Claire A. Franklin

Correlation of urinary pesticide metabolite excretion with estimated dermal contact in the course of occupational exposure to guthion

Exposure to and absorption of Guthion 50 W.P. (azinphos-methyl) were estimated in orchardists from the Okanagan Valley in British Columbia who were involved in mixing, loading, and application with ultra-low volume air blast equipment. Air monitoring and patch techniques were used to estimate exposure, and alkyl phosphate excretion and cholinesterase inhibition were measured to estimate absorption. All workers were issued with standardized cotton shirts, trousers, and long-sleeved coveralls. All wore half-face respirators, gloves, boots, and hats. Eight wore rubberized protective clothing in addition. The indirect method of measuring urinary metabolites appeared to be the most sensitive. All workers had quantifiable levels of alkyl phosphates following exposure, and 24-h urine samples provided a more reliable estimate than first morning voids. A high correlation was observed between 48-h alkyl phosphate excretion and amount of active ingredient sprayed. A fluorescent tracer was added to the tank along with the Guthion. The finding of Guthion on patches beneath the clothing was confirmed by the presence of the tracer on the skin. With the ultralow-volume application used in this study, the rubberized clothing did not appear to be significantly more protective than the heavy coverall. There was no significant depression of either red blood cell or serum cholinesterase activity in any workers.

Dermal absorption of the phenoxy herbicides 2,4‐D, 2,4‐D amine, 2,4‐D isooctyl, and 2,4,5‐T in rabbits, rats, rhesus monkeys, and humans: A cross‐species comparison

Dermal absorption of the 14C-ring-labeled phenoxy herbicides 2,4-D [(2,4-dichlorophenoxy)acetic acid], 2,4-D amine (2,4-dichlorophenoxyacetic acid dimethylamine), 2,4-D isooctyl (2,4-dichlorophenoxyacetic acid isooctyl ester), and 2,4,5-T amine (2,4,5-trichlorophenoxyacetic acid trimethylamine) was examined following topical applications of the herbicides to the back of rabbits, the back and tail of rats, the forearm and forehead of rhesus monkeys, and the forehead of human volunteers. The effect of three pesticide vehicles (water, acetone, and Esteron LV96) was also investigated. The total percent dermal absorption was calculated from the mean percent urinary recoveries from the animal tests and corrected for nonurinary excretion of the radiolabel using data from intramuscular (im) injections. The human data are reported without im correction. The reliability of animal data for modelling human dermal absorption of pesticides is highlighted.

Percutaneous absorption of cis- and trans-permethrin in rhesus monkeys and rats: anatomic site and interspecies variation.

Dermal absorption of cis- and trans-permethrin isomers was determined in rhesus monkeys and Sprague-Dawley rats. Four 14C radiolabels were used (cis alcohol, cis cyclopropyl, trans alcohol, and trans cyclopropyl). One microcurie of each radiolabel was applied to either the forehead or forearm of rhesus monkeys or to the midlumbosacral region of the rat. Urine was collected for 7 or 14 d. Correction factors for incomplete urine excretion were derived from measurements of radiolabel in the urine following im injection of an equivalent dose. It was noted that the total im dose recovered in the urine of both species was lower for the cis isomer than for the trans isomer. There was no significant difference between the dermal absorption of the cis isomer and that of the trans isomer in monkeys. The forehead, however, was more permeable for both isomers than the forearm (alcohol- and cyclopropyl-labeled cis and trans isomers, respectively, showed permeation in forehead, cis 28 +/- 6%, 24 +/- 6%, trans 21 +/- 3%, 14 +/- 4%, forearm, cis 9 +/- 3%, 9 +/- 3%, trans 12 +/- 3%, and 5 +/- 2%). There was no difference between absorption of the isomers (cis 46 +/- 4%, trans 43 +/- 5%) in rats, but absorption was significantly greater than in monkeys. The IM urinary t1/2 values in monkeys and rats were similar for both isomers (0.8-1.1 d).

