Office of Pesticides
and Toxic Substances JANUARY 1990
Washington DC 20460
Office of Pesticide Programs
?/EPA Environmental
Fact Sheet
PESTICIDE TOLERANCES
EPA is responsible for regulating the amount of pesticide
residues that nay remain in or on food and animal feed. EPA's
regulatory authority derives from the Federal Food, Drug, and
Cosmetic Act (FFDCA) and the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA).
OVERVIEW OF THE PESTICIDE TOLERANCE PROCESS
Pesticide tolerances set by EPA are enforced by the Food and
Drug Administration (FDA), the U.S. Department of Agriculture
(USDA), and state enforcement agencies. The U.S. food supply is
monitored not only for compliance with pesticide tolerances, but
also for potential contamination by aflatoxin, salmonella, and
other microbial contaminants. Since surveillance resources are
limited, they must be allocated on the basis of priority
concerns. Pesticide residues are generally considered to be a
lesser concern than microbial contamination.
Federal-and state inspectors commonly sample food and feed
produce for the purpose of tolerance enforcement soon after the
farmer markets the treated commodity, so that any tolerance
violations may be traced to their source. Thus, tolerances are
intended to apply to treated raw agricultural commodities as soon
as they enter into commerce, starting when the produce leaves
"the farm gate."
In general, pesticide residues tend to dissipate or break
down as time passes after harvest. In the majority of cases,
residues are further reduced by washing, peeling, cooking, and
other processing. Almost by definition, tolerances represent
levels of pesticide residues that are not expected to occur as
actual residues in food commodities that reach the consumer, or
that remain in food at "the dinner plate."
The data required for a tolerance are mainly residue
chemistry and toxicity data. (Such data are ri^t, gef&rXted by EPA
laboratories; rather, EPA uses its data collection authorities
under the law to require the pesticide manufacturer to produce
these data.) All of EPA's tolerance data requirements are
designed to answer three key questions. First, what is the
chemical residue? Second, how much residue is there? The "what"
and "how much" information, derived from residue chemistry data,
"is then matched by EPA toxicologists with toxicity data to answer
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the third question: does the residue represent an acceptable
dietary level of exposure? In other words, is there a reasonable
assurance that under the prescribed conditions of use of the
pesticide, no unreasonable adverse effects will result in humans
even after a lifetime of exposure?
RESIDUE CHEMISTRY STUDIES
Residue chemistry data required for tolerance purposes
include several kinds of data ranging from product chemistry
information to food processing study results.
Product Chemistry Data. To characterize the pesticide
substance, EPA requires data on the composition of pesticide
products, called product chemistry data. In particular, these
data include (1) information on the manufacturing process, (2)
chemical analysis to show the amount of the active ingredient and
any associated impurities, (3) "certified limits" on the amounts
of the ingredients in a product, and (4) analytical methods used
to determine the composition of the pesticide.
EPA evaluates these product chemistry data to determine
whether impurities could constitute a significant component of
the residue in food or animal feed. This is an important
consideration because impurities created in the manufacture of a
pesticide may become a residue problem, if they are not
identified before tolerances are established.
Metabolism in Plants and Animals. Plant metabolism data are
required so EPA may characterize the nature of the residue that
occurs on crops intended for consumption as food or animal feed.
To obtain these data, the pesticide is labelled with a
radioactive atom, usually carbon fourteen, and applied to the
crop plant in accordance with proposed use directions. Since the
pesticide molecule is radiolabelled, one or more of the
metabolites or degradation products remaining in the plant at
maturity will be radioactive. The carbon fourteen activity is
separated into various fractions and the chemicals associated
with the activity are identified. It is very important to
identify most of the radioactivity before tolerances are
established. If this is not done, previously unidentified
residues may become problematic in the future as more highly
sensitive analytical methods are developed which could possibly
detect residues of concern.
Plant metabolism studies are required for a minimum of three
diverse crops — for example, a root crop, an oilseed, and a
leafy vegetable. If the metabolism in each of these crops is
similar, then the metabolism in other crops is assumed to be
similar. At the end of this process, EPA has enough information
to answer the question, what is the residue in plants?
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Whenever a proposed use of a pesticide may result in
residues in animal feed, or when a pesticide is intended for
treatment of livestock, animal metabolism studies are required in
addition to plant metabolism data. Animal metabolism studies are
generally carried out on ruminants (cows or goats) and poultry
(chickens).
Like plant metabolism tests, animal metabolism studies use
radiolabelled pesticides. The animals are dosed, and the level
of radioactivity resulting in potential meat or poultry products
(muscle, liver, kidney, milk, and eggs) is analyzed. If
significant activity is found, then the chemical identity
associated with the activity is determined. This process answers
the question, what is the residue in animals?
