NA Bactericide NA Spices, walnuts Folpetb 1955 Fungicide 1,500,000 Cherries, fruits, vegetables Fosetyl Alb (Aliette) 1983 Fungicide NA Pineapples Glyphosateb 1976 Herbicide 8,000,000 Hays, orchard (Roundup) crops Lead arsenate 1955 Insecticide NA Apples, orchard crops Lindane 1955 Insecticide 200,000 Avocados, pecans Linuronb (Lorox) 1966 Herbicide 7,000,000 Soybeans Maleic hydrazide 1955 Growth 300,000 Onions, potatoes regulator Mancozebb 1962 Fungicide 16,000,000 Fruits, small (Dithane M-45) grains, vegetables

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 53 TABLE 3-3 Continued Year First Volume of Use Active Ingredient Tolerance (pounds active Major Crop (common/trade name) Granted Type ingredient/year)a Uses Manebb 1957 Fungicide 10,000,000 Fruits, small grains, vegetables Methanearsonic acid NA Herbicide 4,000,000 Cotton Methomyl (Lannate) 1963 Insecticide 4,500,000 Citrus, cotton, vegetables Metiramb 1967 Fungicide 1,000,000 Fruits, small grains, vegetables Metolachlorb (Dual) 1976 Herbicide 38,100,000 Corn, soybeans O-Phenylphenolb 1955 Fungicide 200,000 Citrus, orchard crops Oryzalinb (Surflan) 1974 Herbicide 1,700,000 Soybeans, vineyards Oxadiazonb (Ronstar) 1977 Herbicide NA Rice Paraquat 1961 Herbicide 2,800,000 Rice, soybeans ( G ram ox o ne ) Parathionb 1955 Insecticide 7,000,000 Citrus, cotton PCNB 1955 Fungicide 2,500,000 Cotton, peanuts, vegetables Permethrinb 1978 Insecticide 500,000 Vegetables (Ambush, Pounce) Pronamideb (Kerb) 1972 Herbicide 100,000 Lettuce Sodium arsenate NA Insecticide NA Pears Sodium arsenite NA Fungicide, NA Grapes herbicide, insecticide Terbutrynb 1959 Herbicide 600,000 Barley, wheat Tetrachlorvinphos 1969 Insecticide NA Cattle, poultry Thiodicarb (Larvin) 1985 Insecticide NA Cotton, soybeans Thiophanate-methyl 1972 Fungicide 30,000 Fruits, nuts, vegetables Toxaphene 1955 Insecticide NA Cattle Trifluralin (Treflan) 1963 Herbicide 39,000,000 Soybeans Zinebb 1955 Fungicide 3,500,000 Fruits, small gra~ns, vegetables aWebb, S.E.H., 1981, Preliminary Data: Pesticide Use on Selected Deciduous Fruits in the United States, 1978, Economic Research Service Staff Report No. AGES810626, Washington, D.C.: U.S. Department of Agriculture; Parks, J. R., 1983, Pesticide Use on Fall Potatoes in the United States, 1979, Economic Research Service Staff Report No. AGES830113, Washington, D.C.: U.S. Department of Agriculture; Ferguson, W. L., 1984, 1979 Pesticide Use on Vegetables in Five Regions, Springfield, Va.: National Technical Information Service; Gianessi, L. P., 1986, A National Pesticide Usage Data Base, Resources for the Future, Washington, D.C., photocopy; and unpublished data from the EPA for the years 1981 through 1985, excluding 1983, for crops affected by PIK. bThese are compounds for which risk estimates were performed.

