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Environmental Backgrounder: Pesticides and Food Safety

Environmental Backgrounder: Pesticides and Food Safety

The Environmental Protection Agency (EPA) is responsible for regulating the amount of pesticide residue that may 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 established 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 microbiological contaminants. Since surveillance resources are limited, they must be allocated on the basis of priority concerns; pesticide residues are generally considered to be of a lesser concern than microbiological contamination.

Federal and state inspectors commonly sample food and feed produce for the purpose of tolerance enforcement soon after a 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."

Pesticide residues tend to dissipate or break down as time passes after harvest, and in the majority (but not all) cases, residues are further reduced by washing, peeling, cooking, and processing of foodstuffs. Almost by definition, tolerances represent levels of pesticide residue that are not expected to occur as actual residues in food commodities that reach the consumer.

In general, the data required for a tolerance are of two kinds -- residue chemistry data and toxicology study results. Such data are not generated by EPA laboratories; rather, EPA uses its data-collection authorities under the law to require the pesticide manufacturer to sponsor testing 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 used by EPA toxicologists to answer 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 effect will result in humans even after a lifetime of exposure?

Residue Chemistry Data

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 composition data for pesticides, called product chemistry data. In particular these data include (1) information on the manufacturing process, (2) chemical analysis of the active ingredient, (3) "certified limits"for unavoidable variations in the amounts of the ingredients in a product, and (4) analytical methods used to determine the composition of the pesticide.

EPA evaluates this product chemistry data set 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 that EPA may characterize the nature of the residue that occurs on crops intended for consumption as food or animal feed. To obtain this kind of 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, any metabolite or degradation product 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, usually 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? 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 (l) 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 have indicated what to look for, and methods have been 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 the 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 are requested. In addition, data are also required for each raw agricultural commodity derived from the crop. As an example, for 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 used for two purposes: (l) 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 during 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-oncogenic effects, or a cancer risk estimate if the pesticide has oncogenic potential. The studies begin with young (post-weanling) animals, and exposure continues through their adulthood (thereby mimicking human exposure beginning in childhood 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 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, adverse developmental effects, 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 (ADI) Level

Using the NOEL, an acceptable daily intake (ADI) level -- which scientists now call a reference dose -- can be proposed for humans by applying a suitable safety factor. The safety factor is intended to allow an extra margin of safety to compensate for (l) 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 safety factor is used in most instances.

In general, the ADI or 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 summed together with 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 as soon as they become available). As a rule of thumb, where basic data requirements are satisfied, EPA has routinely ruled in favor of a proposed tolerance if the TMRC is less than the ADI.

However, as a routine practice, before making tolerance decisions on a pesticide, EPA uses the TAS to calculate TMRC and risk estimates for the two most sensitive subgroups identified by the system as well as the population as an average. In some cases, peak exposures to certain subgroups, such as infants and children, may exceed the ADI by some percentage even though this is not the case for the composite average of the population. Since the ADI is not a precise indicator of risk, exceeding the ADI by a small factor is not necessarily a cause for concern. However, if the TAS analysis indicates that exposure and thus 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 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 in 1985 not to approve tolerances for the pesticide pyrdrin 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 short- term liver toxicity in non-nursing infants and small children, EPA issued a lower action level than would have been required to protect adults from adverse effects.

> EPA's recent announcement 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 is 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: (l) 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.

Thus, for example, since 92 pesticides are registered for use on tomatoes, the TMRC calculations would lead one to assume that all tomatoes contain tolerance level residues of all 92 pesticides. This is never the case in reality. To illustrate, Chart 1[*] gives an overview of the pesticides registered for use on tomatoes, by type: 54 insecticides, 20 fungicides, 7 herbicides, 4 soil fumigants, and 3 growth regulators; plus 4 additional miscellaneous pesticides (not shown). By comparison, Chart 2 shows recent pesticide usage data on tomatoes grown for processing in the State of California, which produces 86% of tomatoes grown for processing in the U.S. California processing tomatoes grown in 1986 were actually treated with very few of these 92 pesticides. Only 3% of California farms reported use of as many as 3 fungicides; 4% used as many as 4 herbicides; 4% used as many as 5 insecticides, 2% used 2 soil fumigants, and none used more than 1 growth regulator.

[*] NOTE: Charts and figures are not included in this version. They are available from the Chemicals-Pesticides Program upon request.

To illustrate the difference between a tolerance limit and actual residues present in consumer products, Chart 3 shows recent data on actual residues of the pesticide chlorothalonil on tomatoes. The established tolerance is 5 parts per million (ppm), indicated by the leftmost vertical bar. All post-harvest "farm gate" residues in tomatoes in these studies were well below 5 ppm. Moreover, there was little or no detectable residue of chlorothalonil in tomatoes by the time the commodity reached the consumer. In fact, 95% of residues were removed during washing at the packing house.

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 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 to the minus 1). Basically, the approach involves determining a quantitative estimate of a pesticide's oncogenic potency, called a "Q star," and comparing the Q star to dietary exposure estimates. Dietary exposure estimates are based on the tolerance level of residue 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 for 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 tests 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, 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 childhood 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 (ADI) estimates. This results in a lower (and more protective) reference dose than would otherwise be the case.

> In setting ADIs or reference doses, EPA generally uses a lO-fold safety factor to compensate for the uncertainty inherent in the process of extrapolating human dietary risk projections from animal data and, in addition, another 10-fold factor to compensate for the 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, the NAS is currently examining issues surrounding pesticides in the diets of infants and children. When the NAS concludes its report, EPA will be considering 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 pertain to acute toxic effects only. These 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 Tolerance Assessment System 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

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), which has published and received public comment on its neurotoxicity testing guidelines. Once these guidelines are revised in light of public comments, they will be submitted to the FIFRA Scientific Advisory Panel for review in summer 1989. EPA will then incorporate the resulting 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 Inqredients

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 are being urged to replace existing "inerts of toxicological concern" with less toxic chemicals. Registrants who fail to substitute must label their products 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 required for pesticide use on food, fewer than half of the active ingredients account for approximately 90 percent of the poundage of agricultural pesticides used. Many 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 very complete data base on the pesticides contributing most heavily to dietary exposure.