Significant Metabolites and Tolerance Expression. Using the
results of plant and animal metabolism studies, EPA determines
which metabolites are of concern and need to be included in the
tolerance. In each case, this decision is based on (1) the
toxicity of the metabolite, (2) the percent and magnitude of its
residue, and (3) whether a practical analytical methodology is
available or can be developed to detect and measure the
metabolite. For metabolites that are toxicologically significant
and occur at significant levels, a suitable analytical
methodology is mandatory. Considered together, the pesticide
active ingredient and any significant metabolites are called the
"total toxic residue."
Residue Field Trial Data. Once the metabolism data indicate
what to look for, and methods are developed to measure the total
toxic residue, field experiments are carried out to answer the
question, how much residue is there? These are studies in which
the pesticide is applied to crops at known application rates, in
a manner similar to the use directions which will eventually
appear on the pesticide label if the tolerance and registration
are approved. The field trial must reflect use conditions that
could lead to the highest possible residues. Generally this
means the highest permissible application rate, the maximum
number of applications allowed, and the shortest pre-harvest
interval permitted by the use directions. Data are normally
required for each crop or crop group for which a tolerance and
registration is requested. In addition, data are also required
for each raw agricultural commodity derived from the crop. For
example, corn residue analyses would be required for both grain
and feed items—forage, silage, and fodder.
Analytical Methods. Based on plant and animal metabolism
study results, EPA requires tolerance petitioners to develop
analytical methods to determine all components of the total toxic
residue. In some cases, it is not possible to develop a single
method that can determine all components of the residue, and
several methods are required. Pesticide analytical methods are
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used for two purposes: (1) to obtain residue data on which
dietary exposure assessments and tolerances are based, and (2) to
enforce the tolerance after it is established. EPA validates
each new analytical method using a method trial, to ensure that
the procedures can actually be used for tolerance enforcement
purposes by FDA, USDA, and state agencies.
Determining the Tolerance Level. A petitioner for a
tolerance proposes a tolerance level, based on residue field
trial data, which reflects the maximum residue that may occur
under "worst-case" conditions as a result of the proposed use of
the pesticide. The tolerance must include significant
metabolites and must be high enough to cover all components of
the total toxic residue. If one component of the residue is
significantly more toxic than other components, two levels may be
included in the tolerance.
Processing Data. While residue field trials provide data
for estimating tolerance levels in raw agricultural commodities,
processing studies are required to determine whether residues in
raw commodities may be expected to degrade or concentrate during
food processing. If residues do concentrate in processing, one
or more food or feed additive tolerances must be established.
However, if residues do not concentrate in processed commodities,
the tolerance for the parent raw commodity applies to all
processed food or feed derived from it.
Feeding Studies. Whenever pesticide residues result in feed
items, data on the transfer of residues to meat, milk, poultry,
and eggs are required. These studies are also required if a
pesticide is to be applied directly to animals. Data from these
studies tell EPA how much and what kind of secondary residues may
result in meat, milk, poultry, and eggs, in cases where this
question arises.
TOXICOLOGY STUDIES
For tolerance purposes, the toxicology data obtained from
studies in which test animals are exposed to the pesticide
chemical, mainly through oral exposure, are used to determine a
lifetime "no observed effect level" (NOEL) for non-carcinogenic
effects, and a cancer risk estimate if the pesticide has
carcinogenic potential. The studies begin with young (post-
weanling) animals, and exposure continues through their adulthood
(thereby mimicking human exposure beginning in adolescence and
continuing over a lifetime).
The toxicological effects of concern here are not the severe
and immediate poisoning symptoms that could result from
accidental massive ingestion of a pesticide, or skin and eye
irritation characteristics. Rather, these long-term feeding
tests are designed to reveal potential adverse effects which may
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result from continuous low-level ingestion of a pesticide — such
as bone marrow damage, cancer, blood effects, and other chronic
effects. Special test procedures also determine the potential of
the chemical to cause birth defects, reproductive effects,
neurotoxicity, and gene damage. In addition, the multi-
generation reproduction study looks at the reproductive effects
on animals exposed to pesticides in the womb and during nursing.
The Reference Dose, or Acceptable Daily Intake (API) Level.
Using the NOEL, an acceptable daily intake (ADI) level — which
EPA scientists now call a reference dose — can be proposed for
humans by applying a suitable uncertainty factor. The
uncertainty factor is intended to allow an extra margin of safety
to compensate principally for (1) the scientific uncertainty
inherent in the process of extrapolating human risk projections
from animal data, and (2) the possibility of differing
sensitivities to the pesticide in individuals or subgroups (such
as children) among the general population. The magnitude of this
factor may vary, depending on the toxicological effects observed
in laboratory animals, and the amount of toxicity data available,
but a 100-fold uncertainty factor is used in most instances.
In general, the reference dose can be defined as an estimate
of a daily exposure to the human population (including sensitive
subgroups) that is likely to be without an appreciable risk of
adverse effects.