OCR for page 45
54 REGULATING PESTICIDES IN FOOD The "Q Star" A pesticide's oncogenic potency is expressed quantitatively as a "Q star" or Q*. The Q* is the slope of the dose response curve from animal tests yielding a positive oncogenic response. The slope represents the change in tumor incidence (YJ over the change in dose (X). The units of the potency factor are tumors/mg of pesticide/kg of body weight/clay. The Q* represents the estimated tumor incidence expected to occur at the relatively low doses of pesticides in the human diet. It is based on a purely mathematical extrapolation of tumor incidence observed at the high doses used in animal tests. The potency factor does not consider the type, site, or diversity of tumors observed in animal tests. In most cases, however, the potency factors used by the EPA express a combination of malignant and benign tumors. A high Q* indicates a strong oncogenic response (more tumors) to the administered dose; a low number indicates a weak response. Most Q*'s that the committee obtained from the EPA are average Q* calculations derived from several positive oncogenicity stuclies. These Q*'s were calculated by EPA scientists and have not been formally peer reviewed. The Q* is considered a conservative or risk-averse model for quanti- fying oncogenic potency. As such, it represents the 95 percent upper- bounri confidence limit (UCL) of tumor induction likely to occur from a given close. On the other hand, the maximum likelihood estimate (MLE) represents the average probability for tumor induction from a given dose. Oncogenic potency factors derived by the two methods are similar in many cases. In some cases, however, the factors differ by several orders of magnitude, with the Q* calculation generally characterizing a com- pound as more potent. The EPA relies on the Q* at the 95 percent UCL in risk assessment to provide a margin of safety for uncertainties in characterizing the oncogenic response, for the existence of more sensitive individuals in the exposed population, and for possible synergism of pesticides and metabol ites. The committee relied solely on the Q* in estimating oncogenic potential. Therefore, the estimated oncogenic risks for certain pesticides may appear overstated. More sophisticated judgments of the human risk from dietary exposure to oncogenic agents consider qualitative evidence. This evidence includes the type of tumors produced and whether they are malignant or benign, have metastasized, or are evident in more than one sex and animal species. Such a judgment would entail a "weight-of-the- evidence" approach to risk assessment, which the EPA relies upon in regulatory decision making. The EPA's weight-of-the-evidence classifica- tion system for carcinogens is explained in the boxed article "The EPA's

OCR for page 45
ESTIMATES OF DIETARY ONCOGENIC RISKS 55 Classification System for Carcinogens," on p. 67. In Tables 3-9 and 3-17 through 3-19, risk estimates are presented with the EPA's classification of the qualitative weight of the evidence. 1 Quantitative Oncogenic Potency Factors (Q*) for Each Active Ingredient Designated by the EPA as Oncogenic Active Ingredient (trade name) Q* Chlordimeform (Fundal, Galecron) 9.4 x 10-i Linuron (Lorox) 3.28 x 10-, Oxadiazon (Ronstar) 1.3 x 10-, Ethalfluralin (Sonalan) 8.7 x 10-2 Alachlor (Lasso) 5.95 x 10 2 Oryzalin (Surflan) 3.4 x 10-2 Permethrin (Ambush, Pounce) 3.0 x 10-2 Captafol (Difolatan) 2.50 x 10-2 Chlorothalonil (Bravo) 2.4 x 10-2 Asulam 2.0 x 10 2 Cypermethrin (Ammo, Cymbush) 1.9 x 10-2 Mancozeb(Dithane M-45) 1.76 x 10 2 Maneb 1.76 x 10-2 Metiram 1.76 x 10 2 Zineb 1.76 x 10-2 Pronamide(Kerb) 1.6 x 10-2 Diclofop methyl (Hoelon) 1.1 x 10-2 Acephate (Orthene) 6.9 x 10-3 Fosetyl Al (Aliette) 4.3 x 10 3 Folpet 3.5 x 10-3 Cyromazine (Larvadex) 2.4 x 10-3 Captan 2.30 x 10-3 Metolachlor(Dual) 2.10 x 10-3 Benomyl (Benlate) 2.065 x 10-3 Terbutryn 1.87 x 10-3 Parathion 1.80 x 10-3 O-Phenylphenol 1.57 x 10-3 Glyphosate (Roundup) 5.9 x 10-5 Azinphos-methyl (Guthion) 1.5 x 10-7 fungicides. The committee received Q*'s for only 7 of 19 oncogenic insecticides. Therefore, it initially appears that the committee examined a disproportionately small number of insecticides. Conclusions regarding relative risk distribution would thus appear to be significantly influenced by the unevenness of the sample. When the sample is adjusted to account for compounds with significant use cancellation, however, the results appear more even. The situation with insecticides is unique because many oncogenic

