Could pesticide toxicology studies be more relevant to occupational risk assessment?

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Abstract

Pesticide toxicology study design has evolved from concern for oral exposure via food residues. The emphasis on the oral route does not generally apply to workers that are exposed primarily via the dermal route either handling pesticides or re-entering treated fields. As a result numerous assumptions about how oral toxicology results relate to dermal exposure must be made when conducting worker risk assessments. These assumptions introduce a high degree of uncertainty. Alternative toxicology study designs are suggested to reduce uncertainty when assessing risk. Because the dermal route is so important to characterizing occupational risk, methods to improve the accuracy of dermal absorption estimates are suggested, including the use of human subjects to study dermal absorption. Additional suggestions include tailoring dermal, oral and inhalation kinetic study designs to reflect worker exposure dosages. Suggestions are made to routinely conduct a single dose toxicity study patterned after the neurotoxicity study design to distinguish single dose effects and NOAELs from those resulting from multiple doses. Finally, interspecies pharmacokinetics studies are proposed to determine which toxicology study regimen of dosing best reflects intermittent worker exposure.

Introduction

Regulation of pesticides has evolved in the United States primarily from concern about dietary exposure. The 1906 Pure Food and Drug Act prohibited unsafe substances in food, and a later statute, the Insecticide Act of 1910, established product-labeling provisions. The Federal Insecticide, Fungicide, and Rodenticide act of 1947 (FIFRA) required registration of pesticide products with the US Department of Agriculture prior to domestic or foreign sales. The Federal Food, Drug, and Cosmetics Act which evolved from the 1906 statute, was expanded in 1954 by the Miller amendment. The amendment established pesticide tolerances in or on agricultural commodities based primarily upon good agricultural practices. Soon thereafter, the Delaney Clause of 1958 prohibited use of any carcinogenic food additive in processed foods. Broad and more unified regulatory authority developed with the 1970 formation of the US Environmental Protection Agency and an additional 1972 FIFRA amendment which required manufacturers to demonstrate that use of the product ‘would not cause adverse effects on human health or the environment.’

Emphasis on promoting food safety has been reflected both in laws regulating pesticides (Food Quality Protection Act) and the regulatory agencies that have been historically responsible for enforcing those laws (Food and Drug Administration, 1958–1972 and US Department of Agriculture 1920–1958). As the required pesticide toxicology studies under FIFRA evolved from, and still closely mirror Food and Drug Administration requirements, they emphasize continuous exposure through the oral route. Thus, they were not designed with worker risk assessment in mind. Nonetheless, regulatory agencies must attempt to relate the toxicological dose response in those studies to the exposure of workers. However, worker exposure to pesticides tends to be intermittent in nature, and mainly via the dermal route (Krieger and Ross, 1993). Because of regulatory focus on dietary exposure, risk assessments for workers are driven by toxicology data generated in laboratory animals with a disparate route, frequency and duration of exposure.

In addition to characterizing ‘traditional’ dose–response in toxicology studies, the frequency and duration of exposures (in addition to magnitude) required to elicit pathology should be considered (Ecobichon, 1992). The route-specific exposure level, frequency and duration (collectively referred to as a multi-dimensional ‘exposure metric’) required to elicit a given toxicological effect should be considered when deciding what exposure scenario to compare it to for purposes of risk characterization (EPA, 1997, EPA, 1992a). Conversely, toxicology studies can be designed to reflect the exposure pattern known to occur in a given subpopulation or occupational cohort.

Examples of exposure metric consideration include focusing on estimates of route-specific aggregate exposures (or absorbed doses) during a time period of interest (e.g., acute exposure) for comparison to route-specific single dose toxicological benchmarks (No-Observed-Adverse-Effect-Levels or NOAELs) such as acute neurotoxicity. In contrast, estimates of route-specific subchronic, time-averaged exposures should be compared to a NOAEL based on dose-related organ toxicity that only occurred following 90 days of repeat exposure by a relevant route (e.g., dermal).

Some chemical expressions of toxicity require repeated exposure (day after day) at a given level to exhaust an organism's capacity to compensate for biochemical imbalances or cellular injury (tolerance mechanisms). Other chemicals express toxicity by disrupting cyclical processes in an organism from a single exposure. Some toxicological manifestations may be related to the progression of related events (e.g., initiation of a genotoxic event and subsequent promotion) resultant from exposures at different stages of an organism's lifespan. Thus, a chemical's toxicological effects can be related to the exposure pattern (dose, frequency and duration) and associated absorption, metabolism, distribution and elimination kinetics. Historically this has been considered under the penumbra of toxicokinetics and toxicodynamics (see Fig. 1).

The purpose of this paper is to examine the toxicology requirements under FIFRA and explore approaches to improve the applicability of the toxicological data for occupational risk assessment either through changes in study design or interpretation. Many of the European requirements for testing pesticides are similar to FIFRA. Thus, several of the recommendations pertain to the EC, as well. We examined toxicology study designs, interpretation of results, and attempted to establish a logical, relevant and scientifically credible basis for risk characterization.

Section snippets

Dermal pharmacokinetics and pharmacodynamics

The dermal route is the primary route of exposure both for operators (mixers, loaders, and applicators; Wolfe, 1976) and re-entry workers (Fenske et al., 1989). Those chemicals with very high vapour pressures, such as fumigants, are exceptions. Most FIFRA toxicology studies are conducted via the oral route. Although, dermal absorption studies are ‘required for compounds having a serious toxic effect as identified by oral or inhalation studies for which a significant route of human exposure is

Oral pharmacokinetics

Oral Absorption, Distribution, Metabolism and Excretion (ADME) studies are required to register most pesticides. These studies, if done thoroughly, permit estimation of the percent of administered dose absorbed, excretory metabolites, rate of excretion and tissue residue levels. This information can be a vital link for interpreting other oral toxicity studies, because it gives indication of residue levels in target tissues and potential for bioaccumulation, and the metabolite(s) that may be

Toxicologic effect of intermittent exposure

Although the exposure regimen (periodicity) in many pesticide toxicology studies is continuous, people are exposed in the workplace intermittently. Typically a worker is exposed a few days per week to an extensively used pesticide, and perhaps less than once per week for specialty use pesticides (hand harvested crops, nursery and residential applicators are notable exceptions). With the exception of inhalation toxicity studies, most studies feature daily exposure; whether by gavage, in drinking

Inhalation toxicity/pharmacokinetics

Although the dermal route is the primary occupational exposure route for most pesticides, there are some exceptions. These include pesticides with very high vapour pressure (typically >1 Pa), such as fumigants. Fumigants exist largely or exclusively in the vapour state, so the inhalation route assumes primary importance. Also, for compounds with very low (<1%) dermal absorption, small inhalation exposures can be the primary source of absorbed dosage because inhalation absorption is generally

Conclusions

The toxicology studies required by law for registration of most pesticides emphasize the oral route of exposure. Regulators must use results of these toxicity studies to assess the risks of pesticide exposures in occupational settings, even though workers are exposed through different routes. Unless the risk assessor is aware of the differences, limitations and assumptions involved in generating both the toxicology NOAEL and the worker exposure estimates, an inaccurate portrayal of occupational

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