The use of biological monitoring in the estimation of exposure during the application of pesticides

In order to assess the occupational health risk to workers using pesticides, accurate data on exposure (including knowledge of the primary route of exposure) and on absorption are needed. In addition, a well-defined no-effect level (NOEL) derived from suitable animal data must be available. Biological monitoring, urinary metabolite excretion in particular, frequently is used to indicate whether a worker has been exposed. Interpretation of the toxicological significance of the observed urinary metabolite levels is often difficult because the relationship between these levels and toxic dose are generally unknown. Another complication is the apparent lack of correlation between patch data and urinary metabolite data. The usefulness of a metabolite to predict exposure depends on many things, including detailed knowledge of absorption and excretion characteristics of the parent compound and identification of the metabolites. These data, when combined with appropriate toxicology data, permit an analysis of the potential health risks associated with an occupational exposure to toxic chemicals. This paper will correlate data from a number of studies in which the dermal penetration of azinphosmethyl (AM) was measured in rats, rabbits, monkeys and man; and urinary alkyl phosphate metabolites were measured in orchardists exposed to AM. The feasibility of utilizing metabolite excretion to estimate exposure and ultimate risk will be discussed.

Respiratory health effects associated with ambient sulfates and ozone in two rural Canadian communities

A cross-sectional epidemiological study investigating the respiratory health of children in two Canadian communities was conducted in 1983-1984 in Tillsonburg, Ontario, located in a region of moderately elevated concentrations of transported air pollutants, and in Portage la Prairie, Manitoba, situated in a low pollution area. There were no significant local sources of industrial emissions in either community. Seven hundred and thirty-five children aged 7-12 were studied in the first town and 895 in the second. Respiratory health was assessed by the measurement of the forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1.0) of each child, and by evaluation of the childs respiratory symptoms and illnesses using a parent-completed questionnaire. Sulfur dioxide (SO2), sulfate, and particulate nitrate levels were significantly higher in Tillsonburg than in Portage la Prairie (P less than 0.05), but nitrogen dioxide (NO2) and inhalable particles (PM10) differed little between the communities. Historical data in the vicinity of Tillsonburg indicated that average annual levels of sulfates, total nitrates, and ozone (O3) did not vary markedly in the 9-year period preceding the study. The results show that Tillsonburg children had statistically significant (P less than 0.001) lower levels of 2% for FVC and 1.7% for FEV1.0 as compared with children in Portage la Prairie. These differences could not be explained by parental smoking or education, the use of gas cooking or wood heating fuels, pollution levels on the day of testing, or differences in age, sex, height, or weight. The differences persisted when children with cough with phlegm, asthma, wheeze, inhalant allergies, or hospitalization before age 2 for a chest illness were excluded from analysis. With the exception of inhalant allergies, which occurred more frequently in Tillsonburg children, the prevalence of chronic respiratory symptoms and illnesses was similar in the two communities.

Dermal exposure and urinary metabolite excretion in farmers repeatedly exposed to 2,4-D amine

Following multiple exposures to 2,4-D amine salts under normal field conditions in which ground rigs were used, farmers who sprayed once or twice had an average dermal exposure of 655 micrograms 2,4-D acid equivalents (a.e.)/kg a.e. sprayed and an average cumulative urinary metabolite excretion of 10.9 micrograms 2,4-D a.e./kg a.e. sprayed. One very high outlier value was excluded from these averages (F). Following 4 to 7 exposures, the average cumulative dermal exposure was 1,077 micrograms 2,4-D a.e./kg a.e. sprayed and the average cumulative urinary metabolite excretion was 21.5 micrograms 2,4-D a.e./kg a.e. sprayed. The amount of 2,4-D metabolite in urine was significantly correlated with the amount of herbicide sprayed and the time required for the urinary metabolite excretion to return to background concentration was related to the amount sprayed and the number of exposures.

