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OCR for page 23
The Current System
Theory and Practice
.:
The issues this report addresses arise from the interaction between two
different statutes, the EPA's administrative practices and the growth in
new information about pesticide toxicity and prevalence. The questions
posed by the Delaney Clause can be understood only in the context of the
system under which the EPA regulates pesticides. This chapter describes
that system and identifies the developments that give rise to questions
about the Delaney Clause. It concludes by summarizing the major issues
the current study is intended to help resolve.
REGISTRATION OF PESTICIDES UNDER FIFRA
The central event in the regulation of a pesticide is registration, which
is EPA approval of one or more of its uses under the Federal Insecticide,
Fungicide and Rodenticide Act (FIFRA). EPA registration of a pesticide
use is required before the pesticide can be lawfully sold in the United
States. The use of a pesticide in a manner inconsistent with the terms and
conditions of its registration is unlawful.
The registration process is linked with the tolerance-setting process.
Pesticides that are to be registered for use on food crops must be granted
tolerances under the Food, Drug and Cosmetic (FDC) Act. Tolerances
authorize and place legal limits on the presence of pesticide residues in or
on raw agricultural commodities and, in appropriate cases, processed
foods. The EPA will not register the use of a pesticide on food crops
unless tolerances have first been granted to cover any residues expected
23
OCR for page 24
24 REGULATING PESTICIDES IN FOOD
to remain in or on food. Registration is nevertheless the logical starting
point for a discussion of pesticide regulation because registration governs
the uses of pesticides that result in food-borne residues.
Section 3 of FIFRA sets forth the standards for registration. The basic
requirements are that the pesticide use must be able to accomplish its
intended effect without causing "unreasonable adverse effects on the
environment," which the law defines as "any unreasonable risk to man or
the environment, taking into account the economic, social, and environ-
mental costs and benefits of the use of any pesticide." In proceedings to
cancel or suspend the registration for use of a pesticide, the law further
directs the EPA to consider the impact of the proposed action "on
production and prices of agricultural commodities, retail food prices, and
otherwise on the agricultural economy."2
Thus, FIFRA is a "balancing" statute. Congress recognized that
pesticide uses can yield both risks and benefits and directed the EPA to
consider both in deciding whether to permit particular uses of a pesticide.
To grant registration, the EPA must conclude that the food production
benefits of a pesticide outweigh any risks.
Under FIFRA the burden rests on the manufacturer or other would-be
registrant to provide the data needed to support registration. The EPA
regulations spell out in detail the data required in 40 CFR Parts 158 and
162.3 Required data include substantiation of the product's usefulness and
disclosure of its chemical and toxicological properties, likely distribution
in the environment, and possible effects on wildlife, plants, and other
elements in the environment. If the applicant's data fail to prove that the
product's use poses "no unreasonable adverse effects on the environ-
ment," registration is denied. In theory, the registrant continues to bear
this burden even after registration and may be called on to prove its case
again if new scientific data cast doubt on the EPA's original assessment of
risk or balancing of benefits.
The conclusion of a successful registration process is the approval of a
label for the product. This label sets forth detailed and legally binding
instructions for use of the pesticide on certain crops, including any
limitations or conditions on how or when the pesticide must be applied or
not applied. Label specifications are generally designed to avoid adverse
effects on the environment or on adjacent or future crops, to ensure
efficacy, and to minimize applicator exposure.
TOLERANCE SETTING UNDER THE FDC ACT
Pesticides that are to be registered for use on food crops must have
been granted tolerances covering expected residues of the pesticide in
raw and processed foods. Two different sections of the FDC Act, enacted
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THE CURRENT SYSTEM: THEORY AND PRACTICE 25
four years apart, apply to the setting of tolerances. One, section 408,
governs tolerances for pesticide residues on raw commodities. The other,
section 409, governs tolerances for pesticide residues that concentrate in
processed foods.
Section 40~The Statutory Standard
Congress enacted section 408 of the FDC Act in 1954 to enhance
regulatory control over pesticide residues in food. It authorizes the
establishment of tolerances for pesticide residues in or on raw agricultural
commodities before they leave the farm gate. These tolerances are to be
set at levels deemed necessary to protect the public health, while
considering the need for "an adequate, wholesome, and economical food
supply." Like the FIFRA standard for registration, section 408 of the
FDC Act explicitly recognizes that pesticide uses confer benefits and
risks and that both should be taken into account. The inquiry authorized
by section 408 may not be as broad as that under FIFRA, yet section 408
clearly allows although does not compel the EPA to consider factors other
than risks to human health.4
Residues of a pesticide on a raw agricultural commodity that exceed a
section 408 tolerance or for which no tolerance has been established are
deemed unsafe. The commodity itself is characterized as adulterated (and
thus unlawful) under the FDC Act.5
Section 409
Section 409 of the FDC Act is the source of the Food and Drug
Administration's (FDA) general authority to regulate the purposeful
addition of substances to food. This provision empowers the FDA to
require premarket approval for a varied universe of food additives,
including artificial sweeteners, preservatives, chemical processing aids,
animal drug residues, and packaging materials. Precisely how section 409
affects the EPA's regulation of pesticides requires some explanation.
Section 201(s) of the FDC Act initially defines the term "food additive"
broadly to include "any substance the intended use of which results or
may reasonably be expected to result . . . in its becoming a component of
food."6 But it then expressly excludes from the definition pesticide
residues in or on raw agricultural commodities, presumably because they
are already covered by section 408. By necessary implication, however,
pesticide residues in processed foods remain food additives and thus
subject to the premarket approval requirement of section 409.7 The FDA
has primary responsibility for implementing section 409, but the EPA has
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26 REGULATING PESTICIDES IN FOOD
been delegated responsibility for regulating pesticide residues that are
food additives.
