RISK ASSESSMENT METHODOLOGY FOR FISH
OFFICE OF PESTICIDE PROGRAMS
August 16, 1990
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BACKGROUND
The Environmental Protection Agency (EPA), through the
Office of Pesticide Programs (OPP), is responsible for regulating
pesticides under the Federal Insecticide, Fungicide, and
Rodenticide Act, as Amended (FIFRA 1988). FIFRA establishes an
overall risk/benefit standard for pesticide registration,
requiring that pesticides perform their intended function, when
used according to label directions, without posing unreasonable
risk of adverse effects on man or the environment. In addition,
for any pesticide intended for use on food or feed crops, EPA is
responsible under the Federal Food, Drug, and Cosmetic Act
(FFDCA) for setting tolerances (maximum permissible residue
levels) for pesticides in or on food and feed commodities.
EPA establishes tolerances on a national basis for residues
of a pesticide in a commodity which result from application of
the pesticide to that commodity. For fish, tolerances are
required if the pesticide is applied to a body of water from
which fish are taken for food and which travel in interstate
commerce. For example, if a pesticide is applied to rice fields
in which catfish or crayfish are farmed, a tolerance is required
for residues of the pesticide in fish. Pesticide tolerances
established by EPA are enforced by the Food and Drug
Administration (FDA), the U.S. Department of Agriculture (USDA),
and state enforcement agencies. Below is a list of established
tolerances for pesticide residues in fish:
Tolerance
Commodity Pesticide (ppm)
Fish dichlorophenoxyacetic acid 1.0
diquat dibromide 0.1
isopropylamine glyphosate 0.25
simazine 12.0
cuprous oxide exem*
polyoxyethylene exem*
fluridone 0.5
triclopyr 0.2T**
bensulfuron methyl ester 0.3T**
dichlorophenoxyacetic acid 1.0
Shellfish cuprous oxide exem*
dichlorophenoxyacetic acid 1.0
diquat dibromide 0.1
polyoxyethylene exem*
triclopyr 0.2T**
isopropylamine glyphosate 3.0
Oysters carbaryl 0.25
Catfish potassium ricinoleate exem*
(meat animal)
*exem = exemption from the requirement of a tolerance
**T = temporary tolerance
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If a pesticide has been cancelled due to health or
environmental risks, it is Agency policy to revoke all food
tolerances and, if necessary, to recommend action levels for
pesticide residues on food and feed crops. While tolerances are
established to reflect pesticide residues resulting from current
pesticide uses, action levels are set for inadvertent pesticide
residues, such as residues of cancelled, but environmentally
persistent pesticides. Action levels, like tolerances, are
established to reflect the maximum allowable pesticide residue in
food or feed in interstate commerce. A policy statement issued
by the EPA (Federal Register/Vol. 47, No. 189/9/29/82) describes
the process of tolerance revocation for cancelled pesticides, as
well as factors which must be considered when replacing these
revoked tolerances with action levels. Among these factors are
the extent to which the pesticide residues are unavoidable and
the safety of these residues considering available exposure and
toxicological data. Although action levels are established for
contaminants other than pesticides, OPP is responsible for
recommending action levels for pesticides only.
Based upon residue monitoring data, such as FDA surveillance
data, EPA determines appropriate action levels and recommends
these levels to USDA and FDA. USDA has the responsibility to
establish and enforce EPA's recommended action levels in meat
products, poultry, and eggs, while FDA has this responsibility in
all other commodities, including fish. Current fish action
levels for pesticides were established prior to the 1982 policy
statement, and most were established prior to EPA's existence
(1970). Information regarding how these were determined is not
readily known. Below is a list of FDA action levels in fish:
Action
Commodity Pesticide Level fppm)
Fish aldrin and dieldrin 0.3
chlordane 0.3
DDT, TDE, and DDE 5.0
endrin 0.3
heptachlor and
heptachlor epoxide 0.3
mirex 0.1
toxaphene 5.0
kepone 0.3
Fish By-products endrin 0.3
Crabmeat kepone 0.4
Shellfish kepone 0.3
Fish, shellfish, mercury 1.0
crustaceans, other
aquatic animals.