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 89 TABLE 3-30 Pesticide Active Ingredients Under Review for Which the Delaney Clause Has Been a Concern Estimated Major Uses and Oncogenic Volume of Usea Pesticide Pesticide Type Risk (pounds AI/year) Special Review Alachlor (Lasso) Corn, soybean herbicide 2.42 x 10-5 85,100,000 Dicofol (Kelthane) Citrus, cotton acaricide/ No risk assess- 1,200,000 insecticide ment per- formed Captan Fruit, vegetable fungicide 4.74 x 10-4 1O,OOO,OOO Daminozide (Alar) Select fruit, vegetable 8.30 x 10-3 825,000 growth regulator Benomyl (Benlate) Registration Standards Multiple-use systemic 1.13 x 10-4 2,000,000 fungicide EBDCs(mancozeb, Group of four widely 1.11 x 10-3 28,000,000 maneb, metiram, used fruit and zineb) vegetable fungicides Chlorobenzilate Citrus acaracide No risk assess- 1,600,000 ment per- formed Metolachlor (Dual) Corn, soybean herbicide 1.44 x 10-6 38,000,000 Oryzalin (Surflan) Citrus, field crop herbi- 1.14 x 10-5 1,600,000 cide Thiophanate-methyl Fruit, vegetable fungicide No risk assess- 28,000 (Topsin M) ment per- formed NOTE: These risk estimates are derived using EPA data and methods described on pages 50 66 and in Appendix B. aThe pounds active ingredient/year are averaged from selected years and are derived from Webb, S.E.H., 1981, 'preliminary Data: Pesticide Use on Selected Deciduous Fruits in the United States, 1978," Economic Research Service Stad Report No. AGES810626, Washington, D.C.: U.S. Department of Agriculture; Ferguson, W.L., 1984, "1979 Pesticide Use on Vegetables in Five Regions," Springfield, Va.: National Technical Information Service; Parks, J. R., 1983, "Pesticide Use on Fall Potatoes in the United States, 1979," Economic Research Service Staff Report No. AGES830113, Washington, D.C.: U.S. Department of AgIiculture; Gianessi, L. P., 1986, "A National Pesticide Usage Data Base," Washington, D.C.: Resources for the Future, photocopy; and unpublished data from the EPA for the years 1981 through 1985. The agency's policy in recent years of not approving tolerances for oncogenic active ingredients that concentrate in processed foods is amply demonstrated in Table 3-30. The EPA has denied all applications for section 409 tolerances since 1978 that involve oncogenic active ingredi- ents, including at least one active ingredient with very small estimated risk (10-~.

OCR for page 45
90 REGULATING PESTICIDES IN FOOD Another important conclusion can be drawn from Table 3-29. In at least three cases involving old and new ingredients, the EPA granted new tolerances when it determined that oncogenic potential came from an impurity, metabolite, or contaminant of the parent active ingredient (dicamba, cyromazine, and thiodicarb). In these cases, the EPA relied on the FDA's interpretations of the Delaney Clause. From these cases, it is clear that the EPA will consider applying, in appropriate cases, the FDA's constituents policy and sensitivity-of-the-method procedures in granting food- and feed-additive tolerances for oncogenic pesticides. (For a more detailed discussion, see Chapter 2.) The estimated additional risk sanctioned by these EPA tolerances for dicamba, cyromazine, and thiodicarb is far less than the estimated risk associated with tolerances that have been denied. These include permethrin tolerances on tomatoes and amitraz tolerances on apples. Risks allowed are on the order of 1 x 10-8 or less. Tolerances denied had risks between 1 x 10-4 and 1 x 10-~. The agency also gave the committee a list of 10 active ingredients for which it suspects that manufacturer or registrant concern about the impact of the Delaney Clause significantly influenced the content of tolerance applications (see Table 3-311. In each case, the agency is aware of section 408 and section 409 tolerance petitions that a registrant withdrew or declined to file because of concerns about the Delaney Clause. The committee believes that the Delaney Clause has been more influential than this table reveals. Once a pesticide is determined to be oncogenic, most registrants withdraw or do not submit petitions for section 409 tolerances. One reason is that tolerance petitions must be accompanied by a fee that must be paid regardless of the agency's decision. Companies will often attempt to obtain registrations, however, when they regard evidence of oncogenicity as equivocal or believe that the oncogenic risks are very low TABLE 3-31 Pesticides with Retracted or Unpursued Tolerance Applications Amitraz (Bamm) Benomyl (Benlate) Captan Cypermethrin (Ammo, Cymbush) EBDCs (mancozeb, maneb, metiram, zineb) Fosetyl Al (Aliette) Metolachlor (Dual) Permethrin (Pounce, Ambush) Vinclozolin (Ronilan) NOTE: In these cases, the EPA believes the petitioners either retracted or failed to pursue applications for tolerances under section 408 or 409 because of potential problems from the Delaney Clause.