Like section 408, section 409 establishes a procedure to secure ap-
proval for the uses of food additives. However, the standard for granting
approvals under section 409 differs fundamentally from the risk-benefit
standard of section 408. Section 409 requires the sponsor of a food
additive to prove with reasonable certainty that no harm to consumers
will result when the additive is put to its intended use.8 This so-called
"general safety standard" for food additives is strictly risk based. It
allows consideration of an additive's potential health risks and, by
negative implication, seems to preclude consideration of any economic or
other benefits.
In section 409, Congress also created a special rule for food additives
that have been found to induce cancer in humans or animals. Under the
famous Delaney Clause—enacted as a proviso to the general safety
standard- no such additive can be approved (in the case of a pesticide
this means "granted a tolerance") under section 409.9
A food additive that has not been approved under section 409 or that is
present in food at a level exceeding a section 409 tolerance is deemed
unsafe. Unsafe food additives, as well as the foodstuffs containing them,
are adulterated and subject to the same enforcement procedures and
penalties applicable to raw agricultural commodities.
If Congress had stopped here, pesticide residues in raw commodities
and those in processed foods would be subject to different standards, but
the distinction would be clear. The former would be regulated under the
balancing criteria of section 408; the latter would be regulated under the
risk-only standard of section 409, reinforced by the Delaney Clause. But
Congress did not stop here, and it is Congress' further effort to integrate
sections 408 and 409 that contributes much of the complexity in pesticide
tolerance setting. In brief, not all pesticide residues in processed foods are
regulated as food additives.
When it adopted section 409 in 1958, Congress realized that many, if
not most, processed foods would contain at least some of the residues of
pesticides lawfully present (under section 408) on the raw agricultural
commodity used in their production. To facilitate regulation of pesticide
residues falling within the definition of food additive—and hence requiring
approval under both section 408 and section 409- Congress in effect
exempted from "food additive" regulation residues that are present in a
processed food at levels no higher than sanctioned on the raw agricultural
commodity. Section 402(a)~2~(C) of the FDC Act provides
that where a pesticide chemical has been used in or on a raw agricultural
commodity in conformity with an exemption granted or a tolerance prescribed
under section 408 and such raw agricultural commodity has been subjected to
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THE CURRENT S YSTEM: THEOR Y. AND PRACTICE 27
processing such as canning, cooking, freezing, dehydrating, or milling, the residue
of such pesticide chemical remaining in or on such processed food shall,
notwithstanding the provisions of sections 406 and 409, not be deemed unsafe if
such residue in or on the raw agricultural commodity has been removed to the
extent possible in good manufacturing practice and the concentration of such
residue in the processed food when ready to eat is not greater than the tolerance
prescribed for the raw agricultural commodity....~°
As a general rule, this proviso allows EPA approval of a residue under
section 408 to suffice, as long as any residues in food processed from the
raw agricultural commodity do not exceed the level authorized under
section 408 (see the boxed article "Concentrating Residues". Such
residues remain subject to the balancing standard of section 408, and they
escape the Delaney Clause.
Under this statutory framework, the concentration of a pesticide's
residues in processed food has profound implications. To expose them,
the committee first summarizes the procedural and analytical steps the
EPA follows in setting tolerances under sections 408 and 409 and
describes the universe of tolerances promulgated to date. Then the
committee examines more fully the significance of discovering that
pesticide residues concentrate in processed food.
The Tolerance-Setting Process Under Sections 408 and 409
OVERVIEW OF THE PROCESS
Most tolerance-setting proceedings are initiated when a pesticide
manufacturer files a petition with the EPA requesting establishment of a
tolerance. The petition must be accompanied by or make reference to
scientific data and technical information that the manufacturer believes
satisfy the agency's data requirements. This information also must
support a judgment that the tolerance can be established in compliance
with statutory standards. The formal procedures for handling completed
petitions under sections 408 and 409 differ slightly, but the same basic
supporting data are mandated.
After reviewing a petition for completeness, the EPA publishes a notice
in the Federal Register inviting comment on the proposed tolerance. At
this point the underlying safety and residue data generally are not subject
to examination by members of the public. After analyzing all the
available data and considering any comments submitted in response to the
proposal, the EPA either denies the petition or establishes a final
tolerance. A notice announcing the EPA's action, including a brief
summary of reasons, is published in the Federal Register. The tolerance
is eventually codified in the Code of Federal Regulations (CFR). Both
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28 REGULATING PESTICIDES IN FOOD
Concentrating Residues: What Are They and When Does Delaney Apply?
The FDC Act dispenses with the need for a food or feed additive tolerance
for any pesticide residue in processed food or feed when "the concentration
of such residue in the processed food . . . is not greater than the tolerance
prescribed for the raw agricultural commodity.... " Concentrating residues
requiring food or feed additive tolerances must meet the act's safety
standard. Under the Delaney Clause, the pesticide presumably cannot be
approved if found to induce cancer in man or animal. Thus, the EPA's
interpretation of the language relating to concentration can be critical. The
central issue is whether the law makes the fact or the /eve/ of concentration
the determining factor. Although there has been some confusion on the
matter, the EPA's current position is clear. It is the fact of concentration that
necessitates section 409 tolerances and thus potentially triggers the app~ica-
tion of the Delaney Clause.
Raw agricultural commodity tolerances are based on the results of field
trials designed to achieve the highest residue levels likely under normal
agricultural practice. These studies include such methods as using the
highest recommended application rates under weather and climatic condi-
tions that prolong and in some cases exacerbate residues. Because of this,
the tolerance is often higher than the actual residues found at harvest on
crops grown in regions where application rates are tower and where residues
dissipate more rapidly. In these cases a residue theoretically could concen-
trate during processing yet not exceed the level allowed on the raw
agricultural commoclity, which is the section 408 tolerance.
On occasion, tolerance petitioners have asked the EPA to set section
408 tolerances high enough to allow concentration of residues during
processing to levels below these tolerances. The EPA reports it has denied
all such requests and has relied on 40 CFR § 180.4 (1 986), which states:
"The tolerance established ordinarily will not exceed that figure which
the Administrator of the Environmental Protection Agency states, in his
opinion, reasonably reflects the amounts of residue likely to result."
