Metabolites of Pyrethroid Insecticides in Urine Specimens: Current Exposure in an Urban Population in Germany.Pyrethroids pyrethroids synthetic substances with activity similar to the naturally occurring pyrethrins. They include cypermethrin, cyhalothrin, deltamethrin, flumethrin, permethrin. are important insecticides insecticides, chemical, biological, or other agents used to destroy insect pests; the term commonly refers to chemical agents only. Chemical Insecticides used in agriculture, forestry, horticulture horticulture [Lat. hortus=garden], science and art of gardening and of cultivating fruits, vegetables, flowers, and ornamental plants. Horticulture generally refers to small-scale gardening, and agriculture to the growing of field crops, usually on a large , and in the home. In humans, they are rapidly metabolized and renally eliminated. In numerous studies, pyrethroid py·re·throid n. Any of several synthetic compounds similar to pyrethrin, used as an insecticide. metabolites Metabolites Substances produced by metabolism or by a metabolic process. Mentioned in: Interactions have been detected in urine after occupational exposure to insecticides. In this study, we used a new, reliable, easy, and sensitive analytical method to assess the internal pyrethroid exposure of an urban population without exposure to pyrethoids at home or at work (children and adults). A total of 1,177 persons took part in this investigation, including 331 children under 6 years of age and 247 children between 6 and 12 years of age. None of them reported exposure to pyrethroids at home or at work. Accordingly, the levels of permethrin permethrin /per·meth·rin/ (per-meth´rin) a topical insecticide used in the treatment of infestations by Pediculus humanus capitis, Sarcoptes scabiei, or any of various ticks; also applied to objects such as furniture and bedding. found in household dust from their homes were lower than expected (median [is less than] limit of detection; 95th percentile percentile, n the number in a frequency distribution below which a certain percentage of fees will fall. E.g., the ninetieth percentile is the number that divides the distribution of fees into the lower 90% and the upper 10%, or that fee level , 4.8 mg/kg; maximum value, 19 mg/kg). Urine specimens were analyzed an·a·lyze tr.v. an·a·lyzed, an·a·lyz·ing, an·a·lyz·es 1. To examine methodically by separating into parts and studying their interrelations. 2. Chemistry To make a chemical analysis of. 3. for cis-3-(2,2-dibromo-vinyl)-2,2-dimethylcyclopropanecarboxylic acid ([Br.sub.2]CA), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-carboxylic acid (cis-[Cl.sub.2]CA and trans-[Cl.sub.2]CA), and 4-fluoro-3-phenoxybenzoic acid (F-PBA) using a gas chromatographic chro·mat·o·graph n. An instrument that produces a chromatogram. tr.v. chro·mat·o·graphed, chro·mat·o·graph·ing, chro·mat·o·graphs To separate and analyze by chromatography. method with mass-selective detection. The limit of detection for pyrethroid metabolites was between 0.1 and 0.2 [micro]g/L. trans-[Cl.sub.2]CA was detected in 65% of the urine specimens tested, cis-[Cl.sub.2]CA was detected in 30%, and [Br.sub.2]CA and F-PBA were found in 19% and 16%, respectively, of the urine specimens. The urinary urinary /uri·nary/ (u´ri-nar?e) pertaining to, containing, or secreting urine. u·ri·nar·y adj. 1. Relating to urine and its production, function, or excretion. 2. metabolite metabolite, organic compound that is a starting material in, an intermediate in, or an end product of metabolism. Starting materials are substances, usually small and of simple structure, absorbed by the organism as food. levels in children did not differ from those in adults, and there was no correlation between the levels of metabolites and indoor exposure to permethrin in household dust. Moreover, no seasonal correlations could be found. The 95th percentile levels in urine specimens were as follows: [Br.sub.2]CA, 0.30 [micro]g/L; cis-[Cl.sub.2]CA, 0.51 [micro]g/L; trans-[Cl.sub.2]CA, 1.43 [micro]g/L; F-PBA, 0.27 [micro]g/L. Background exposure to pyrethroids was found in the general population; it seems to be caused by the uptake uptake /up·take/ (up´tak) absorption and incorporation of a substance by living tissue. up·take n. of pyrethroids with the diet. This hypothesis needs to be tested in duplicate diet studies combined with biomonitoring. As long as representative data are lacking, however, the rounded 95th percentile values obtained in our study may be used as reference values ref·er·ence values pl.n. A set of laboratory test values obtained