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 9 ~ and the use proposed may fall within an exception to the Delaney Clause. Another strategy is to change a pesticide's use pattern in a way that keeps residues below the level detectable on raw agricultural commodities (see Appendix E). CASE STUDIES OF POTENTIAL POLICY PRECEDENTS Tolerances for New Active Ingredients Recent reports have criticized the EPA for not articulating a clear policy for application of the Delaney Clause in the tolerance-setting and reassessment process. ]2 In fact, the need for such a policy was the reason the EPA initated this project. Even in cases when the EPA has applied the constituents policy or the sensitivity-of-the-method procedure, it has stressed that such action does not represent a formal change in policy. The agency has defended its authority to use these options on a case-by- case basis until a more definitive policy is adopted. In this section, recent agency actions are analyzed to determine what patterns emerge from the EPA's application of the Delaney Clause in the tolerance process. First, the application of the Delaney Clause to new pesticides and pesticide uses seems clear-cut. New section 409 tolerances are not approved for clearly oncogenic pesticides. New section 408 tolerances are not approved for crops routinely processed into food forms in which oncogenic residues are expected to concentrate. The agency is willing to approve new tolerances for very low risk oncogens if there is a reasonable basis for doing so within FDA precedents, however. The greatest area of uncertainty is how the EPA will proceed in cases involving currently registered pesticides that have been found to be oncogens and have several existing section 409 tolerances or are shown to need these tolerances as residue chemistry data requirements are satis- fied. The committee finds no convincing legal or scientific basis for the EPA, as it completes the special review and reregistration processes, to avoid applying the standards of section 409, including the Delaney Clause, to currently registered compounds. Prior-Sanctioned Pesticides The prior-sanction exception to the Food Additives Amendment of the FDC Act would arguably render the Delaney Clause inapplicable to any pesticide residue in processed foods approved before 1958. (The FDC Act's definition of a food additive excludes substances regulated as food additives before 1958 from the food additive amendments of 1958, including the Delaney Clause.) Because of this, some pesticide residues

OCR for page 45
92 REGULATING PESTICIDES IN FOOD could technically escape the current requirements for food additives (including the Delaney Clause) if it could be shown that the FDA or the USDA sanctioned these residues before 1958. The committee briefly attempted to determine the number of pre-1958 tolerances to which the prior-sanction exception might apply. The com- mittee could find no tolerances issued between 1954 and 1958 that could be described as food-additive tolerances by current standards. Neverthe- less, such tolerances may have been issued and there may have been earlier approvals of residue-producing uses of agents still in use. The committee believes, however, that the number of prior-sanctioned resi- dues that might technically escape the strict standards of the food- additive regulation is quite small. Even when the prior-sanction exception might be invoked to preserve a tolerance, the committee can discern no health or scientific basis for treating residues sanctioned before 1958 differently from those sanctioned after 1958. The following review of seven case studies sheds some light on how the agency may resolve the issues surrounding Delaney Clause applications. Tolerance Actions and New Active Ingredients FOSETYL AL Fosetyl Al is a systemic organophosphorous fungicide used to control downy mildew and other diseases. It is currently widely used in Europe. In this country, the only registered use of fosetyl Al is on pineapples. The registrant, Rhone-Poulenc, in 1983 applied for tolerances for fosetyl Al on hops. Fosetyl Al residues were determined to concentrate during the drying of hops, and it has demonstrated weak but positive oncogenic effects in animals. Therefore, the EPA cited the Delaney Clause in denying section 408 and