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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 46
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 47
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 48
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 49
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 50
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 51
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 52
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 53
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 54
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 55
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 89
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-~.
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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.
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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
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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
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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
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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
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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
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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
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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.
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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 99
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.
Representative terms from entire chapter:
delaney clause