When seeking a section 408 tolerance for a specific crop, the petitioner
must address the need for section 409 tolerances by showing whether the
residues concentrate as a result of specific processes such as drying,
milling, or juicing. In determining whether a section 409 tolerance is
required, the EPA focuses on whether residues in any processed product
exceed those found on the unprocessed crop, not whether residues
concentrate above some hypothetical section 408 tolerance. If residues
concentrate, an average concentration factor is determinecl. The section
409 tolerance is set at a level equal to the section 408 tolerance
multip~iecl by this concentration factor.
The logic of the EPA's practice is clear. A section 408 tolerance
represents a residue ~eve! that may in some cases be rea~izecl. A section
409 tolerance must reflect the possible residue levels in processed foods
derived from that raw commodity. (Source: 40 CFR § 1 80.4 (1986~.)
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THE CURRENT SYSTEM: THEORY AND PRACTICE 29
statutes permit opponents of a tolerance to object, request a hearing, and
ultimately challenge the EPA's final decision in court, but these formal
procedures are almost never invoked. Indeed, relatively few tolerance
petitions evoke written comment from members of the public other than
those affiliated with the pesticide industry.
SPECIFIC DATA REQu~REMENTs
Data requirements for tolerance petitions are spelled out in EPA
regulations and guidelines. Much of the required information duplicates
that needed to support registration under FIFRA, and is already avail-
able. Key elements of the data package include a description of the
chemistry of the pesticide itself; identity and quantity of residues ex-
pected to be present in food; analytical procedures used in obtaining the
residue data, which must be complete enough to permit replication by a
competent analyst; residues in animal feed derived from crop by-products
or from forages and resulting residues, if any, in meat, milk, poultry, fish,
and eggs; and toxicity tests on the parent compound and any major
impurities, degradation products, or metabolites.
The gathering and interpretation of residue chemistry data are some of
the most difficult technical challenges that the registrant and the EPA
face. The objective is to estimate and fully track the principal food
residues, including metabolites and degradation products, that are likely
to result from the commercial use of a pesticide under varying climatic
and soil conditions. This generally requires extrapolation from data on a
limited number of field trials in different parts of the country where the
pesticide would possibly be used. In considering the level at which to set
a tolerance, the EPA will generally select the highest residue levels
reported in such tests.
The toxicity data required for each active ingredient and for major
impurities or metabolites typically include the results of the following
studies and reflect the need for data on all risks as well as those posed by
residues in food:
· Acute oral, dermal, and inhalation studies;
· Two-generation reproduction study;
· Chronic feeding studies on rodents and nonrodents;
· Oncogenicity studies on mice and rats;
· Mutagenicity studies on gene mutation, structural chromosomal
aberration, and other effects toxic to genetic material;
· Teratogenicity studies on rats and rabbits;
· Delayed neuropathy studies on chickens; and
· Plant and animal metabolism studies.
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30 REGULATING PESTICIDES IN FOOD
The agency may grant exemptions from one or more of these require-
ments when the petitioner can show it is scientifically appropriate to do
so.
ONCOGENICITY AND CARCINOGENICITY
Throughout its work, the committee encountered disparate usages of
the terms oncogen, oncogenicity, carcinogen, and carcinogenicity. In
conventional scientific terminology, oncogen means a substance capable
of producing benign or malignant tumors. The EPA has adopted this
definition. The term carcinogen is generally reserved for substances
capable of producing malignant tumors. The committee will follow these
usages in this report.
Confusion can arise when these terms are used in a regulatory context.
For example, the FDA apparently interprets the Delaney Clause as
prohibiting approval of carcinogens, whereas the EPA apparently treats it
as prohibiting oncogens" theoretically a broader interpretation. It is
unclear to the committee how significant this difference is in actual
practice. It seems likely, though, that there are more oncogenic pesticides
than carcinogenic ones; chronic feeding studies will sometimes reveal
oncogenicity even when a pesticide's capacity to cause malignant tumors
is uncertain. Thus, the EPA's more conservative approach generally
expands the universe of pesticides to which the Delaney Clause applies.
The description of a substance that is merely a suspect oncogen or
carcinogen also may be confusing. A substance may be characterized as
an oncogen or carcinogen even though the evidence on which the
statement is based may be incomplete (for example, it consists of results
from a single test in one species or sex), weak (for example, a trend was
seen in a chronic bioassay but not at a statistically significant level), or
otherwise flawed (for example, a statisically significant effect was ob-
served in a study of flawed design or execution). In such cases, the EPA
may evaluate the potential human risk of such substances as suspect or
possible oncogens or carcinogens. The criteria the EPA uses in judging
whether a compound is an oncogen for the purposes of the Delaney
Clause constitute a critical regulatory variable. The implications will be
considered later in this report.
Finally, the important scientific distinction between substances found
to be oncogenic or carcinogenic in animals and those found to have the
same effects in humans is often obscured or overlooked. Because of the
limits of epidemiological data, regulatory agencies typically rely solely
upon animal studies in evaluating the safety of compounds for humans. In
the absence of convincing data documenting causality between pesticide
exposure and cancer in humans, however, it is inaccurate to refer to such
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THE CURRENT SYSTEM: THEORYAND PRACTICE 31
substances as human oncogens or carcinogens. Rather, such chemicals
are animal oncogens or carcinogens. (It should be noted, however, that
the Delaney Clause does not require proof of carcinogenicity in humans.)
In its scheme for categorizing evidence of carcinogenicity, the EPA
properly reserves the term "human carcinogen" for substances where
available human data are sufficient to support that finding. In other cases,
the EPA uses the terms "probable human carcinogen" and "possible
human carcinogen," depending on the strength of available animal
evidence, short-term in-vitro mutagenicity assays, and any other relevant
data.13
Appreciation of these distinctions and possible differences in the
approaches of the EPA and the FDA is important to complete under-
standing of the impact of the Delaney Clause. One set of issues lies within
the gray areas of the sciences of toxicology, pathology, and risk assess-
ment. Another set clusters around the regulatory consequences of a given
scientific judgment. In recent years, the EPA and the FDA have agreed in
their regulatory judgments on chemicals with clear, strong indications of
carcinogenic potential and on chemicals with very weak or equivocal
evidence of oncogenicity. But chemicals that fall between these extremes
are vexing.
