Jeffrey H. Driver

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.

Dialkylphosphates (DAPs) in fruits and vegetables may confound biomonitoring in organophosphorus insecticide exposure and risk assessment.

Trace residues of organophosphorus (OP) pesticides are associated with fruits and vegetables that have been sprayed with those OP pesticides to guard against insect pests. Human dietary exposure to these OP pesticides is commonly estimated by measuring the amount of OP metabolites in urine, assuming a stoichiometric relationship between a metabolite and its parent insecticide. Dialkylphosphates (DAPs) are the OP metabolites that are most often used as markers in such biomonitoring studies. However, abiotic hydrolysis, photolysis, and plant metabolism can convert OP chemicals (OP residues) to DAP residues on or in the fruits and vegetables. To evaluate the extent of these conversions, OPs and DAPs were measured in 153 produce samples. These samples from 2 lots were known to contain OP insecticide residues based on routine monitoring by California producers and shippers. A total of 12 OPs were quantified, including mevinphos, naled, acephate, methamidophos, oxidemeton-methyl, azinphos-methyl, dimethoate, malathion, methidathion, phosmet, chlorpyrifos, and diazinon. All OP insecticide residues were below their respective residue tolerances in 2002-2004. A total of 91 of 153 samples (60%) contained more DAP residues than parent OPs. The mean mole fractions [DAPs/(DAPs + OPs)] for the first and second lots of produce were 0.62 and 0.50, respectively, and the corresponding geometric means were 0.55 and 0.34. The corresponding mean mole ratios (DAPs/OP) were 7.1 and 3.4, with geometric means of 2.1 and 0.9. Any preformed DAPs ingested in the diet that are excreted in urine may inflate the estimated absorbed OP insecticide doses in occupational and environmental studies. In subsequent prospective studies, time-dependent production of dimethylphosphate (DMP) and dimethylthiophosphate (DMTP) in strawberries and leaves following malathion sprays occurred concomitant with the disappearance of the parent insecticide and its oxon. DAPs are more persistent in plants and produce at routinely measured levels than their parent OP insecticides.

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk

Recent epidemiological studies have claimed to associate a variety of toxicological effects of organophosphorus insecticides (OPs) and residential OP exposure based on the dialkyl phosphates (DAPs; metabolic and environmental breakdown products of OPs) levels in the urine of pregnant females. A key premise in those epidemiology studies was that the level of urinary DAPs was directly related to the level of parent OP exposure. Specific chemical biomarkers and DAPs representing absorbed dose of OPs are invaluable to reconstruct human exposures in prospective occupational studies and even in non-occupational studies when exposure to a specific OP can be described. However, measurement of those detoxification products in urine without specific knowledge of insecticide exposure is insufficient to establish OP insecticide exposure. DAPs have high oral bioavailability and are ubiquitously present in produce at concentrations several-fold greater than parent OPs. Studies relying on DAPs as an indicator of OP exposure that lack credible information on proximate OP exposure are simply measuring DAP exposure and misattributing OP exposure.

2,4-D exposure and risk assessment: comparison of external dose and biomonitoring based approaches

Conventional chemical exposure assessment relies upon measurements or estimates of chemical concentrations in environmental media, food, or products, in combination with assumptions regarding contact rates, in order to estimate external doses (ppm in air) or intake rates of chemicals (e.g., mg/kg/day ingested). A risk assessment is conducted by comparing these external or intake dose estimates to appropriate (e.g., route-specific) exposure guidance values (e.g., Reference Dose or Reference Concentration) to assess whether exposures are exceeding levels of concern. Human biomonitoring, in which concentrations of chemicals are measured in blood or urine, is being increasingly used as an alternative or complementary exposure assessment. The Biomonitoring Equivalent, which is the translation of a Reference Dose to an equivalent concentration of a compound in blood or urine, provides a parallel means to interpret biomonitoring data in order to assess whether chemical-specific exposures exceed levels of concern. This manuscript presents a side-by-side comparison of the two approaches for assessing exposures and risks for a case study compound, 2,4-dichlorophenoxyacetic acid (2,4-D). The findings from this case study indicate that the external dose-based assessments result in estimates of exposure and resulting hazard quotients that are consistently several-fold higher than those based on biomonitoring data. These comparisons support a conclusion that exposure assessments conducted as part of the registration process for 2,4-D incorporate sufficiently conservative assumptions.

Concurrent 2,4-D and triclopyr biomonitoring of backpack applicators, mixer/loader and field supervisor in forestry

Two herbicides, 2,4-D and triclopyr esters (application ratio 1.6:1 acid equivalents) were applied as a tank mix by a crew of 8 backpack sprayer applicators, a mixer/loader, and a field supervisor. The crew was employed in a conifer release program in northern California during the summer of 2002. Biomonitoring (urine, 24 h) utilized 2,4-D and triclopyr (a.e.) as rapidly excreted exposure biomarkers. The absorbed dosages of 2,4-D and triclopyr were calculated based upon cotton whole body suits and biomonitoring. Dosages based upon accumulation of the herbicides on body suits averaged 42.6 μg (a.e.) 2,4-D/kg-d and 8.0 μg (a.e.) triclopyr/kg-d. Six consecutive days of concurrent urine collections showed that backpack applicators excreted an average of 11.0 μg (a.e.) 2,4-D/kg-d and 18.9 μg (a.e.) triclopyr/kg-d. Estimates based upon curve fitting were 17.1 and 29.3 μg (a.e.)/kg-d, respectively. Results suggest that passive dosimetry for 2,4-D consistently overestimated the dosage measured using biomonitoring by a factor of 2-3 fold, while for triclopyr, passive dosimetry underestimated the absorbed dose based on biomonitoring by a factor of 2-4 fold.

