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TRAC 6/22-23/98

Staff Paper #7
EPA'S RISK ASSESSMENT PROCESS
for TOLERANCE REASSESSMENT

INTRODUCTION

The Office of Pesticide Programs (OPP) evaluates the safety of pesticides to humans through a process that is known as a health risk assessment. This process involves assessing the toxicity or hazard potential of a chemical and determining how much exposure is likely to occur to ensure that when a pesticide is used, humans are adequately protected. The process described in this paper focuses on the risk assessment process underlying tolerance reassessment. It is similar to the process used to assess proposed new tolerances. However, it does not include a description of ecological risk assessment except for the human drinking water exposure necessary for aggregate exposure assessment. Although the process can be described in a linear fashion, it often is not conducted linearly. In fact, there are many opportunities to resolve issues and refine the assessment by obtaining better information about exposure (e.g., use and usage information) or performing more sophisticated analyses (e.g., Monte Carlo).

DATA FOR RISK ASSESSMENT

To perform a risk assessment, OPP needs data. Generally, pesticide manufacturers (i.e., registrants) are required to submit a full and comprehensive battery of toxicity, residue chemistry, and other data. (These standard data are required by regulation at 40 CFR Part 158.) The toxicity data are used to identify the hazard potential of a pesticide. Residue chemistry data are used to determine the amounts of pesticide residues in and on all foods and food products, including milk and meats. All the submitted data are reviewed by Agency scientists for conformity with standard practices within the discipline and Agency Test Guidelines.

In addition to these toxicity and residue chemistry data, OPP may also use other data when it is necessary to refine and make more realistic exposure assessments. These additional data may include residue measurements from the U.S. Department of Agriculture, the Food and Drug Administration, and state monitoring programs. Registrants or users might provide market basket or grocery store surveys, information on the actual percentage of a crop treated, or field-level information about how a pesticide is actually used, including actual application rates, and timing and frequency of application. As with the base toxicity and residue chemistry data, OPP reviews these data to assure their reliability and accuracy.

Within OPP, the Special Review and Reregistration Division (SRRD) manages the reregistration and tolerance reassessment process for most conventional chemical pesticides. As part of implementing the 1988 amendments to the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), OPP required and received the basic toxicity and residue chemistry data for all pesticides registered before November 1984 (the date when 40 CFR Part 158 became effective). After that date, these data were also routinely required before registration for any new pesticide chemical used on food crops. SRRD starts the risk assessment process by submitting all these studies and any other relevant information to the Health Effects Division (HED) for an evaluation of human health risks and to the Environmental Fate and Effects Division (EFED) for an evaluation of drinking water exposure (as well as other environmental effects). Throughout the process, SRRD is responsible for requesting, receiving, and putting into review information necessary for reassessing food safety.

CONDUCTING THE RISK ASSESSMENT

HED evaluates the toxicity data, the residue chemistry data, information on use, more realistic exposure measurements, percent crop treated to establish endpoints (or effects) of concern, and to characterize residential and dietary exposure. These analyses, along with the drinking water exposure evaluation are the basic elements of a risk assessment.

In risk assessment terminology, the identified effects are referred to as toxicological endpoints. Effects appearing quickly are known as acute and longer term effects are called chronic.
Risk assessment follows a four-step process:

(1) Hazard Identification; (2) Dose-Response Assessment; (3) Exposure Assessment; and (4) Risk Characterization.

Hazard Identification

Toxicity tests are conducted on animals dosed by different routes of exposure: oral, dermal, and inhalation. The toxicity tests are designed to explore a wide spectrum of effects that may occur (e.g., birth defects, cancer, changes in fertility or ability to reproduce, neurotoxicity, harmful effects to the kidney or liver, etc.). Other sources of toxicity data include the open literature, epidemiological information, and voluntary submissions by the registrants.

Unless indicated otherwise, OPP assumes that test results in animals are relevant to the identification of hazards in humans. During hazard identification, all available toxicology data are reviewed to see what harm the pesticide might cause. Some effects may appear quickly (e.g., headache and nausea). Other effects will appear only after years of exposure (e.g, cancer). Knowing whether the effects are acute, chronic, or both is important in dietary exposure assessment.

Dose-Response Assessment

In evaluating a toxicity test, the HED science review team determines at what dose level the effects occurred. In some cases, there will be no response in the animals until a certain dose level is reached. This type of effect - no response until a certain dose level is reached - is called a threshold effect (for example, weight loss). An effect that operates so there is some response

(however small) at every dose level is called a nonthreshold effect. The classic example of a nonthreshold effect is cancer. The distinction between threshold and nonthreshold effects is important when considering the extra 10-fold safety provision of FQPA because, according to the statute, this provision only applies to threshold effects.