In this study, the committee follows the EPA's criteria and terminol-
ogy. The term oncogen will be used in cases when the EPA would judge
the animal evidence sufficient to trigger the Delaney Clause. The com-
mittee will attempt to clarify its terms throughout the report and cautions
readers to remember that tables and text generally depict only potential
human risk, usually under worst-case scenarios.
TOLERANCE SETTING FOR NON-ONCOGENIC PESTICIDES UNDER
SECTION 408
The core of the typical tolerance-setting process under section 408 is
the effort by the EPA to compare the quantity of residues to which
humans might be exposed through consumption of pesticide-treated food
with the level it judges, based on the available toxicological data, as safe.
If the EPA finds that the pesticide (or its expected impurities, metabolites,
and degradation products) does not cause a statistically significant in-
crease in the incidence of tumors in animals, it concludes the Delaney
Clause is not applicable. Then, the EPA calculates a safe level of
exposure, following the conventional analysis of calculating an Accept-
able Daily Intake (ADI) for the substance in question.
The first step in calculating an ADI is determining from the battery of
toxicity studies the "no observable effect level" (NOEL) for the most
sensitive toxic response that is considered to be of potential human health
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32 REGULATING PESTICIDES IN FOOD
concern. In any study, the NOEL is the highest dose level of pesticide
(consumed in the daily diet per unit of body weight) at which no adverse
effect was observed. It is the dose level nearest to but less than the lowest
dose producing observable indications of toxicity. The study displaying
the lowest NOEL is generally selected to establish the ADI. This is
calculated by dividing the NOEL by a safety factor (typically 100) to yield
the ADI, which is also expressed in milligrams of pesticide per kilogram
of body weight per day. (The safety factor of 100, an accepted convention
in toxicology, is derived by assuming that t1] humans are 10 times as
sensitive as the most sensitive animal tested, and t2] some humans are 10
times as sensitive as the least susceptible human.) Regulatory scientists
regard the ADI arrived at in this fashion as a level of dietary exposure that
virtually all individuals could consume on a daily basis and even exceed
on occasion without experiencing adverse effects.
The next step in evaluating whether a proposed tolerance is toxicolog-
ically supportable is calculation of the theoretical maximum residue
contribution (TMRC) for each food form in which the pesticide could
occur. The sum of the TMRCs for all food forms represents the cumula-
tive TMRC for the pesticide. If the TMRC for a proposed use combined
with the TMRC for all other already-approved uses is less than the ADI,
the proposed new tolerance that has met other requirements is generally
approved. If the TMRC exceeds the ADI, the EPA either denies the
tolerance or explores with the petitioner ways to lower the TMRC from
the proposed or other uses.
In calculating the TMRC, the EPA seeks to avoid underestimating food
consumption and exposure to residues by assuming that (1) each pesticide
is used on all harvested crop acres for which a tolerance exists or is
proposed and (2) pesticide residues are present at the full tolerance level
in every food consumed. Together these assumptions generally exagger-
ate estimates of dietary exposure to residues. Very few pesticides are
used on anywhere near 100 percent of the total acreage of a crop grown
in the United States, and measured residues are usually below the
tolerance. However, the EPA routinely uses these conservative assump-
tions to account for gaps in information about actual exposure and
uncertainties about health effects.
Although the EPA is empowered by law to consider the benefits of
pesticide use in establishing section 408 tolerances, it rarely does so.
Residues that pass the foregoing ADI/TMRC analyses are regarded as
safe. (Indeed, given the 100-fold safety factor and the conservative
assumptions about exposure built into the TMRC, there is thought to be
a wide margin of safety.) The petition is then said to be toxicologically
supportable and is generally approved without examination of benefits. If
the TMRC exceeds a pesticide's ADI, the agency may examine the
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THE CURRENT SYSTEM: THEOR Y AND PRACTICE 33
benefits or, as noted above, explore with registrants possible ways to
reduce the TMRC by changing the timing, rate, method, or diversity of
crop uses for the given pesticide. Before the pesticide use is registered,
however, other important potential environmental effects of the
pesticide's use and other routes of human exposure must be evaluated.
These include the pesticide's effects on birds, fish, and wildlife; ground-
water contamination; and hazards to applicators.
TOLERANCE SETTING FOR ONCOGENIC COMPOUNDS UNDER
SECTION 408
The EPA's analysis proceeds somewhat differently if the pesticide is a
suspected oncogen. In this case, the agency does not seek to identify a
NOEL or calculate an ADI. Its approach is based on quantitative risk
assessment models developed specifically to provide upper-bound esti-
mates of human cancer risks, based on animal bioassay data, assuming a
lifetime of exposure to the pesticide. On the basis of such risk assess-
ments, the EPA makes a judgment about whether a given tolerance for a
specific pesticide use poses an unreasonable risk to humans.
The use of quantitative risk assessment in this context raises questions
that go beyond the scope of this report. 14 However, a basic understanding
of the methodology and limitations of risk assessment is essential to the
analysis presented in subsequent chapters.
In brief, risk assessment is a complex extrapolation process. It involves
first extrapolating from the effects seen at the generally high doses used in
animal studies to the much lower dosages ordinarily consumed by humans
in the diet. Then, one predicts from the animal test model results that
might occur in humans under actual exposure conditions. The assessment
of the oncogenic risk posed by any given substance thus reflects both the
potency of the substance and human exposure to it. Once potency is
determined, the level of risk to food consumers from a particular pesticide
use is a function of exposure to residues in food: the higher the residue
levels in foods (or frequency of consumption), the higher the risk.