from an individual or from a group in a defined state of health. for pyrethroid metabolites in urine samples from the population in Germany; 95th percentile values for children and adults are as follows: [Br.sub.2]CA, 0.3 [micro]g/L; cis-[Cl.sub.2]CA, 0.5 [micro]g/L; trans-[Cl.sub.2]CA, 1.5 [micro]g/L; and F-PBA, 0.3 [micro]g/L Key words: biomonitoring, cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid, cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 4-fluoro-3-phenoxy-benzoic acid, permethrin, pyrethroids, urinary metabolites. Environ en·vi·ron tr.v. en·vi·roned, en·vi·ron·ing, en·vi·rons To encircle; surround. See Synonyms at surround. [Middle English envirounen, from Old French environner Health Perspect 109:213-217 (2001). [Online 14 February 2001] http://ehpnet1.niehs.nih.gov/docs/2001/109p213-217heudorf/abstract.html Pesticides are widely used throughout the world in agriculture to protect crops and in public health to control diseases transmitted by vectors or intermediate hosts. Up to the 1960s organochlorines organochlorines see chlorinated hydrocarbons. organochlorines poisoning cause excitement and irritability, tremor, ataxia, weakness, paralysis, convulsions. such as DDT DDT or 2,2-bis(p-chlorophenyl)-1,1,1,-trichloroethane, chlorinated hydrocarbon compound used as an insecticide. First introduced during the 1940s, it killed insects that spread disease and feed on crops. were used intensively, but due to their accumulation in the environment and in humans their use was prohibited pro·hib·it tr.v. pro·hib·it·ed, pro·hib·it·ing, pro·hib·its 1. To forbid by authority: Smoking is prohibited in most theaters. See Synonyms at forbid. 2. in the 1970s in many industrialized in·dus·tri·al·ize v. in·dus·tri·al·ized, in·dus·tri·al·iz·ing, in·dus·tri·al·iz·es v.tr. 1. To develop industry in (a country or society, for example). 2. countries. Carbamates carbamates effective insecticides which exert their effect by temporarily inhibiting cholinesterase activity. They are also capable of poisoning. Clinical signs are pupillary constriction, muscle tremor, salivation, ataxia and dyspnea. , organophosphates, and pyrethroids were subsequently developed and used extensively. Today, pyrethroids are among the most frequently used pesticides. They are used in agriculture, forestry, horticulture, public health (e.g., hospitals), and homes, as well as for the protection of textiles, such as carpets. Because natural pyrethrins pyrethrins the active insecticidal ingredients of the flowers of the pyrethrum plant. Can cause systemic or cutaneous allergic reactions. Are esters of pyrethrolone and cinerolone with chrysanthemum mono- and dicarboxylic acids. , derivatives of chrysanthemums, are unstable in sunlight, efforts were undertaken to modify the chemical structures of natural pyrethrins to obtain substances with improved physical and chemical properties and greater biological activity. The pyrethroids commercially available include permethrin, cypermethrin, cyfluthrin, deltamethrin, and fenvalerate. Exposure to pyrethroids of the general population is thought to occur mainly via residues in the diet. Residue residue n. in a will, the assets of the estate of a person who has died with a will (died testate) which are left after all specific gifts have been made. Typical language: "I leave the rest, residue and remainder [or just residue] of my estate to my grandchildren. levels in crops grown according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. good agricultural practice are generally low. The resulting exposure of the general population is expected to be low, but precise data in the form of total-diet studies are lacking (1). Additional exposure via inhalation inhalation /in·ha·la·tion/ (in?hah-la´shun) 1. the drawing of air or other substances into the lungs.inhala´tional 2. the drawing of an aerosolized drug into the lungs with the breath. 3. or ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth. in·ges·tion n. 1. The act of taking food and drink into the body by the mouth. 2. of contaminated contaminated, v 1. made radioactive by the addition of small quantities of radioactive material. 2. made contaminated by adding infective or radiographic materials. 