In practice, a threshold effect is evaluated by looking at all the doses given to the animals in a specific study and identifying the highest one where no effect was seen. This level is called the No-Observed-Effect-Level (NOEL). Nonthreshold effects are evaluated differently. All the doses and their corresponding effects are fed into a computer model which calculates something called a Q1*. In technical terms, a Q1 *represents the upper 95th percentile estimate of the dose-response. Use of the upper 95th percentile is believed to account for possible interspecies or intraspecies differences in sensitivities to the carcinogen. In practice, a Q1* can be thought of as the slope of the doses plotted against their corresponding effects.

When an HED science review team has completed its primary assessment of endpoints or effects of concern, an internal peer review committee known as the Hazard Identification Assessment Review Committee evaluates the science review team's work to ensure its consistency and quality and to quantify the dose-response relationship.

In assessing risk, one of the goals is to come up with a number that represents a person's margin of safety (e.g., a margin of 100 would mean people are exposed at a level 100 times below the level shown in animal studies not to cause a toxic effect) or in some cases their probability of experiencing the toxic effect (e.g., a 1x10-6 cancer risk means that the person has a one in a million chance of developing a tumor from exposure to the pesticide). Simply put, RISK = toxicity × exposure. The process of putting a number (i.e., quantifying) on the toxicity portion of RISK is called dose-response assessment.

Dose-response Assessment:

For threshold effects, an RfD

For nonthreshold effects, a Q1*.

For threshold effects, dose-response is quantified by a reference dose (RfD). A chronic reference dose is an estimate of the level of daily exposure to a pesticide residue, which over a 70-year life span is believed to have no significant harmful effects. An acute reference dose is an estimate of the exposure to a pesticide residue in a single day which is believed to have no harmful acute effects. The pesticide program routinely calculates an RfD by dividing the no-observed-effect level from an animal study by two uncertainty factors - a 10-fold factor to account for uncertainty in extrapolating from animals to humans (i.e., interspecies) and a 10-fold factor to account for the variation within the human population (i.e., intraspecies). [In addition to these two 10-fold uncertainty factors, there is also the FQPA safety factor to address special sensitivities to infants and children. The decision to retain, reduce, or remove the FQPA safety factor is made at a later stage in the risk assessment process.]

Depending on the type of effects associated with a pesticide and the outcome of the peer review done by the Hazard Identification Assessment Review Committee, other internal Science Assessment Review Committees (SARCs) also may evaluate the science review team's work for specific issues. These committees include the Cancer Assessment Review Committee, the Reproductive and Developmental Toxicity Assessment Review Committee, and the Mechanism of Toxicity Assessment Review Committee.

Exposure Assessment

Pesticide exposure can occur through three routes of exposure - oral, dermal, and inhalation, depending on where the person is and what the person is doing. EPA has interpreted the FQPA provision on aggregate exposure to mean that in addition to the pesticide exposure that occurs through the diet, OPP also must include exposure that occurs from non-occupational sources, which include drinking water and residential exposure. HED evaluates exposure through food and in the residential activities; EFED evaluates drinking water exposure. HED aggregates exposure from these sources.

Exposure through Food

As with toxicity data, an HED science review team evaluates a full battery of testing to estimate the amount of pesticide residue that may be in foods. The actual pesticide residue measurements are done using raw agricultural commodities (i.e., grains, fruits and vegetables that are grown in the fields). To estimate the amount of pesticide residue that would be found in other food forms such as apple juice and raisins, OPP may gather additional data or perform calculations, using its knowledge based on data on how pesticide levels change during processing, etc.

It is important to note the nature of actual crop field trials, the studies conducted to determine the legal maximum amount of pesticide (or tolerance) that may remain in or on food. These studies are conducted with the pesticide applied at the highest rate allowed, according to the label instructions. When the crop is harvested, sampling is done at the 'farm gate,' which means that sampling occurs before the crop has gone through any sort of processing such as washing or has entered the channels-of-trade. This will represent the highest level of pesticide that might occur on that fruit or vegetable from legal use.

In reality, consumers generally are not exposed to pesticide residues in food at the tolerance levels. So, in refining or developing more realistic dietary exposure assessments, OPP often uses (as appropriate) pesticide residue measurements that were taken from foods sampled under more 'real-life' situations, such as at the grocery store or through FDA or USDA monitoring efforts. OPP also may use information on typical use rates to determine both typical and maximum exposure. Information on typical use rates may come from registrants, growers, or other appropriate stakeholders.

In acute dietary exposure assessments, OPP generally uses high end exposure estimates assuming foods are consumed with tolerance-level residues. This is because it is realistic that at least some consumers could have a one-time exposure to foods with residues at the tolerance level. In chronic exposure assessments, OPP uses more realistic estimates because individual exposures over time are very unlikely to continue at the full tolerance level.

A final piece of information that can be used in assessing dietary exposure and risk is the percent of a given crop that is actually treated with the pesticide. Percent of crop treated corrections are applied for foods with national or broad regional distribution and for chronic consumption patterns (e.g., the food is eaten over time). Without percent crop treated data, OPP will conservatively assume that 100 percent of the crop gets treated. Such an assumption can lead to an overestimate of the actual exposure level, especially for chronic exposure estimates.