TOLERANCE DECISIONS
Traditionally, in making tolerance decisions, EPA has
compared the reference dose with the Theoretical Maximum Residue
Contribution (TMRC) of the pesticide to the daily diet. The TMRC
is a mathematical construct obtained when the proposed
tolerance(s) is added to any other tolerances that have already
been established for the pesticide, and multiplied by average
food consumption estimates based on USDA data from its Nationwide
Survey of Food Consumption. (Currently, EPA is using data from
USDA's 1977-78 survey since these are the most recent
comprehensive survey results available. USDA is in the process
of analyzing results from its 1987-88 Nationwide Survey, and EPA
will use these more recent survey results when they become
available.) As a rule of thumb, where basic data requirements
are satisfied, EPA has routinely established a proposed tolerance
if the TMRC is less than the reference dose.
However, as a routine practice, before making tolerance
decisions on a pesticide, EPA uses the Dietary Risk Evaluation
System (ORES) — former known as the Tolerance Assessment System
— to calculate TMRC and risk estimates for the general
population and a number of subgroups including the two most
sensitive subgroups identified by the system. In some cases,
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peak exposures to certain subgroups, such as infants and
children, may exceed the reference dose by some percentage even
though this is not the case for the composite average of the
population. Since the reference dose is not a precise indicator
of risk, exceeding the reference dose by a small factor is not
necessarily a cause for concern. However, if the ORES analysis
indicates that exposure and thus estimated risk to such a
subgroup is so high that adverse effects are likely to occur, the
Agency will not approve a tolerance even if the estimated risks
to the average population are acceptable.
Examples of cases where dietary concerns for infants and
children in particular have been the overriding consideration
include:
> A decision bu EPA in 1985 not to approve tolerances for the
pesticide pydrin for proposed new uses on alfalfa and
sorghum, due to risks to children from secondary residues in
milk.
> An action level for the occurrence of heptachlor epoxide in
milk from cows fed pineapple greens that had been treated
with heptachlor. Based on the potential for short-term
liver toxicity in non-nursing infants and small children,
EPA recommended and FDA issued a lower action level than
would have been required to protect adults from adverse
effects.
> EPA's announcement in early 1989 to expedite a notice of
cancellation for all uses of Alar (daminozide), meanwhile
extending a temporary tolerance for Alar residues in apples
and urging voluntary restraint on its use. In the case of
Alar, EPA was particularly concerned about the upper-limit
cancer risk for Alar exposure to infants and toddlers for
the first year and one-half of childhood.
It is important to note that the TMRC is a very rough-hewn
tool of the tolerance process. Taken out of context, and applied
literally, the TMRC can be used to make calculations that
misrepresent risks from pesticides as artificially high. It is
necessary to go beyond the TMRC approach, using real data on
pesticide usage rates and anticipated residue levels, in order to
evaluate actual dietary exposure and risk to consumers from
pesticide residues in the food supply. Certain standard TMRC
assumptions tend to greatly exaggerate the dietary risks
attributable to pesticides; for example: (1) that 100% of each
crop that may legally be treated with a pesticide is in fact
treated with the pesticide, and (2) that pesticide residues in
each commodity that may be treated with the pesticide are always
present at tolerance levels at the time of consumption. Studies
have shown that either is rarely the case, and that therefore the
amount of residues on foods when they reach the consumer is
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typically well below the established tolerance level.
There is an important exception to the reference dose
approach described above. EPA has not used the reference dose
concept, which implies a threshold level of risk, in considering
tolerances for pesticides that induce cancer in test animals.
Instead, the Agency takes a more conservative approach, based on
widely used quantitative risk assessment models, which projects
upper-bound (worst-case) estimates of additional risk above the
background cancer risk in the general population of 1 in 4 or
0.25 (2.5 x 10*1) . Basically, the approach involves determining
a quantitative estimate of a pesticide's carcinogenic potency,
called a "Q star," and comparing the Q star to dietary exposure
estimates. Dietary exposure estimates are based on the tolerance
level of residues unless verifiable data on actual residues of
the pesticide in agricultural commodities and consumer products
are available.
In regulating pesticides that induce cancer in laboratory
animals, EPA applies the "negligible risk" concept recommended by
the National Academy of Sciences (NAS) to the extent possible in
making registration and tolerance decisions under FIFRA and
FFDCA.
In sum, the tolerance process is highly protective in that
it is based on the most sensitive animal test results available
and a combination of highly conservative assumptions and risk
assessment practices. Tolerances are set at the lowest level
necessary to accommodate the maximum application rate and
frequency being proposed for the pesticide use, even when higher
levels would be safe for human consumption.