3. an infective surface or object. household dust may occur after the indoor application of pesticides. Because of their low volatility, pyrethroids are detected in indoor air only in very small concentrations up to the lower nanogram nanogram /nano·gram/ (ng) (nan?o-gram) one billionth (10-9) of a gram. nan·o·gram n. Abbr. ng One billionth (10-9) of a gram. range, or are not detectable. Therefore, the assessment of indoor exposure is usually carried out by analyzing household dust. In Germany, representative data for pesticide pesticide, biological, physical, or chemical agent used to kill plants or animals that are harmful to people; in practice, the term pesticide is often applied only to chemical agents. contamination in household dust were obtained in 1985 and 1990-1991. Of the eight different pyrethroids analyzed (cyfluthrin, cyhalothrin, cypermethrin, [Alpha]-cypermethrin, deltamethrin, empenthrin, [Delta]-phenothrin, and permethrin), only permethrin was detected regularly, whereas the other substances were found only very rarely [[is less than] 2% [is greater than] limit of detection (LOD Lod (lōd), city (1994 pop. 51,200), central Israel. It is also known as Lydda. Its manufactures include paper products, chemicals, oil products, electronic equipment, processed food, and cigarettes. )]. In 1990-1991 permethrin was detected in 91% of the samples, with a 98th percentile of 30.5 mg/kg and maximum value of 267 mg/kg (2). Comparable results were obtained in other epidemiologic studies epidemiologic study A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect in Germany (3,4): permethrin was the main pyrethroid used in the home, and other pyrethroids were hardly ever detected. In humans, pyrethroids are rapidly metabolized by esterases, mainly in the liver. The detoxified metabolites are renally eliminated, with the elimination half time (t.sub.1/2]) for the metabolites being about 6 hr (5). In recent years, methods for determining pyrethroid metabolites in urine have been developed that are sensitive enough for biomonitoring. In this paper we report data on the internal pyrethroid exposure of an urban population in Germany not known to have been exposed to pyrethroids. All the persons included in the study lived on the former U.S. Forces housing estates in Frankfurt am Main, where polycyclic aromatic hydrocarbons polycyclic aromatic hydrocarbon n. Any of a class of carcinogenic organic molecules that consist of three or more rings containing carbon and hydrogen and that are commonly produced by fossil fuel combustion. and some pesticides, such as DDT and chlorpyrifos, were detected in 1997. In all fiats and houses, household dust was analyzed for these substances, and redevelopment measures were performed when elevated levels were detected. Household dust from about 300 homes was also analyzed for different pyrethroids; only permethrin was found, and the mean and maximum levels were well below the levels of the representative data (median [is less than] LOD; 95th percentile, 4.8 mg/kg; maximum level, 19 mg/kg). The results were in accordance Accordance is Bible Study Software for Macintosh developed by OakTree Software, Inc.[] As well as a standalone program, it is the base software packaged by Zondervan in their Bible Study suites for Macintosh. with information from the U.S. Army that chlorpyrifos and pyrethrum pyrethrum (pīrē`thrəm): see chrysanthemum. pyrethrum Any of certain plant species of the genus Chrysanthemum (see were previously used as indoor insecticides, but no other pyrethroids, including permethrin, had been used. The residents were offered the opportunity of participating in biomonitoring tests to determine their internal exposure to the substances of interest (i.e., polycyclic aromatic hydrocarbons, DDT, and chlorpyrifos) (6,7). Although we found no evidence of indoor exposure to pyrethroids, we also analyzed pyrethroid metabolites in the urine samples to assess background exposure to these substances. Methods Collective. The residents were first offered the opportunity to receive consultation and take part in biomonitoring tests at an information evening organized after a first meeting of the experts, on 5 February 1998 in Frankfurt am Main. In addition, the residents were informed via the mass media and the distribution of leaflets. All residents of the former U.S. housing estates--flats and houses--were invited to take part in the tests, without any preclusion pre·clude tr.v. pre·clud·ed, pre·clud·ing, pre·cludes 1. To make impossible, as by action taken in advance; prevent. See Synonyms at prevent. 