Exposure through Residential Activities

Reliable residential and other non-occupational exposure estimates are needed to aggregate exposure. However, specific data actually measuring these exposures were not routinely required in the past. HED is using currently available information. This includes available data for residential uses, including data generated for handler and post-application exposures. It also includes using data from generic databases, such as the Pesticide Handlers Exposure Database, which relies on actual measured residue values; and results derived from models included in EPA's Standard Operating Procedures (SOPs) for Residential Exposure Assessment. These SOPs were presented to the SAP in 1997 and published the same year.

Exposure through Drinking Water

EFED begins the drinking water exposure assessment by reviewing registrant-submitted data designed to show whether a pesticide can easily move to groundwater or surface water and whether it will degrade quickly or persist. These data on how a pesticide behaves in the environment are routinely required but data on levels of pesticides in drinking water are not. (EPA has required and/or accepted studies conducted by registrants which evaluate certain pesticides' potential to contaminate groundwater.) After the review of the base data on behavior in the environment, the Agency continues its assessment by using simulation models as screening tools to estimate pesticide residues in ground and surface water. The use scenarios for these models are based on efforts to account for high end exposure potential and are currently being revised to assure more realism. The models use extensive actual data on each chemical's environmental behavior (e.g., persistence and mobility) and actual environmental conditions (e.g. soil type, rainfall). These models provide rough estimates of pesticide concentrations in vulnerable groundwater and surface water. These estimates are used primarily to screen out pesticides that will not be a drinking water concern. Such pesticides do not require further evaluation. If the screening numbers are high, EPA will evaluate data from the U.S. Geological Survey, states, and other sources to attempt to refine the estimates.

Risk Characterization

The final step in risk assessment is characterization, which is the process of combining the dose-response and exposure information to describe the overall magnitude of the public-health impact. For threshold effects, risk can be expressed via a margin-of-exposure (MOE) or as a percent of the reference dose (% RfD). For nonthreshold effects, risk is expressed as a probability (e.g., 1x10-6). The formulas for these are:

Aggregate Exposure is the combination of dietary exposure from food residues, nonoccupational exposure from residential pesticide applications, and drinking water exposure. Dietary exposure is based on what we know about what people in the United States eat and in what proportions. This information is known as food consumption data and is supplied by the U.S. Department of Agriculture. Food consumption data allows EPA to estimate dietary risks for the U.S. population as a whole along with 26 different population subgroups, including eight that are specific to infants and children.

Until recently, OPP conducted both acute and chronic dietary risk assessments using its Dietary Risk Evaluation System (DRES) software. Acute dietary risk assessments conducted with DRES assume all crops with registered uses of a pesticide are treated and bear residues at tolerance or near level. The resulting acute risk estimates are considered high-end estimates. These are likely to significantly overstate chronic exposure, although they have more validity for consideration of potentially realistic high-end acute exposures.

More recently, OPP has received from some registrants probabilistic assessments (Monte Carlo assessments) of dietary risk that use more refined information than can be used in the DRES calculation. In these assessments, the range or distribution of residue levels from field trials and percent crop treated or monitoring data can be used to estimate exposure more accurately. OPP itself now has the capability to do these types of assessments.

After internal peer review of the risk characterization components by the various Science Assessment Review Committees (SARCs), the overall risk assessment is developed for the pesticide. For example, the Cancer Assessment Review Committee evaluates any cancer concerns if appropriate. The Reproductive and Developmental Toxicity Assessment Committee will assure appropriate endpoints have been used to assess hazard to infants and children and women of child bearing age. The Mechanism of Toxicity Assessment Review Committee considers whether a common mechanism of toxicity may exist with other pesticides. The risk assessment presents a comprehensive picture of any risk concerns associated with uses of the pesticide. The last SARC, the Risk Assessment Review Committee, reviews all risk assessments for consistency.

To make a recommendation on the appropriate application of the FQPA safety factor, OPP has created the FQPA Safety Factor Committee, composed of both risk assessors (including toxicologists and exposure experts) from its science divisions and risk managers from the conventional chemical regulatory divisions (SRRD and Registration Division). When HED completes the risk characterization, this committee reviews all risk characterization information (dietary, residential, and drinking water exposure as well as toxicity endpoint selection) and recommends retention, reduction, or removal of the FQPA safety factor in line with the approach presented to the FIFRA Scientific Advisory Panel in January 1998. The committee considers completeness of the toxicity database, type and severity of effects observed, and nature and quality of available exposure data.

Once a risk assessment, such as a "chapter" for a Reregistration Eligibility Decision, has been approved by HED management, it may be shared by SRRD with affected registrants in an effort to see if they have additional data or analysis that may significantly add to the quality of the assessment. It is often at this stage that registrants may develop or gather additional data or conduct Monte Carlo or other analyses of existing data if the initial risk assessment did not include them.


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