The risk assessment process is beset by uncertainty and by gaps in
knowledge, even on such basic points as the relevance of particular
animal test models to humans and the true qualitative and quantitative
relationships between effects seen at high doses and those likely to occur
at low doses. To compensate for such gaps in knowledge, the EPA and
other agencies that use quantitative risk assessment typically adopt
conservative assumptions that are designed to avoid understating the
potential human risk. For example, results from the most sensitive animal
species are used in extrapolating from high doses to low doses, mathe-
matical models are selected that are thought to avoid understating
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34 REGULATING PESTICIDES IN FOOD
potential human risk, and assumptions are made concerning potential
human exposure to the substance that almost certainly overstate true
human exposure. Most experts believe that these conservative assump-
tions together produce risk estimates that represent the likely upper
bound of potential human risk. It is generally accepted that the true
human risk is probably less than the reported risk estimate.
Risk estimates are typically expressed in terms of the probability that
an individual member of a population will experience cancer from
exposure to the substance in question over his or her lifetime. Thus, a
risk estimate of 1 in 1 million or (1 x 10-6) from a specified level of
exposure is a statement that at the 95 percent upper-bound confidence
limit, there is no greater than a 1 in 1 million chance that an exposed
individual, or that 1 person out of 1 million exposed individuals, will
experience cancer from daily lifetime exposure to the substance in
question. To keep these risk estimates in perspective, all individuals
now face about a 1 in 4 chance of contracting cancer. Heavy smokers
face far worse odds.
In setting tolerances for oncogenic pesticides under section 408, the
EPA performs the risk assessment described above and decides whether
the risk posed is acceptable that is, whether the risk is negligible enough
to justify a tolerance. To the committee's knowledge, the EPA has not
formally adopted any numerical cutoff for oncogenic risks it views as
negligible. Without question, however, the EPA has approved many
section 408 tolerances for oncogenic pesticides. (See the case studies in
Appendix C.)
The committee's review of EPA tolerance actions in recent years
suggests that when the estimated upper-bound risk is less than 1 in 1
million (1 x 10-6), the agency rarely disapproves a tolerance. Tolerances
likely to pose greater risk than 1 in 10,000 (1 x 10-4) are rarely granted.
Decisions to approve tolerances carrying an upper-bound risk between 1
in 1 million and 1 in 10,000 are generally, but not always, made after
taking steps to reduce dietary exposure and confirming that risks from
other routes of exposure are also small.
In reaching decisions on dietary risks that fall between 1 x 10-4 and 1
x 10-6, the EPA enlarges its inquiry. Under section 408, the agency may
consider the benefits of a pesticide's use. The agency generally evaluates
benefits in relation to all risks, when data are available, in deciding
whether to grant a tolerance for a pesticide for which the upper-bound
oncogenic risk estimate falls between 10-4 and 10-6. On occasion the
EPA's consideration of benefits has been relatively thorough and its
judgment has proved central to the ultimate decision. (See the case
studies in Appendix C.) In most cases, however, whether dealing with an
oncogen or non-oncogen the EPA rests its tolerance decision on a
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THE CURRENTSYSTEM: THEORY AND PRACTICE 35
judgment about the safety of the pesticide residue without regard to
benefits.
TOLERANCE SETTING U NDER SECTION 4O9
As noted, section 408 of the FDC Act allows the EPA to consider the
benefits of pesticide use and does not forbid approval of oncogenic residues.
Section 409, which applies to concentrated residues in processed food,
differs in both respects. It does not expressly allow the EPA (or the FDA in
its consideration of direct food additives) to consider the benefits of a
pesticide's use. is In the Delaney Clause, it forbids the approval as safe of any
food additive shown to "induce cancer in man or animal."
In the case of non-oncogens, these differences in statutory language have
little practical importance. The EPA evaluates the human risk associated
with a proposed section 409 tolerance for a non-oncogen using the same
ADI/TMRC analysis it follows under section 408. If the TMRC is less than
the ADI, the residue is judged safe, and a 409 tolerance is granted.
In regulating oncogens, however, the EPA immediately confronts the
Delaney Clause. When a pesticide that requires a section 409 tolerance
(because its residues concentrate in some processed foods) has also been
found to be oncogenic in animals, the EPA simply declines to grant a
tolerance. There is no consideration of whether the residue poses a risk to
humans or whether the risk might be judged acceptable. Tolerances in the
CFR as of June 1986 are shown in Table 2-1.~6
It is obvious how the fact of concentration can decisively affect the
regulatory fate of a pesticide use. If residues of an oncogenic pesticide
occur but do not concentrate in processed food, the EPA can estimate
risk, make a safety judgment, and then balance risks with the pesticide's
benefits. In these cases, a food additive tolerance is not required; the raw
agricultural commodity tolerance suffices. If the oncogenic pesticide
concentrates in the processed food, the EPA automatically denies a
tolerance without further analysis.
Although the impacts of the Delaney Clause on petitions to establish
TABLE 2-1 Food Tolerances in the CFR
Type of Pesticide
Number
Insecticides
Herbicides
Fungicides
Other
Total
3,806
2,s43
,305
823
8,477
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36 REGULATING PESTICIDES IN FOOD
TABLE 2-2 Food Tolerances in the CFR for 53
Oncogens
Number
T~ ~ ~ ~,,,~_,
ype or
Pesticide Section 408 Section 409
Herbicides 91S 9
Insecticides 843 3
Fungicides 712 12
Other 55 7
Total 2,525 31
new section 409 tolerances for oncogenic pesticides are clear-cut, its
impact on already-established tolerances has been very different. New
information demonstrating that a pesticide has oncogenic potential and
concentrates in processed food would seem to necessitate the Delaney
Clause prohibition. Yet, the EPA has not invoked this provision to revoke
a single such tolerance.
As shown in Table 2-2, 31 section 409 tolerances and 2,525 section 408
tolerances exist for pesticides shown to be oncogenic in animal tests.
