HUMAN HEALTH RISK ASSESSMENT OF BIOCHEMICAL PESTICIDES
A health assessment in the Biochemical Pesticides Branch begins with the classification of a proposed active ingredient because biochemical pesticides are, by definition, expected to be less harmful than conventional pesticides (Overhead #1). They do not have a toxic mode of action, and they tend to have a very limited range of target species. This class of pesticides is typically effective against its target species in very small quantities and can usually decompose rapidly after use in the environment which should reduce exposure significantly. Therefore, human health risk assessments for biochemical pesticides often have less specific information on potential hazards and exposure than would be considered in an assessment of a conventional pesticide.
Although biochemical pesticides are assumed to pose reduced risk, their human health risk assessments must still address the same issues found in any pesticide's risk assessment (Overhead #2). The Agency is required by law (FIFRA, FFDCA and FQPA) to evaluate the quality of information submitted in support of registration of a biochemical pesticide, the relationship between use of the biochemical and potential risks to humans, sensitive subpopulations, etc. The Agency provides guidance on many of the details of risk assessment including public policies, test guidelines, risk assessment guidelines for specific types of hazards, and other resources (e.g., the Exposure Factors Handbook).
After a substance has been classified as a biochemical pesticide, the review process (Overhead #3) continues with a pre-registration meeting or conference call to produce a memorandum of understanding (MOU) between the registrant and BPPD. This document begins the development of appropriate data requirements and data waiver rationales, and information on the biochemical is organized and presented according to recommendations in Pesticide Registration Notice 86-5 (guidance on format of submissions) and the Data Matrix (Form 8570-35). Additional guidance on the types of information needed for the hazard identification, dose-response assessment, exposure assessment, and risk characterization components of risk assessment (Overhead #4) indicate that the PR 86-5 format guidance and Data Matrix form are important tools in organizing the information needed by the Agency for the risk assessment process. The review of submitted information organized according to the recommended formatting usually accelerate the hazard and exposure assessment phases of the risk assessment process.
In general, the purposes for categories of data requirements are explained in 40 CFR §158.202; the categories important to human health risk assessment include residue chemistry (§158.202(c)), environmental fate (§158.202(d)), hazards to humans and domestic animals (§158.202(e)), reentry protection (§158.202(f)), and pesticide spray drift evaluation (§158.202(g)). These categories are useful in exposure [§158.202(c), (d), and (f)] and hazard assessment for all pesticides, but as noted above, biochemical pesticides may not require as thorough an evaluation as conventional pesticides need. An example of appropriate points from §158.202(e) addressing the first tier of data requirements for biochemical pesticides are shown in Overhead #5).
More detail about the data requirements for biochemical pesticides can be found in 40 CFR §158.690(a) through (d). These regulations organize the data requirements into a matrix according to several general use patterns including food and non-food uses, terrestrial and aquatic environments, forest uses, domestic indoor and outdoor uses, etc. Three forms of the active ingredient including pure, technical grade and end-use product may be tested, but the data tables indicate which form is supposed to be evaluated to satisfy each requirement. Each data requirement in the matrix also has footnotes explaining why it is needed or why a waiver can be granted. In the case of §158.690(c), data requirements are also organized in tiers with footnotes to indicate criteria for the requirement of additional testing from Tiers II and III. Because data requirements depend on many circumstances summarized in the §158.690 tables, the Data Matrix is a quick reference that can be compared with the biochemical pesticides data requirements to determine how complete a package of information may be before it is submitted. It is important at this point in the process to realize that two substances intended for the same use pattern may not have the same data requirements satisfied because the results of certain studies may determine the need for additional studies to complete the risk assessment process. In other words, there may be different paths through the data requirement matrix toward completion of the risk assessment process.
It should also be noted that the test guideline reference numbers listed in §158.690 do not correspond with the harmonized guideline reference numbers found on the OPPTS test guidelines web page, reference numbers in other parts of §158 (e.g., §158.340, "Toxicology Data Requirements" for conventional pesticides), or guideline reference numbers used by the Organization for Economic Cooperation and Development (OECD) even though the studies are the same (see Overhead #6 for examples from health effects test guidelines typically submitted to satisfy Tier I requirements).
Review of submitted studies begins soon after they have passed the 86-5 screen. This review is documented in a Data Evaluation Record/Report (DER) which summarizes results of each study according to its purpose (e.g., to determine LD50 values from acute toxicity studies, no-observed-adverse-effect levels [NOAEL] and lowest-observed-adverse-effect levels [LOAEL] from subchronic studies, to identify target organs, etc). The DERs also classify studies with respect to their acceptability, whether they can be upgraded, and whether they are consistent with guidelines (e.g., acceptable-guideline, unacceptable-nonguideline-upgradable, acceptable-nonguideline-nonupgradable, etc.).
A description of the use pattern (time, frequency, and duration of exposure; types of exposure such as residential, occupational, etc.) is used to identify populations likely to be exposed. The amount of exposure is estimated from this type of information or from studies that may provide measurements of exposure, and an exposure profile identifying the major routes of exposure (oral, dermal, inhalation, dietary) and exposed populations (infants and children, females 13+ years of age, etc). Important resources for guidance on this aspect of the risk assessment process include the Agency's Exposure Factors Handbook (available online) and various guidelines and regulations indicated in Overhead #4.
After DERs for all submitted studies have been completed, toxicity and exposure profiles are prepared, and toxicity endpoints are selected for use with exposure estimates as appropriate in the risk characterization phase of the assessment process (Overhead #7). In the dose-response assessment, LD50 values and irritation scores will be used to classify a biochemical pesticide's acute toxicity to support precautionary labeling; NOAELs and LOAELs are identified for calculating reference doses and comparison with exposure estimates in risk characterization; and slope coefficients (Q1*) are determined to estimate potential carcinogenicity.
The extent of a given biochemical pesticide's data base depends on the exposures and hazards indicated. There can be cases in which negligible exposures exist and the need for hazard evaluation is reduced, or some biochemicals can have a complete Tier I data base (see Overhead #6 for example) that indicates no significant toxicity endpoints reducing the need for exposure assessment. Most biochemical pesticides have some combination of both hazard and exposure information which may satisfy a data requirement or may support a waiver for a data requirement (Overhead #8). As more information becomes available, the use of conservative default assumptions decreases in a risk assessment providing more realistic characterizations specific to the pesticidal use of biochemicals.
The future of guidance and regulations in the risk assessment process is changing with the development and introduction of alternative test methods into the risk assessment process (Overhead #9). The Agency presently accepts alternative designs such as the Up-and-Down, Fixed Dose, and Acute Toxic Class methods to reduce the number of animals in acute oral toxicity studies. The Acute Toxic Class method refines the use of animals by classifying test substances on the basis of evident toxicity rather than lethality, and other in vitro methods are being developed to replace animals in toxicity testing.
As indicated herein, the human health assessment of biochemical pesticides is similar to that for other types of pesticides. The Biochemical Pesticides Branch applies the same regulations, test guidelines, principles of risk assessment, and policies the other parts of the Office of Pesticide Programs uses. The risk assessment process is also consistent with the rest of the OPP in that preliminary discussions and screening processes are used to enhance the quality and timing of the review of data and the assessment of potential risks for use of each active ingredient. The balance between hazard and exposure information in risk characterization for biochemical pesticides is critical because these substances are expected to cause little harm to human health. The risk assessment done in BPPD should communicate with reasonable certainty a realistic characterization of potential risks without overstating nonexistent risks or overlooking unexpected hazards.