section 409 tolerances for residues in or on hops. Significantly, the risk presented by fosetyl Al residues in hops would have been far less than the risk from fungicides currently used on hops. According to the EPA, the additional risk presented by fosetyl Al residues on hops would have been 1 x 10-8, or 1 in 100 million or less. This risk is several orders of magnitude less than the estimated risk from ethylenebisdithiocarbamate (EBDC) fungicide residues widely used on hops, which is between 1 x 10-4 and 1 x 10-s. PERMETHRIN Permethrin is a widely used synthetic pyrethroid insecticide. In setting tolerances for permethrin, the EPA granted a section 408 tolerance for the fresh-market portion of tomato crops, but denied section 409 tolerances

OCR for page 45
ESTIMATES OF DIETARY ONCOGENIC RISKS 93 for the processed portion. This was the first time the EPA had set a tolerance for an oncogenic pesticide only on the raw portion of a crop with the knowledge that this pesticide's residues concentrate during processing. The EPA's general policy is to deny a raw agricultural tolerance for an oncogen when a section 409 tolerance is also needed. The agency departed from this policy in approving the use of permethrin on fresh tomatoes grown in Florida, because 98 percent of the Florida tomato crop is produced for the fresh market. In this case the agency was prepared to consider fresh tomatoes from Florida a distinct crop from processed tomatoes grown elsewhere. No tolerances for the use of permethrin on tomatoes grown outside Florida have been granted. Under the terms of the EPA's approval, surplus Florida tomatoes may not be processed. The agency has not drawn similar distinctions for other pesticides or tolerance applications. This may be because providing proof that a crop would be sold exclusively through the fresh market would be very difficult. Section 408 tolerances granted for the use of permethrin on corn and soybeans provide other insights. In these cases, the agency initially denied petitions for section 408 and section 409 tolerances because of residue concentrations in processed soybean and corn products. After further testing, the agency granted section 408 tolerances based on proposed changes in the label directions designed to reduce residues in the raw form of the crop below a level detectable by widely accepted analytical methods. The key change was extension of the time between application and harvest, allowing residues to degrade below detection levels by harvest. With residues theoretically eliminated from the raw commodity, the issue of concentration in the processed foods was moot. THIODICARB Thiodicarb is a newly registered carbamate insecticide, effective on a range of insect pests. Thiodicarb itself is not oncogenic. A metabolite of thiodicarb, acetamide, is oncogenic when administered to test animals at relatively high doses (12,500 to 80,000 ppm). Animals fed treated crops metabolize thiodicarb residues into acetamide. Residues of acetamide are then present in minute amounts in animal products. For example, 1.8 parts per billion (ppb) are present in beef liver, assuming that thiodicarb residues are at the tolerance level and that all feed is treated. In issuing section 409 feed-additive tolerances for thiodicarb, the EPA adopted the FDA's sensitivity-of-the-method procedure. This interpreta- tion requires the applicant for a feed-additive tolerance for an oncogenic substance to prove that the risk to humans from eating animals fed treated

OCR for page 45
94 REGULATING PESTICIDES IN FOOD feed is less than 1 in 1 million or 1 x 10-6. (See Chapter 2 and the thiodicarb case study in Appendix C for further examination of these issues.) On the basis of EPA calculations, meat and poulty could contain up to 90 ppb of acetamide and the risk would be below 10-6; milk and eggs could contain up to 30 and 90 ppb, respectively. Expected residues in meat and poultry, milk, and eggs were 1.8, 0.3, and 0.07 ppb, respec- tively, resulting in risk far less than 10-6. In every case, even at the highest allowable levels, the risk from acetamide in food as a result of thiodicarb use is well below the 10-6 standard. For purposes of the committee's work, it is noteworthy that the risks involved here were insufficient to trigger a special review of thiodicarb. As stated