THE DATA CALL-IN PROGRAM
A driving force that will compel the EPA to confront the implications of
the Delaney Clause is FIFRA's requirement that all registered pesticides
be reregistered on the basis of contemporary scientific standards and
data, with priority given to pesticides used on food. To implement this
long-standing mandate, the EPA in 1981 instituted the Data Call-In
Program, which was designed to elicit the toxicity information needed to
make reregistration decisions. The agency also requests a wider range of
data in their registration standards program. The toxicity and residue
chemistry data generated by these programs in the future will substan-
tially enlarge the number of pesticides that, under current law and policy,
seem to require section 409 tolerances and thus could be affected by the
Delaney Clause.
By 1990, the agency should have received updated oncogenicity data
for nearly all pesticides registered for use on foods. It is impossible to
predict which or how many active pesticide ingredients will be found to be
oncogenic once all are adequately tested. But, based on past experience
(53 out of 289 pesticides used on foods are determined by the EPA to be
oncogenic) and assuming continuity in the EPA's interpretation of
oncogenicity studies, about 20 percent of the registered pesticides for
which data are submitted may be found to be oncogenic.
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THE CURRENT SYSTEM: THEORY AND PRACTICE 37
The EPA determines whether a pesticide residue concentrates in
processed food and thus requires a section 409 or food additive tolerance
on the basis of residue chemistry data. The EPA currently has complete
residue chemistry data on less than 25 percent of pesticides used on
foods. The agency is working to complete this segment of its data base
although residue data are coming in at a slower pace than toxicity data.
The EPA confronts some difficult issues in this area. EPA scientists
acknowledge that the agency's current requirements for food-processing
studies do not cover all foods in which residues are likely to concentrate.
Concerned food-processing companies have asked the EPA to review the
need for evaluating residue concentration in 20 additional crops. The
agency must decide how far to pursue metabolites, degradation products,
and impurities to determine whether there is concentration. And the EPA
is debating how and when to test for concentration in certain dried foods,
animal feeds, animal products, and complex mixtures in highly processed
foods.
It would be an enormous task to reliably determine whether residues of
all pesticides now covered by section 408 tolerances concentrate in
processed foods. For those pesticides with scores of raw food tolerances,
it would require more time and money to satisfy residue chemistry data
requirements than to develop a complete new set of chronic toxicity data.
(See Appendix E for a discussion by industrial research directors.) One
outcome seems clear. Completion of the data base on pesticide residues
in processed foods will substantially enlarge the number of pesticide uses
for which section 409 tolerances will be required. The Delaney Clause will
halt many of the required tolerances because the pesticides will be found
to be oncogenic in animal tests. Residue chemistry data, required to elicit
information to assess dietary exposure to pesticide residues in raw and
processed foods, will reveal many concentrating residues for which no
409 tolerances are now approved.
THE DELANEY CLAUSE CLOSER EXAMINATION
The foregoing discussion explains the role that the Delaney Clause
plays in pesticide tolerance setting and suggests why the provision will
loom larger in future EPA decisions. This impending collision between
law and practice triggered the current study and independently inspired a
closer examination of the history and current interpretation of this
noteworthy provision. The FDA, the agency principally responsible for
implementing the Delaney Clause, has examined these issues for many
years.
In the early 1970s the FDA first suggested the possibility of using
quantitative risk assessment to evaluate the safety of substances found
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38 REGULATING PESTICIDES IN FOOD
oncogenic or carcinogenic in animal studies. The FDA proposed this
method of evaluation when it implemented the DES Proviso, which was
added to the Delaney Clause in 1962.~7 As part of the Drug Amendments
in 1962, Congress provided that the Delaney Clause would not bar
approval of carcinogenic drugs and feed additives administered to food-
producing animals if upon examination by methods acceptable to FDA no
residue of the material could be found in the edible tissues of the
animals. Convinced that the use of any animal drug would leave some
residue, the FDA in 1979 interpreted this proviso to mean no residue
above a level posing no significant increased risk of cancer in humans,
that is, a level judged by the FDA to be safe. The agency proposed to use
quantitative risk assessment to determine the residue level corresponding
to an increased lifetime risk of no more than 1 x 10-6 for an individual. It
termed this the sensitivity-of-the-method (SOM) approach and continues
to use it in regulating residues of carcinogenic animal drugs and feed
additives in human food.
Throughout the 1970s, the FDA continued to grapple with develop-
ments in science (paralleling those now confronting the EPA) that put
great pressure on the traditional understanding of the Delaney Clause.
Increased and more sensitive chronic toxicity testing and advances in
analytical methods identified many more natural and man-made carcino-
gens in human food. Many of these were residual reactants, trace
constituents of direct food additives, or components of packaging mate-
rials that migrated into food in minute amounts.
One source of authority for the exercise of judgment is found in the
language of the clause itself. The Delaney Clause applies only if the FDA
(or the EPA) finds that a substance "induces cancer when ingested by
man or animal." The legislative history makes clear that Congress
intended the agencies to exercise sound scientific judgment in deciding
whether a substance induces cancer. The clause seems to preclude the
agency from ignoring the results of an animal ingestion study solely on the
basis of the conclusion that such results are irrevelant to humans. Yet, the
agency is surely allowed, perhaps even required, to evaluate whether the
study was properly designed and conducted. The statute also leaves open
the questions of whether cancer induction must be demonstrated by more
than a single well-conducted study or how to weigh conflicting results
from two or more studies. In practice, a single, properly conducted,
positive test has been adequate, in the EPA's judgment, to trigger a
finding of oncogenicity.
The statute is also silent on exactly what "induce cancer" means. Is it
sufficient that an additive or pesticide increases the incidence of benign
tumors in the test animals? Or must there be convincing or at least
some evidence of malignancy? How should benign and malignant tu-
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THE CURRENT S YSTEM: THEOR Y. AND PRACTICE 39
mors seen in the same study be interpreted? The FDA has not chosen a
rigid position, but generally it has looked for evidence of malignancy
before taking action solely on the basis of the Delaney Clause. EPA
scientists have been more conservative. In several cases they found that
a substance meets the "induce cancer" criterion where there has been no
indication of malignancy (see Appendix C).
