Could pesticide toxicology studies be more relevant to occupational risk assessment?☆
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
References (82)
- et al.
Characterisation of risks associated with the use of molinate
Reg Toxicol Pharmacol
(1997) - et al.
Percutaneous penetration of some pesticides and herbicides in man
Toxicol Appl Pharmacol
(1974) - et al.
Toxicity of an anthraquinone violet dye mixture following inhalation exposure, intratracheal instillation, or gavage
Fund Appl Toxicol
(1994) Pesticide exposure assessment
Toxicol Lett
(1995)- et al.
Chlorpyrifos: pharmacokinetics in human volunteers
Toxicol Appl Pharmacol
(1984) - et al.
Conservatism in pesticide exposure assessment
Reg Toxicol Pharmacol
(2000) - et al.
Dose and time as variables of toxicity
Toxicology
(2000) - et al.
Absorption, metabolism, and excretion of N.N-diethyl-m-toluamide following dermal application to human volunteers
Fund Appl Toxicol
(1995) - et al.
Long vs. short monitoring intervals for peach harvesters exposed to foliar azinphos-methyl residues
Toxicol Lett
(1995) - et al.
Evaluation of the developmental toxicity of ethylene glycol in CD-1 mice by nose-only exposure
Fund Appl Toxicol
(1995)
Quantitative exposure of humans to an octamethylcyclotetrasiloxane (D4) vapour
Toxicol Sci
The effect of chronic ingestion of lead on gastrointestinal transit in rats
Toxicol Appl Pharmacol
Relationship of topical dose and percutaneous absorption in rhesus monkey and man
J Invest Dermatol
In vivo and in vitro percutaneous absorption of isofenphos in man
Fund Appl Toxicol
Deposition and retention of 0.1 um 67Ga2O3 aggregate aerosols in rats following whole body exposures
Fund Appl Toxicol
Biotransformation and kinetics of excretion of methyl-tert-butyl ether in rats and humans
Toxicol Sci
Uptake of solvents in the blood and tissues of man. A review
Scand J Work Environ Hlth
Exposure to trichlorethylene. I. Uptake and distribution in man
Scand J Work Environ Hlth
Critical review of time-weighted average as an index of exposure and dose, and of its key elements
Am Ind Hyg Assoc J
Modeling dermal pharmacokinetics using in vitro data: part II. Fluazifop-butyl in man
Human Exptl Toxicol
Metabolism and excretion of trichlorethylene after inhalation by human subjects
Br J Ind Med
The single exposure carcinogen database: assessing the circumstances under which a single exposure to a carcinogen can cause cancer
Toxicol Sci
Dermal absorption and disposition of formulations of malathion in Sprague–Dawley rats and humans
Use of spot urine sample results in physiologically based pharmacokinetic modeling of absorbed malathion doses in humans
Exposure factors handbook
Methods for assessing fieldworker hand exposure to pesticides during peach harvesting
Bull Environ Contam Toxicol
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2017, Regulatory Toxicology and PharmacologyThe failure to detect drug-induced sensory loss in standard preclinical studies
2015, Journal of Pharmacological and Toxicological MethodsHandler, bystander and reentry exposure to TCDD from application of Agent Orange by C-123 aircraft during the Vietnam War
2015, Science of the Total EnvironmentCitation Excerpt :Dermal absorption of TCDD was assumed to be 9%. This value applies to both drift and reentry exposures and is based on a range of 2–18% observed with in vitro and in vivo empirical data characterizing uptake rate constants and daily absorption rates for humans (Shu et al., 1988; Durkin et al., 1995; Ross et al., 2001; 2005; Anderson et al., 1993; Roy et al., 2008; Weber et al., 1991; Weber, 1993; Marple et al., 1992). We note that this is three times greater than the 3% dermal absorption value assumed in EPA (2004).
Risk Assessment for Acute Exposure to Pesticides<sup></sup>
2010, Hayes' Handbook of Pesticide Toxicology
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