Modeling duration of time lived in a residence, a community and mobility in rural areas of Merced and Ventura, California to assess potential health risks to airborne contaminants.

A de novo population mobility survey of 800 households (random digit dialing-based phone interviews) was conducted in high demand areas of the agricultural fumigant, 1,3-dichloropropene (1,3-D) in Merced and Ventura counties of California. The survey included approximately 20 questions relating to the length of time individuals had lived in the high demand areas in each county, and also relating to weekly and annual mobility patterns. Lifetime inhalation exposures to 1,3-D are determined, in part, by the number of years individuals spend in an area where the fumigant is used. The purpose of the survey was to provide location-specific data for probabilistic modeling of long-term inhalation exposures to 1,3-D. The survey found that the majority of residents do not live in a high demand area or in the same house (99.99%) for 70years (a default assumption used by some regulatory agencies). It was also observed that residents move frequently and are mobile day-to-day and week-to-week, within the use area. Finally, estimates of total residency duration, derived from the survey results indicate that median times spent within a high demand area (which could include more than one residential location) were 18 and 26years for Ventura and Merced high demand areas, respectively. The average time spent in the high demand areas was 22 and 27years for the Ventura and Merced community, respectively. Less than 0.01% of the populations in either of the high demand areas spend 70years in the same house.

Estimating Human Exposure: Improving Accuracy with Chemical Markers

Exposure to chemicals, natural as well as anthropogenic, occurs in the human environment. In the absence of chemical-specific data for the wide variety of exposure scenarios, federal agencies have adopted two approaches to estimating exposures. The first is to set chemical standards for exposures, usually through a single route. These standards are set based on risk assessment principles and economic feasibility. When there are standards, measurement of environmental chemical concentrations can be used to prevent unacceptable levels of exposure. The second approach is to estimate external exposure (typically route-specific) and/or an absorbed dose using a series of assumptions regarding translation of chemical concentrations from one part of the environment to another, human activity patterns, and chemical absorption through various routes into the body. These assumptions have been converted into algorithms that can be used to estimate a human exposure and dosage, typically expressed on body weight basis. These algorithms, designed to avoid underestimations of human exposure, have, in some instances, been incorporated into computer models. Chemical markers, measured either as the parent compound or as metabolites in human populations with known exposure to the parent compound, can be applied to improve the accuracy of these estimates of exposure.

Estimating Human Exposure

Exposure to chemicals, natural as well as anthropogenic, occurs in the human environment. In the absence of chemical-specific data for the wide variety of exposure scenarios, federal agencies have adopted two approaches to estimating exposures. The first is to set chemical standards for exposures, usually through a single route. These standards are set based on risk assessment principles and economic feasibility. When there are standards, measurement of environmental chemical concentrations can be used to prevent unacceptable levels of exposure. The second approach is to estimate external exposure (typically route-specific) and/or an absorbed dose using a series of assumptions regarding translation of chemical concentrations from one part of the environment to another, human activity patterns, and chemical absorption through various routes into the body. These assumptions have been converted into algorithms that can be used to estimate a human exposure and dosage, typically expressed on body weight basis. These algorithms, designed to avoid underestimations of human exposure, have, in some instances, been incorporated into computer models. Chemical markers, measured either as the parent compound or as metabolites in human populations with known exposure to the parent compound, can be applied to improve the accuracy of these estimates of exposure.

Letter to the Editor re: "a plot simulation study of arsenic tracked from CCA-treated decks onto carpets" (Patch, SC, et al. 2009; Sci Total Environ. DOI: 10.1016/j.scitotenv.2009.07.022).

The purpose of this letter is to offer additional insight on the topic of potential consumer exposure to arsenic from chromated copper arsenate (CCA)-treated lumber, in relation to the recent article by Patch et al., (2009). We commend the journal editors for providing supplemental material regarding the studys quality assurance, disclaimer details, and most importantly, the significant limitations of this study. The description of study limitations documents numerous issues, including that the data from this study cannot be used to estimate mass transfer and resulting As concentrations in real homes and thus, cannot support any human exposure estimation. A key issue is that the transferable residue measurement method (HUD method) described in Patch et al., 2009 is not consistent with any recognized method that has been used to quantitatively estimate any human exposure. Other limitations highlighted include the exclusion of decks with paints or sealants, uncertainties regarding the relevancy of the track in simulation method used to real-world conditions and human behavior, regional variability, the impact of carpet cleaning, and uncertainty regarding the measurements made and human exposure and/or biomonitoring measurements. It is critically important for readers to appreciate the above limitations and associated research needs. The level of detail in the documentation provided by the supplemental information was very beneficial, and we are pleased to see that more scientific journals are moving in this direction to improve transparency and reader comprehension. CCA wood preservatives have been used in the United States since the 1940s to protect against wood destroying organisms. Treated wood products are found in a variety of residential, landscape, industrial and building structures, as well as home, school and community playground equipment. CCA manufacturers voluntarily amended their respective pesticide registrations with the U.S. EPA effective as of December 31, 2003, due to market demand for alternative preservatives to use in non-industrial treated wood products (68 FR 17366, April 9, 2003). Evaluation of childrens potential exposures with relation to surfaces of existing treated wood structures and any related residues was the focus of probabilistic modeling efforts conducted by the U.S. Environmental Protection Agency (EPA), Office of Research and Development (ORD), (Zartarian et al., 2006; Xue et al., 2006). These modeling efforts evaluated exposure routes and pathways “anticipated as realistic, considering activity patterns and behavior of young children near residential playsets, public playsets, and residential decks.” Childrens exposure to As was assumed to potentially occur through dermal contact with CCA-treated wood and CCA-contami-