In addition to the SOM approach, the FDA has used other interpreta-
tions of the Delaney Clause intended to limit application. Two of these-
the constituents policy and the de minimis interpretation deserve dis-
cussion here.
The constituents policy rests on an interpretation of the phrase "no
additive shall be deemed to be safe if it is found to induce cancer...."
The FDA now interprets the term "additive" to refer to the added
substance as a whole and not to each of its individual constituents. Thus,
if a constituent of a food additive or color additive has been found to
induce cancer, but the parent additive has not, the FDA will not invoke
the Delaney Clause. Instead it will evaluate the safety of the additive
under the general safety standard. The carcinogenicity of the trace
constituent will be taken into account by performing a quantitative risk
assessment. The parent additive will be approved as safe under the
general safety standard if the assessed risk from the carcinogenic constit-
uent is insignificant. The FDA's benchmark for judging safety in this
context is a lifetime upper-bound risk estimate of 1 x 10-6.
The FDA has applied its constituents policy in evaluating several
residual reactants in color additives and some migrating components of
packaging materials. One reviewing court upheld this interpretation of the
Delaney Clause. A significant example of the application of the constitu-
ents policy to pesticide tolerance setting is discussed later in this report.
The FDA's latest and potentially most far-reaching effort to expand its
discretion under the Delaney Clause is its de minimis interpretation. The
FDA first used this interpretation in evaluating certain color additives that
induced cancer in animals. The levels of human exposure to the colors
were extremely small. Risks posed were estimated to be extremely low
in some cases orders of magnitude below 1 x 10-6. The FDA announced
in June 1985 that it interpreted the Delaney Clause as not prohibiting such
extremely small risks. Six months later, the agency used the de minimis
concept to approve the use of methylene chloride to decaffeinate coffee,
based on the conclusion that the risks posed by permitted residues were
no greater than 1 x 10-6.~9
The FDA's de minimis interpretation of the Delaney Clause has been
more controversial than the agency's constituents policy. The de minimis
interpretation recently has been challenged in a petition for judicial
review of the FDA's decision to permanently list two color additives.20
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40 REGULATING PESTICIDES IN FOOD
Because the de minimis interpretation departs from the FDA's traditional
interpretation of the Delaney Clause, the policy's legality will remain
uncertain until there is a definitive court ruling.
From a policy standpoint, the FDA's de minimis interpretation is an
important development. If upheld, it would replace the zero-risk inter-
pretation of the Delaney Clause with a no-significant-risk standard. For
carcinogens, the requirements of the general safety clause and the
Delaney Clause would have become congruent. Even if the FDA's
statutory interpretation is overruled, its policy judgment that cancer risks
of less than 1 x 10-6 may be considered safe when derived by methods
using a clearly defined set of conservative assumptions could have
important implications for pesticide tolerance setting.
SUMMARY OF PROBLEMS AND ISSUES POSED BY THE
DELANEY CLAUSE
Q
The committee identified four different risk standards in the current law
which could apply to residues of an oncogenic pesticide on the food and
feed forms of a single crop.
· For residues on raw agricultural commodities consumed as food,
tolerances may reflect a weighing of risks and benefits.
· When residues concentrate in processed food, the Delaney Clause
would bar any tolerances for that crop.
· For concentrated residues in processed animal feeds such as soybean
hulls, tolerances may be denied under the Delaney Clause unless approv-
able under the SOM approach discussed above.
· For most hays, fodders, and other nonprocessed livestock feeds,
tolerances would be granted under section 408 regardless of whether
residues concentrate, based on an assessment of the cancer risks associ-
ated with dietary exposure to residues in the animal products ultimately
consumed by humans.
This diversity dramatizes the problems presented by the current framework
for setting tolerances for pesticide residues on agricultural commodities.
Inconsistency
The current system treats pesticide residues inconsistently in two
ways. One is exemplified by the dichotomous risk standards in sections
408 and 409. From the outset of its deliberations, the committee has been
unable to identify any sound scientific or policy reason for regulating
pesticides present in or on raw commodities differently than those present
on processed foods. From the standpoint of consumer protection, the
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THE CURRENT SYSTEM: THEORY AND PRACTICE 41
source of exposure raw commodity versus processed food- seems
irrelevant.
The other inconsistency is the system's disparate treatment of old and
new pesticides. Old pesticides, especially those first registered before
1972, generally were not tested adequately for oncogenicity. They were
approved on the basis of limited residue chemistry data, particularly
concerning metabolites. Consequently, there was very limited knowledge
of the pesticides' capacity to concentrate in processed food. Many of
these pesticides are widely used today even though some are suspected
oncogens and usually lack section 409 tolerances that would almost surely
be required if complete residue chemistry data were available. Pesticides
recently registered for use on foods, on the other hand, have generally
been tested rigorously. With more complete residue chemistry data, the
EPA is more likely to recognize the need for section 409 tolerances which,
if a pesticide proves even weakly oncogenic, cannot be granted.
This inconsistency in treatment of old and new pesticides is very
important. If the standards applied to new chemicals are justified to
protect the public, the same standards should be applied to older
pesticides. If older pesticides are judged to not pose a public health
problem, then contemporary requirements restricting new, less oncogenic
pesticides may be overly protective and may impede introduction of
useful new pesticides.
The Issue of Concentration in Processed Foods
Another major problem derives from the current law's emphasis on
whether a pesticide residue concentrates in processed food. For an
oncogenic pesticide, this fact can prove crucial. If it is found to concen-
trate, it will be denied a section 409 tolerance under the current system.
Consequently, the pesticide will lose the underlying section 408 tolerance
and FIFRA registration for that use. If a crop has no recognized
processed form (see the boxed article "Subsection O"), then tolerances
for an oncogen can be granted if the risks are deemed acceptable. If a crop
has a processed form but residues do not concentrate, an oncogen can be
granted a tolerance under the general safety clause of section 409. Such
differences based on the fact of concentration in certain processed foods
make no discernible sense in terms of public health protection.