by the EPA in the final rule: There are no regulatory actions pending against the registration of thiodicarb. On the basis of the available studies on acetamide and the chronic oncogenicity studies for thiodicarb, the agency has concluded that the human risks posed by the use of thiodicarb on cotton and soybeans does [sic] not raise prudent concerns of unreasonable adverse effects and that a special review under 40 CFR 162.11 is not warranted. (Federal Register 50(No. 128~: 27464) In the agency's opinion, the regulatory actions surrounding thiodicarb arise entirely from the Delaney Clause and concern the issuance of tolerances, not the granting of product registration. In the absence of the Delaney Clause, therefore, the risk associated with thiodicarb tolerances would not have warranted agency review. D~cAMsA Dicamba is a broadleaf herbicide widely used in the production of soybeans, corn, and other row and field crops. Studies submitted to the EPA do not show dicamba as oncogenic. However, studies have shown a contaminant of dicamba, dimethylnitrosamine (DMNA), to be an animal oncogen. The EPA relied on the FDA's constituents policy in granting section 409 tolerances for dicamba residues in or on sugarcane molasses. The FDA articulated its constituents policy in the April 2, 1982 Federal Register (bracketed phrases are added to describe how the EPA applied the constituents policy to dicamba): "The constituents policy states that the safety of any undesired tin this case oncogenic] nonfunctional constituents tin non-oncogenic substances] should be judged under the general safety clause of the FDC Act Enot the Delaney Clausel, using risk assessment as one of the decision-making tools." The FDA has interpreted the general safety clause of the FDC Act as allowing an additional risk no greater than 1 x 10-6. The EPA assessed

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 95 the additional risk from exposure to DMNA in sugarcane molasses as no greater than 2.9 x 10-~. Accordingly, the agency approved section 409 tolerances. The EPA explained its policy as follows: EPA does not regard deliberately added active or inert ingredients, or metabolites thereof, as potential candidates for clearance under the constitutents policy rationale. Rather, EPA will only consider applying this rationale to impurities arising from the manufacture of the pesticide (residual reactants, intermediates, and products of side reactions and chemical degradates). Furthermore the Agency will consider using this rationale in issuing a food additive regulation only where the potential risk from the impurity is extremely lowed (The Federal Register notice did not define low potential risk. The FDA criteria, however, is 1 x 10-6.) Tolerance Actions and Old Active Ingredients DICOFOL AND CHLOROBENZILATE Dicofol and chlorobenzilate are insecticides, acaricides, and miticides registered before the creation of the EPA in 1970. They are widely used in citrus production. Dicofol is also extensively used on cotton. Both compounds have demonstrated oncogenic effects in animal experiments. The agency has scrutinized each for several years. Residues of both pesticides at concentrated levels have been found in food products, primarily citrus oil. The EPA has not altered the citrus tolerance for either chemical, however, because it believes that the oncogenic potential of the pesticides is so weak, and citrus oil is consumed in such small quantities, that a quantitative assessment of the oncogenic risk from consumption of citrus oil cannot be supported by the available data. In essence, the agency has chosen to defer action on these tolerances indefinitely. These cases suggest that there is a de minimis risk standard below which the agency will not calculate risks. BENOMYL Benomyl is the most widely used systemic fungicide in the world. It is important because its existing section 409 tolerances will probably be the first to force an EPA decision on retroactive application of the Delaney Clause. Benomyl is one of the most extensively studied pesticides in use. It has been through the EPA's special review process and then through its registration standards procedure. The data supporting its current regis- trations are generally of high quality. The registrant and the EPA agree that benomyl causes an oncogenic response in animal experiments, and that it concentrates in certain processed foods. It appears that existing