Edible portion only
Fresh, frozen, or
processed.
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HAZARD IDENTIFICATION AND CHEMICAL RESIDUE ANALYSIS
The Office of Pesticide Programs in EPA uses its data
collection authorities under FIFRA to require the pesticide
manufacturer to produce data needed to determine the hazard and
chemical properties of a pesticide. The data required to set
tolerances in fish and other commodities are mainly residue
chemistry and toxicity data. Specific studies which are required
to support a registration and tolerance petition are codified in
the Code of Federal Regulations, 40 CFR, Part 158. In addition,
OPP publishes Pesticide Assessment Guidelines which contain the
standards and protocols for conducting acceptable tests, guidance
on evaluation and reporting of data, and further guidance on when
data are required. Although specific analytical method limits of
detection (LODs) are not specified for these studies, OPP
recommends that the LODs be sufficiently low so that the combined
risk from all commodities calculated is acceptable.
Below is a summary of the residue chemistry and toxicity
studies required to support a fish tolerance request:
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 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 Fish. Metabolism data are required so EPA may
characterize the nature of the residue that occurs in fish
intended for consumption as food or animal feed. To obtain these
data, the pesticide is labeled with a radioactive atom, usually
carbon fourteen, and applied to the water in accordance with
proposed use directions. Since the pesticide molecule is
radiolabeled, one or more of the metabolites or degradation
products remaining in the fish will be radioactive. The carbon
fourteen activity is separated into various fractions, and the
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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 possible detect residues of concern.
Metabolism studies are required for fish and shellfish.
Fish metabolism studies use radiolabeled pesticides. The water
is treated, and the level of radioactivity resulting in fish is
analyzed. If significant activity is found, the chemical
identity associated with the activity is determined. This
process answers the question, what is the residue in fish?
Significant Metabolites and Tolerance Expression. Using the
results of fish 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."
Fish 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 bodies of water 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. These trials 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 a top-feeding fish, a
bottom-feeding fish, and for shellfish.
Analytical Methods. Based on fish 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 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
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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 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 fish residue field trials provide
data for estimating tolerance levels in fish, studies may also be
needed for fish meat derived from fish in treated water. 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 to water which is consumed by animals
or if fish meal is fed 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
Pesticides having tolerances in fish are considered aquatic
food crop pesticides under CFR 158.340. The toxicity data base
(as described below) required for this use includes the
following: acute, subchronic feeding in rat and dog, chronic
feedings in rat and dog, teratology (developmental toxicity) in
rats and rabbits, reproduction study in rats, cancer evaluation
usually in rats and mice), metabolism and a mutagenic battery.
Other studies may be required on a case-by-case basis.
Acute Studies. Determination of acute oral, dermal, and
inhalation toxicity is usually the initial step in the assessment
and evaluation of the toxic characteristics of a pesticide.
These data provide information on health hazards likely to arise
soon after, and as a result of, short-term exposure. They also
provide information used in establishing the appropriate dose
levels in subchronic and other studies and provide initial
information on the mode of toxic actions(s) of a substance.
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Subchronic Studies. Subchronic tests provide information on
health hazards that may arise from repeated exposures over a
limited period of time. They provide information on target
organs and accumulation potential. The resulting data are also
useful in selecting dose levels for chronic studies and for
establishing safety criteria for human exposure. These tests are
not capable of detecting those effects that have a long latency
period for expression (e.g., carcinogenicity).
Chronic Studies. Chronic toxicity (usually conducted by
feeding the test substance to the test species) studies are
intended to determine the effects of a substance in a mammalian
species following prolonged and repeated exposure. Under the
conditions of this test, effects which have a long latency period
or are cumulative should be detected. The purpose of long-term
oncogenicity studies is to observe test animals over most of
their life span for the development of neoplastic lesions during
or after exposure to various doses of a test substance by an
appropriate route of administration.