Percutaneous absorption of the insecticides fenitrothion and aminocarb in rats and monkeys

The dermal penetration of 14C-ring-labeled fenitrothion and aminocarb was determined in rats and rhesus monkeys. In monkeys, 49 +/- 4% (t1/2 = 14 h) of the fenitrothion and 74 +/- 4% (t1/2 = 25 h) of aminocarb were absorbed from the forehead, while 21 +/- 10% (t1/2 = 17 h) fenitrothion and 37 +/- 14% (t1/2 = 31 h) aminocarb were absorbed from ventral forearm. Monkey forehead was 2.3 times and 2.0 times more permeable than the forearm for fenitrothion and aminocarb, respectively. In rats, 84 +/- 12% (t1/2 = 20 h) of the fenitrothion and 88 +/- 6% (t1/2 = 17 h) aminocarb was absorbed from the middorsal region. These results were corrected for incomplete excretion by intramuscular injections of fenitrothion in money, 95 +/- 7% (t1/2 = 12 h), and rat, 69 +/- 9% (t1/2 = 12 h), and aminocarb in monkey, 95 +/- 14% (t1/2 = 8 h), and rat, 63 +/- 6% (t1/2 = 15 h). These results suggest rapid dermal absorption of these pesticides in rats and monkeys and the use of these animal models for measuring dermal penetration is discussed.

The effect of DEET (N,N‐diethyl‐m‐toluamide) on dermal persistence and absorption of the insecticide fenitrothion in rats and monkeys

The in vitro persistence of 14C-ring-labeled fenitrothion in acetone (F-A) or N,N-diethyl-m-toluamide (DEET) (F-D) vehicles was determined, and in vivo studies were conducted to determine the persistence and absorption of [14C]fenitrothion in acetone or DEET applied to the skin of rats and rhesus monkeys. In vitro persistence of [14C]fenitrothion was significantly enhanced in DEET vehicle, and the percent residual 14C activity at 24 h was positively correlated with the amount (micrograms) of DEET employed (e.g., in vitro, 98.6 +/- 1.7% 14C recovery after 24 h with [14C]fenitrothion in DEET versus 1.9 +/- 0.3% without DEET). Significantly greater (p less than 0.05) fenitrothion 14C activity was detected in skin swabs taken after 24 h at the dose site with DEET vehicle from rats [acetone (F-A): 15.0 +/- 5.8%; DEET (F-D): 31.5 +/- 3.9%)] and monkeys (F-A: 3.2 +/- 1.5%; F-D: 9.7 +/- 6.0%). A lag in the urinary excretion kinetics was observed for F-D in comparison with F-A for both rats and monkeys. The total percent urinary 14C recovery was significantly higher in rats dosed with F-A (73.0 +/- 7.4%) than with F-D (52.4 +/- 8.8%) but not in monkeys (F-A: 34.7 +/- 7.1%; F-D: 36.7 +/- 2.9%). The observed species-related differences are discussed in context with the use of animal models for predicting dermal penetration of pesticides in humans.

CORRELATION OF URINARY DIALKYL PHOSPHATE METABOLITE LEVELS WITH DERMAL EXPOSURE TO AZINPHOS-METHYL

Abstract Dimethyl thiophosphate (DMTP), one of the primary metabolites of azinphos-methyl, was measured in the urine of rats following dermal application of 100, 200 or 400 μg azinphos-methyl. A very strong correlation was found between the amount of pesticide applied and urinary DMTP levels. Using DMTP levels in urine following dermal and intramuscular (i.m.) dosing the percutaneous absorption was estimated to be approximately 60% of the applied dose. Increasing the dose from 100 to 400 μg/rat did not appreciably affect this. Percutaneous absorption was also determined using 14C ring-labeled azinphos-methyl and was found to be 91% of the applied dose. The underestimate by the DMTP method may be related to the lower sensitivity of the G.C. in determining the low levels of DMTP excretion which occurred for a number of days following dosing. Since absorption is calculated on the basis of total amount excreted, this could lead to the observed underestimate. The significant correlation between DMTP excretion and the amount of dermal exposure in rats is useful and has led to the initiation of studies in humans to establish whether a similar relationsip exists.