OCR for page 45
96 REGUrATING PESTICIDES IN FOOD TABLE 3-32 Number of Cancer Studies Due for Pesticide Active Ingredients, 198~1990 Chronic Year Oncogenicity Feeding Total 1986 10 5 15 1987 27 16 43 1988 21 17 38 1989 24 28 52 1990 3 3 6 Total 85 69 154 SOURCE: U.S. Environmental Protection Agency. 1986. Data Generation Schedule Status Report. Washington, D.C. section 409 tolerances for benomyl violate the Delaney Clause. The agency has deferred action on these tolerances pending public comment on the benomyl registration standard, recently invited by notice in the Federal Register. The resolution of the benomyl issue could provide a basis for agency actions in the future. The impact of tolerance revocations for benomyl and other oncogenic active ingredients included in the committee's risk estimates is projected in the next section and discussed in further detail in Chapter 5. PROJECTING PAST ACTIONS INTO THE FUTURE Over the next five years, the EPA will receive new data on the oncogenicity of many agriculturally important chemicals through the data call-in, special review, and registration standards programs. The ap- proaches the EPA devises for reassessing tolerances in light of the Delaney Clause will have a tremendous impact on how these new data are evaluated and incorporated into the pesticide reregistration process.~4 Table 3-32 shows an approximate schedule for the submission of new chronic feeding and oncogenicity bioassay results for major food-crop pesticides in response to data call-in letters issued from 1982 to 1986. From 1987 through 1989, the EPA should receive about 40 to 50 new tests each year. In completing the call-in, the EPA gave priority to data on chronic health effects. It has requested relatively few new residue concentration studies. The agency has recently begun to seriously evaluate the com- plexity and cost of modernizing residue chemistry data. It is already clear

OCR for page 45
ESTIMATES OF DIETAR Y ONCOGENIC RISKS 97 that the costs can be sizable. They may exceed the cost of a complete new chronic toxicology data base for active ingredients used on many foods. THE SHORT-TERM POTENTIAL IMPACT OF THE DELANEY CLAUSE Tables 3-33 and 3-34 show the approximate dates the EPA is expected to have enough information to compel decisions on certain pesticide am. ... ~ r ~ ~~ = ~ Jo ~ ~ tolerances. the committee s criteria for ~nc~ua~ng spec~nc compounds on these lists are that the pesticides are oncogenic compounds used on foods for which a special review and a registration standard will be complete by the date listed.~5 The committee's analysis supports several important conclusions. First, the EPA will soon be faced with several significant decisions regarding section 409 tolerances for oncogenic pesticides. These deci- ~ions involve commercially important chemicals, which present sizable estimated risks. Second, the estimated dietary risk associated with these pesticides represents approximately 85 percent of all estimated dietary oncogenic pesticide risks. Third, agency actions could have the greatest impact on fungicide use and on associated dietary risk. Over the next three years the EPA is scheduled to make decisions on active ingredients that account for about 85 percent of fungicide use. Fourth, most fungi- -~.~ - ~ ~^~ ^~ a ----or TABLE 3-33 Potential Short-Term Impact of the Delaney Clause on Selected Fungicides Fungicide Possible Market Date for Estimated Risk on Commodities Share Active Tolerance (% acre Ingredient Revocation Action Raw Processed Total treatments) Benomyl 1986 Rsa 3.42 x 10-5 7.91 x 10-5 1.13 x 10-4 15 EBDCs 35 Mancozeb 1987 RS 2.43 x 10-4 9.44 x 10-5 3.38 x 10-4 Maneb 1987 RS 3.90 x 10-4 5.22 x 10-5 4.42 x 10-4 Metiram 1987 RS 7.65 x 10-5 3.91 x 10-5 1.15 x 10-4 Zineb 1987 RS 4.71 x 10-4 2.45 x 10-4 7.17 x 10-4 Captafol 1987 sRb 4.34 x 10-4 1.59 x 10-4 5.94 x 10-4 5 Folpet 1987 RS 1.81 x 10-4 1.43 x 10-4 3.24 x 10-4 5 Captan 1988 SR 2.80 x 10-4 1.93 x 10-4 4.74 x 10-4 15 Chlorothalonil 1988 SR 1.89 x 10-4 4.82 x 10-5 2.37 x 10-4 10 NOTE: These risk estimates are derived using EPA data and methods described on pages 50-66 and in Appendix B. aRS is registration standard. bSR is special review.