Teratogenicity (Developmental Toxicity) and Reproduction
Studies. The teratogenicity study is designed to determine the
potential of the test substance to induce structural and/or other
abnormalities to the fetus as the result of exposure of the
mother during pregnancy. Two-generation reproduction testing is
designed to provide information concerning the general effects of
a test substance on gonadal function, estrus cycles, mating
behavior, conception, parturition, lactation, weaning, and the
growth and development of the offspring. The study may also
provide information about the effects of the test substance on
neonatal morbidity, mortality, and preliminary data on
teratogenesis and serve as a guide for subsequent tests.
Mutagenicitv Studies. For each test substance, a battery of
tests are required to assess potential to affect the mammalian
cell's genetic components. The objectives underlying the
selection of a battery of tests for mutagenicity assessment are:
(1) to detect, with sensitive assay methods, the capacity of a
chemical to alter genetic materials in cells; (2) to determine
the relevance of these mutagenic changes to mammals; and (3) when
mutagenic potential is demonstrated, to incorporate these
findings in the assessment of heritable effects, oncogenicity,
and possibly other health effects.
Metabolism Studies. Data from studies on the absorption,
distribution, excretion, and metabolism of a pesticide aid in the
valuation of test results from other toxicity studies and in the
extrapolation of data from animals to man. The main purpose of
metabolism studies is to produce data which increase the Agency's
understanding of the behavior of the chemical in its
consideration of the human exposure anticipated from intended
uses of the pesticides.
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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 noncarcinogenic
effects, and a cancer risk estimate if the pesticide has
carcinogenic potential. The studies begin with young
(postweanling) animals, and exposure continues through their
adulthood (thereby mimicking human exposure beginning in
adolescence and continuing over a lifetime). Using the NOEL, an
acceptable daily intake (ADI) level — which EPA scientists now
call a reference dose (RfD) — can be proposed for humans by
applying a suitable uncertainty factor.
Three studies (rat reproduction, chronic rat feeding, and
chronic dog feeding) generally form the basis for determining the
RfD or ADI. The lowest dose causing no adverse effects from
these three studies is divided by a safety factor to determine
the RfD or ADI. The safety or 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. The RfD is peer reviewed in the Office of
Pesticide Programs prior to discussion by the Agency and is
incorporated into the EPA Integration Risk Information System
(IRIS).
In addition to residue chemistry and toxicology studies, the
Agency requires data on environmental fate, reentry protection,
spray drift, and effects on nontarget organisms for establishing
tolerances. All of these studies are used to assess exposure and
toxicity to humans and the environment.
RISK ASSESSMENT
Risk Assessments for tolerances and action levels in fish
and other commodities are determined by integrating
toxicological, consumption, and residue data according to the
following formula:
toxicological residue
risk = value (qi* or RfD) x value x consumption
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For carcinogenic pesticides such as DDT, chlordane, and
aldrin/dieldrin, the toxicological value is determined by using
both the cancer potency factor (qi*) and a reference dose (RfD)
or acceptable daily intake (ADI). The qi*is expressed as a human
qi* derived by multiplying a surface area conversion factor by
the animal qi*. If the pesticide does not cause cancer or causes
such a weak carcinogenic response that the qi* calculation would
be inappropriate, the risk would be determined by comparing the
exposure to the reference dose. Both the qi* and reference dose
can be found on the Agency's Integrated Risk Information System
(IRIS).
Consumption information is taken from OPP's Dietary Risk
Evaluation System (ORES) — formerly known as the Tolerance
Assessment System (TAS). ORES is a computerized data management
system which can estimate dietary exposure for the U.S.
population and 22 subgroups. The consumption data in ORES is
based on USDA's 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.)