ISSUES RELATED TO INFANTS AND CHILDREN
Several points should be highlighted regarding the tolerance
process that relate to the protection of children:
> As mentioned above, in animal studies used for human risk
assessment purposes, chemicals are administered to test
animals beginning with young animals (post-weanling) and
continuing through adulthood (mimicking human exposure that
begins in adolescence and continues over a lifetime). The
body dose received by the young animals may be double that
of the adult animals, due to changes in their consumption
patterns. However, the lower (adult) body dose is typically
used in reference dose estimates. This results in a lower
(and more protective) reference dose than would otherwise be
the case.
> In setting reference doses, EPA generally uses a 10-fold
uncertainty factor to compensate for the uncertainty
inherent in the process of extrapolating human dietary risk
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projections from animal data and, in addition, another 10-.
fold factor to compensate for ^he possibility of differing
sensitivities in individuals or subgroups — such as
children — among the general population.
> In cases where carcinogenicity is the potential effect of
concern, EPA considers the upper limits of risk that may
result from a lifetime exposure. Where these upper limit
risks are not unreasonable from lifetime exposure, EPA
concludes that the risk from a portion of lifetime exposure
(e.g., between ages 1 and 12 or between 1 and 21) is
likewise not unreasonable — regardless of changes in eating
habits expected to occur between infancy and adulthood.
This practice is consistent with EPA's published cancer risk
assessment guidelines and with current, mainstream thinking
in the scientific community. EPA does not at this time have
data to support specific modifications to this approach with
respect to infants and children. However, at the request of
the Agency, the HAS is currently examining issues
surrounding pesticides in the diets of infants and children.
When the NAS concludes its report, EPA will consider whether
its present approach should be adjusted in light of the
Academy's findings.
> Data on the comparative toxicity of pesticides in adult
versus young weanling mammals are very limited and
principally pertain to acute toxic effects only. A series
of acute studies show mixed results. In studies of 37
chemicals administered to adult and weanling rats, weanlings
demonstrated greater sensitivity in 8 cases. Adults showed
greater sensitivity than weanlings in 23 cases. In 6 cases
the sensitivity of adult and weanling rats was roughly the
same.
> When estimating dietary exposure to infants and children,
EPA's ORES uses milligram-per-kilogram body weight (rather
than body surface) comparisons with dietary intake levels
for risk assessment purposes. As the FIFRA Scientific
Advisory Panel has pointed out, this practice is likely to
overstate dietary risk to infants.
OTHER AREAS OF CONCERN
Pesticide Residues in Imported Foods and the "Circle of
Poison". The tolerances established by EPA and enforced by FDA
apply equally to domestically grown and imported food
commodities. FDA monitors food crops imported from other
countries to ensure that they do not contain pesticide residue
levels higher than those determined acceptable for food crops
grown in the U.S. Imported food crops may be denied entry into
the U.S. if they are found to contain pesticide residue levels
that exceed the established U.S. tolerances.
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Also, to ensure that U.S. consumers are not eating residues
of pesticides that have been banned in this country, EPA revokes
the tolerances for pesticides that are cancelled. Once
tolerances are revoked, neither domestic nor imported foods may
lawfully contain residues of the banned pesticides. By revoking
tolerances for banned pesticides, EPA prevents a "circle of
poison" situation from occurring since pesticides banned in the
U.S. are prevented from reentering the U.S. food supply through
foods grown in other countries where the pesticide still may be
lawfully used.
Neurotoxicity testing. EPA is in the process of upgrading
its guidelines for neurotoxicity testing requirements. On this
initiative, EPA's Office of Pesticide Programs (OPP) is working
in concert with the Office of Toxic Substances (OTS), in
publishing and reviewing public comment on neurotoxicity testing
guidelines. These guidelines have been revised in light of
public comments, and were recently submitted to the FIFRA
Scientific Advisory Panel for review. EPA will incorporate the
guidelines into its data requirement regulations under 40 CFR
Part 158 and will require such data on a case-by-case basis until
the revisions become final and effective.
Inert Ingredients. EPA published a Federal Register notice
on April 22, 1987, describing a policy of increased scrutiny of
inert ingredients. New inerts are subject to data requirements
and registrants were urged to replace existing "inerts of
toxicological concern" with less toxic chemicals. Registrants
who failed to substitute were required to label their products to
reveal the identity of the toxic inert, and will be required to
submit the extensive data necessary for a product-by-product
risk/benefit evaluation.
Data Gaps. Although a large number of active ingredients
are registered for pesticide use on food, fewer than half of the
active ingredients account for approximately 90 percent of the
poundage of agricultural pesticides used. However, some of these
products were first registered after 1984, and EPA has very
extensive information on these pesticides. Other pesticides have
been registered for some years and are undergoing reregistration.
Since EPA has concentrated its reregistration efforts on
reviewing these large agricultural use pesticides, EPA either has
now, or will have in a very few years, a more complete data base
on the pesticides contributing most heavily to dietary exposure.
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