Paradoxical Regulatory Results
The committee can envision situations in which the current system
would compel results that, at least in the short term, actually increase the
human cancer risks from pesticides. For example, suppose a registered
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42 REGULATING PESTICIDES IN FOOD
Subsection O
The Delaney Clause prohibits a food or feed additive tolerance for any
pesticide that is found to cause cancer in humans or animals when the
residues of that pesticide concentrate in a processed food or feed above
the ~eve! allowed in the raw agricultural commodity. The Delaney Clause
does not directly govern residues of these pesticides in raw foods. The
clause can have a significant effect on raw food tolerances, however. The
EPA has successfully used the Delaney Clause to deny tolerances for an
oncogenic pesticide on an entire crop when residues are found to
concentrate in the processed portion of that crop.
As a result, the definition of a processed food is critical to the scope and
impact of the Delaney Clause. The criteria that the EPA uses to define
processed foods and feeds are in a nonregulatory companion to 40 CFR
158, Subpart K, entitled "Pesticide Assessment Guidelines Subdivision 0:
Residue Chemistry." These criteria are guidelines, not regulations. Yet,
they represent the EPA's current thinking on processed versus raw foods
and feeds. The EPA is currently reviewing and revising the criteria. When
the criteria emerge in final form they could have a significant effect on
which crops and pesticides might be most affected by the Delaney
Clause. Currently, however, most pesticides lack residue studies on a
range of processed foods.
pesticide X with known oncogenic effects and an existing substitute Y
which is a weaker oncogen are under review. Both agents produce
roughly equal benefits for comparable uses. X does not concentrate in any
processed apple products, but Y concentrates marginally. The EPA could
be forced by the Delaney Clause to deny a section 409 tolerance for Y and
also would be compelled to cancel its section 408 tolerance and registra-
tion. Pesticide X would claim a larger share of the market. Human cancer
risk would rise, not fall.
Another example involves a registration application and tolerance
petition for a new pesticide with data that show weak indications of
oncogenicity. The new pesticide is destined for a crop use for which there
are two registered, relatively potent oncogenic pesticides. Registration of
the new product is delayed by a prolonged dispute over whether a
metabolite causes the potential oncogenicity and whether it concentrates
in processed foods. Even though approving the new chemical may reduce
dietary cancer risk because it would displace more potent, approved
oncogens, the EPA probably would maintain the status quo under current
policy. Examples of this scenario can also be found in actions now
pending before the EPA.
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THE CURRENT SYSTEM: THEOR Y. AND PRACTICE 43
Another twist of the old standards versus the new creates other
paradoxes. Suppose the EPA is deciding whether to cancel an old
compound that poses clear oncogenic hazards. The availability of effec-
tive registered substitute chemicals is important in estimating the
material's benefits and, hence, in balancing its risks and benefits. The
agency's inability under current law and policy to register a new, weakly
oncogenic substitute chemical when residues concentrate in processed
food exaggerates the perceived benefits of the older products. Registra-
tions and tolerances may be denied even though EPA scientists are
convinced that the new chemical would pose less risk and provide
essentially equal food-production benefits.
The following chapters explore the likelihood that the current system
will often produce such paradoxical, indefensible results. Alternative
policy constructs are explored that might help the agency more efficiently
reduce public health hazards while ensuring an adequate inventory of
pesticides.
NOTES
1. 7 USC § 136(a) (1978).
2. Ibid.
3. 40 CFR Parts 158 and 162 (1986).
4. 21 USC § 346(b) (1984).
5. 21 USC §§ 342(a)(2)(B) and 348(a) (1984).
6. 21 USC § 321(s) (1984).
7. H.R. 2284. 84th Cong., 2d sees. (1958).
8. 21 CFR § 170.3(i) (1986).
9. 21 USC § 348(c)(3)(A) (1984).
10. 21 USC § 342(a)(2)(C) (1984).
11. This is because previously unpublished data are the registrant's confidential proprietary
information. The EPA sometimes will press a petitioner to allow public access to its
safety data. This occurs when the agency regards the tolerance decision as difficult or
potentially controversial, such as when significant safety questions are posed.
12. 40 CFR § 162.3(bb) (1986).
13. U.S. Environmental Protection Agency. 1986. Guidelines for Carcinogenic Risk As-
sessment. Federal Register 51(185): 33,992-34,003.
14. National Research Council. 1983. Risk Assessment in the Federal Government:
Managing the Process. Washington, D.C.: National Academy Press.
15. There is disagreement whether section 409 allows the EPA or the FDA to consider the
benefits of individual food additives in deciding whether they are safe. The FDA has
consistently taken the view that it does not. In the past, the FDA weighed a pesticide's
benefits in deciding whether to approve a 409 tolerance. This interpretation seems
difficult to reconcile with the section's language and history. It also conflicts with the
view of the FDA, the agency primarily responsible for interpreting and administering
this section of the FDC Act. No court squarely holds that the EPA's view is untenable.
16. 21 CFR Parts 193 and 561 (1986); 40 CFR Part 180 (1986).
17. 21 USC § 348(c)(3)(A) (1984).
18. Ibid.
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44 REGULATING PESTICIDES IN FOOD
19. In August 1986 the FDA applied the de minimis interpretation to approve two color
additives, D&C Orange No. 17 and D&C Red No. 19. This approval inspired the
interpretation's development. U.S. Food and Drug Administration. 1986. Federal
Register 51 (August 7): 28,331-28,346.
20. Ibid. The colors are D&C Orange No. 17 and D&C Red No. 19. The petition for review
was filed by Public Citizen in the U.S. Court of Appeals for the District of Columbia
Circuit. Public Citizen v. Young, No. 86-1548 (D.C. Cir. filed Oct. 9, 1986) (a decision
could be rendered later this year).
Representative terms from entire chapter:
processed foods