ORES is composed of data files for food consumption
estimates, toxicology summaries for each chemical and residue
concentrations for each chemical in specific foods. ORES is
capable of breaking fish consumption down by season (4),
geographical region (4), ethnic group (4), and age-sex (10
subgroups), and can be used to estimate separate consumption of
freshwater finfish, saltwater finfish, dried saltwater finfish,
shellfish, and caviar. The average fish consumption value in
ORES is 0.25 fish/kg body weight/day. To estimate consumption of
fish by high fish consumers, conservative estimates of red meat
replacement by fish (2.24g fish/kg body weight/day) and red meat
and poultry replacement by fish (3.00g fish/kg body weight/day)
have been assumed using DRES consumption for red meat and
poultry.
The residue value used in the risk assessment will vary
depending on the nature of the toxic effect. For acute effects,
an upper bound residue value will be used, while for carcinogenic
effects, an average residue level is appropriate. The residue
level used in calculating dietary exposure is the tolerance or
maximum permissible residue level.
Although the Dietary Exposure Branch in OPP does not have a
routine procedure for calculating action levels, the Branch has
used the following method for recalculating action levels which
may be potentially recommended to FDA. The residue value used in
calculating dietary exposure for action levels is the composite
average residue of all fish species consumed nationally, weighted
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by the percent of national consumption for each species. The
composite average residue is calculated assuming all fish above a
specified maximum level (action level) are removed from the
market (i.e., residues in these fish are not included in the
calculations). Other factors which could influence the residue
value chosen include the variability of the residues within or
among species, the quality of the available monitoring data, the
required confidence in the risk assessment, and many other
factors. Deciding on the appropriate residue level to use for
risk assessment depends on these many factors and is done on a
case-by-case basis for specific pesticides and exposure
scenarios.
While the residue level used for risk assessment varies as
described above, the residue level recommended as an action level
must represent the maximum allowable pesticide residue. It
should be noted that the residue level used for risk assessment
and the residue level used for an action level need not be the
same, and for carcinogenicity and other chronic effects, they are
usually not the same. For example, the Agency's current models
of carcinogenesis relate the frequency of carcinogenesis to the
amount of pesticide exposure over a long time period. At any one
meal, lower or higher levels of pesticide residue may be
consumed, but over a period of time, residue consumption will
likely approach an average residue level which can be used for
risk assessment. For calculating an action level, the maximum
allowable residue (which reflects a specific average residue)
should be used.
Residue data are normalized to reflect the total residue
(including metabolites) in the edible portion of the fish.
Nondetectable residues may be incorporated into the calculations
as the LOD, 1/2 LOD, or a more complicated analysis may be done
depending on the toxic effects and on the quality of the
available residue data. Depending on the toxicological effect,
either average or upper bound residues are determined from these
data. When performing risk assessments for contaminated fish as
part of an action level evaluation, consumption of commodities
other than fish is not considered. Also risk from each pesticide
chemical is considered separately since use of the mixtures
approach, which would require some knowledge of the relative
quantities of pesticides in fish, is not feasible because of the
large variability in relative pesticide levels.
As previously mentioned in the Background of this paper,
most action levels for pesticides in fish were established by FDA
prior to EPA's existence. At the request of Region V, OPP has
initiated a study to reassess fish action levels for chlordane,
DDT, aldrin/dieldrin, heptachlor, and mirex. OPP's analysis
considered several possible options for assessing fish action
levels, ranging from maintaining the status quo to lowering
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action levels to the limit of detection (LOD). Intermediate
options were based on 90th and 95th percentile residue
determinations weighted to account for variations in the
consumption of different species of fish. OPTS management has
been briefed on these options, and a decision concerning the
appropriate methodology should be forthcoming.
ECONOMIC IMPACT ANALYSIS
In general, OPP performs economic analyses for chemical-
specific regulatory actions (i.e., Special Reviews), as well as
for major policies and regulations. For the most part, OPP does
not perform economic analyses for the registration of a pesticide
or for the establishment of a tolerance, with the exception of
minor use exemption waivers and tolerance fee waivers.