OCR for page 45
9~3 REGULATING PESTICIDES IN FOOD TABLE 3-34 Potential Short-Term Impact of the Delaney Clause on Selected Herbicides Possible Date for Estimated Risk on Commodities Active Tolerance Ingredient Revocation Action Raw Processed Total Herbicide Market Share (pro pounds applied) Pronamide 1986 (Kerb) Terbutryn 1986 Trifluralin 1986 (Treflan) Paraquat 1986 Alachlor (Lasso) Linuron (Lorox) 1986 1987 Rsa 7.14 x 10-6 6.28 x 10-7 7.77 x 10-6 RS RS RS SR <1 2.86 x 10-' No risk assessment conducted 2.86 x 10-7 <1 8 No risk assessment conducted 1.36 x 10-5 1.06 x 10-5 2.42 x 10-5 18 1.12 x 10-3 3.96 x 10-4 1.52 x 10-3 <1 NOTE: These risk estimates are derived using EPA data and methods described on pages 50-66 and in Appendix B. aRS is registration standard. bSR is special review. cides have few section 409 tolerances; some will have to be granted if certain uses on food crops are to continue. The EPA faces an especially difficult challenge with the fungicides. To guarantee that its regulatory actions actually reduce real risks, the agency must carefully assess all fungicides registered for each crop and base its actions on reducing risk after predictable substitutions have been made. One principle should guide the EPA's actions to reduce dietary oncogenic risks. It should focus its efforts on all oncogenic pesticides used on the most widely consumed crops that in turn present the greatest dietary risk. NOTES 1. National Agricultural Chemical Association. 1986. Industry Profile Survey: 1985 Washington, D.C. 2. Gianessi, L. P. 1986. A National Pesticide Usage Data Base. Washington, D.C.: Resources for the Future. 3. Ballard, G., W. Cummings, M. Luther, and N. Pelletier. 1980. Fungicides: An Overview of Their Significance to Agriculture and Their Pesticide Regulatory Implications. Washington, D.C.: U.S. Environmental Protection Agency. 4. U.S. Department of Agriculture. 1985. Economic Indicators of the Farm Sector: Farm Sector Review, 1984. ECIFS 4-2. Washington, D.C.: U.S. Government Printing Office. 5. U.S. Environmental Protection Agency. 1986. Guidelines for Carcinogenic Risk As- sessment. Federal Register 51(185): 33992-34003. 6. Paynter, O. E. 1984. Standard Evaluation Procedures for Oncogenicity Potential:

OCR for page 45
ESTIMATES OF DIETARY ONCOGENIC RISKS 99 Guidance for Analysis and Evaluation of Long-term Rodent Studies. Washington, D.C.: U.S. Environmental Protection Agency. 7. U.S. Environmental Protection Agency. 1985. Captan Special Review Position Docu- ment 2/3. Washington, D.C. 8. U.S. General Accounting Office. October 1986. Pesticides: Need to Enhance FDA's Ability to Protect the Public From Illegal Residues. GAO/RCED-87-7. Washington, D.C. 9. National Research Council. 1984. Cancer Today: Origins, Prevention, and Treatment. Washington, D.C.: National Academy Press. 10. U.S. Environmental Protection Agency. 1983. Ethylene Dibromide Special Review Position Document 4. Washington, D.C. 11. 40 CFR Part 158 (1986). 12. U.S. General Accounting Office. 1986. Pesticides: EPA's Formidable Task to Assess and Regulate Their Risks. GAO/RCED-86-125. Washington, D.C. 13. U.S. Environmental Protection Agency. 1984. Tolerances for Pesticides in Food Administered by the Environmental Protection Agency; Animal Drugs, Feeds, and Related Products; Tolerances for Pesticides in Animal Feeds; Dicamba; Denial of Stay. Federal Register 49(235): 47481~7483. 14. U.S. Environmental Protection Agency. 1986. Data Generation Schedule Status Report. Washington, D.C. 15. U.S. Environmental Protection Agency. 1986. Report on the Status of the Chemicals in the Special Review Program, Registration Standards Program, and Data Call-In Program. Washington, D.C.