Modification of action levels for fish or other commodities,
however, would require an analysis and comparison of the risk
reduction and economic costs associated with various policy
options during regulatory development. The results of these
analyses would be used to determine the trade-off between costs
and risks for each option under consideration. In this fashion,
OPP can identify and propose the most cost-effective option
(i.e., the option which has the lowest cost-to-risk ratio).
In the options paper (mentioned above) in which OPP analyzed
the impacts of reducing action levels for certain pesticides, the
program completed a risk assessment and an economic impact
assessment for each option under consideration (as required under
E.O. 12291). Because the uses for these pesticides have been
cancelled, modifications to existing action levels would not
affect their use or environmental loading. In addition,
pesticide users (i.e., farmers, homeowners, and commercial
applicators) would not be directly affected. Instead, the Agency
expects that most of the regulatory costs would be borne by
commercial and recreational fisherman and that some of these
impacts would be passed down to the consumer level in the form of
higher prices for fish. The following sections identify the
implications of lowering fish action levels and outline the
Agency's analytical methodology.
As previously mentioned, EPA recommended action levels are
usually adopted by the FDA. FDA inspects food for the presence
of contaminants exceeding its established action levels, and has
the power to seize contaminated shipments which are intended for
interstate commerce. When the Agency lowers the action levels
(i.e., becomes more stringent), the amount of fish that can be
seized by FDA increases. Eliminating fish with relatively high
levels of contamination reduces the average amount of pesticide
residues in marketable fish. This reduction in residues lowers
dietary exposure and subsequent risks to human health. To
determine the most cost-effective approach, the economic costs
are compared to the risk reduction achieved under each regulatory
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option. The methodology used to determine regulatory costs is
outlined below.
While EPA action levels for fish have no binding effect on
the regulation of commercial fish in interstate commerce, either
for fish inspection programs or fishing restrictions, some states
have developed their own maximum residue levels which trigger
regulatory and/or nonregulatory actions. Changes in EPA action
levels may cause a state to re-evaluate its own risk assessments
for fish consumption, which may, in turn, result in some type of
policy action intended to restrict fish consumption. These
actions include seizing intrastate shipments, prohibiting
shipments, closing fisheries, issuing "catch and release"
restrictions, and issuing consumption advisories.
The impacts of seizing shipments are fairly straight forward
to estimate. However, predicting the response of state and local
government agencies, consumers, and the fishing industry is more
difficult to determine. In response to restrictions on fishing
in certain areas or for certain species, fisherman may simply
fish other areas or species. Similarly, consumers may change
their fish consumption patterns rather than reduce total
consumption of fish in response to consumption advisories. Given
these uncertainties, the Agency quantified only the economic
impacts on commercial fisherman for the RIA on fish action
levels. A qualitative discussion of impacts on the sports
fishing industry was also included.
The value of economic impacts is based on residue data
regarding pesticide concentrations in fish. These data enable
the Agency to determine the percentage of each fish species that
would exceed current action levels (baseline), and the action
levels proposed under the regulatory options. Based on these
results, OPP estimated the volume and value of fish that would
not be marketable under each option. These estimates assume
perfect enforcement of the assumed action level under each
regulatory scenario (i.e., all fish contaminated above the action
level are inspected and seized, and no fish below the action
level are included in seized shipments).
As mentioned earlier, changes in pesticide action levels in
fish have no direct effect on sports fishing. However, changes
may trigger states to issue new or revised consumption advisories
or issue "catch and release" restrictions. Since these responses
are difficult to predict, and the resulting changes in behavior
of sports fishermen are even more difficult to predict, OPP has
not attempted to estimate the (monetary) impacts on the sports
fishing industry. To address this issue, OPP economists have
presented information regarding the value of sports fishing
(i.e., direct cash outlays as well as downstream benefits to
local economics), and a qualitative discussion of the possible
impacts associated with changing action levels. In particular,
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examples of economic impacts resulting from known fish
contamination have been cited. OPP believes this type of
information will help frame the level of impacts that could
result in affected areas.
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