2. criteria. Most of them attended the consultation meetings between March and August 1998. Only a few people came later, so that by the end of December these special consultation meetings were brought to a close. A total of 9,548 persons inhabited in·hab·it·ed adj. Having inhabitants; lived in: a sparsely inhabited plain. Adj. 1. inhabited - having inhabitants; lived in; "the inhabited regions of the earth" the former U.S. housing estates at the time of the investigation. Urine samples from 1,177 persons were tested for pyrethroid metabolites; this represents urine specimens from 13% of the total residents of the former American Forces housing estates in Frankfurt. Considered according to age group, 24% of the children younger than 6 years of age, 16.6% of older children and teenagers, and 8% of adults older than 20 years of age were tested for pyrethroid metabolites in urine. The study population was a self-administered random sample. Though participation in this study was voluntary, there were no hints for selection bias with regard to pyrethroid exposure because these substances were not in the focus of interest of the people. Biomonitoring. The urine samples were frozen until anaylsis for the following four pyrethroid metabolites: cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid ([Br.sub.2]CA), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (cis-[Cl.sub.2]CA and trans-[Cl.sub.2]CA), and 4-fluoro-3-phenoxybenzoic acid (F-PBA) (Figure 1). Analyses were carried out using a sensitive and selective capillary capillary (kăp`əlĕr'ē), microscopic blood vessel, smallest unit of the circulatory system. Capillaries form a network of tiny tubes throughout the body, connecting arterioles (smallest arteries) and venules (smallest veins). gas chromatographic procedure with mass-spectrometric detection (GC/MS GC/MS Gas Chromatograph/Mass Spectrometer GC/MS Gas Chromatograph/Mass Spectrometry GC/MS Gas Chromatograph/Mass Spectrograph ). Briefly, after hydrolysis hydrolysis (hīdrŏl`ĭsĭs), chemical reaction of a compound with water, usually resulting in the formation of one or more new compounds. using sulfuric acid sulfuric acid, chemical compound, H2SO4, colorless, odorless, extremely corrosive, oily liquid. It is sometimes called oil of vitriol. Concentrated Sulfuric Acid , the urinary solution was drawn through a C18 column on which the pyrethroid metabolites were enriched. After elution elution /elu·tion/ (e-loo´shun) in chemistry, separation of material by washing; the process of pulverizing substances and mixing them with water in order to separate the heavier constituents, which settle out in solution, from the the metabolites were converted to their derivatives using methanol/sulfuric acid. 2-Phenoxybenzoic acid served as an internal standard. The calibration calibration /cal·i·bra·tion/ (kal?i-bra´shun) determination of the accuracy of an instrument, usually by measurement of its variation from a standard, to ascertain necessary correction factors. was carried out using pooled urine to which known amounts of pyrethroid metabolites were added and which was processed and analyzed in the same manner as the samples. Curves were linear between 1 and 200 [micro]g/L of each of the metabolites. The between-day imprecision im·pre·cise adj. Not precise. im  pre·cise ly adv. for
the determination of the above-mentioned analytes was between 6.2 and
8.7% at a concentration of 10 [micro]g/L urine. The LOD was in the range
of 0.1-0.2 [micro]g/L urine. For each of the analytes, two or three
fragment ions were scanned (cis/trans-[Cl.sub.2]CA M/e: 163, 187, 222;
[Br.sub.2]CA M/e: 231,253, 312; F-PBA M/e: 215, 246) (8). The method has
been proven for its analytical reliability from the analytical chemistry analytical chemistry: see under chemistry. working group of the "senatcommission for the investigation of
health hazard health hazard Occupational safety Any agent or activity posing a potential hazard to health. Cf Physical hazard. of chemical compounds in the work area" of the
Deutsche Forschungsgemeinschaft The Deutsche Forschungsgemeinschaft (abbreviated DFG, German Research Foundation in English) is an important German research funding organization. The DFG supports research in science and the humanities through a large variety of grant programmes, prizes and by (9). To ensure the reliability of our
data, we regularly and successfully take part in the German external
quality assurance system for the analyses of toxic substances in human
body fluid. For internal quality assurance, we used urine samples which
were spiked spike 1 n. 1. a. A long, thick, sharp-pointed piece of wood or metal. b. A heavy nail. 2. A spikelike part or projection, as: a. with the pyrethroid metabolites to concentrations between 6 and 8 [micro]g/L. The between-day imprecision during this study was between 5 and 7%. Because the LOD for the determination of 3-phenoxybenzoid acid (3-PBA) is higher by a factor of about 5, we did not determine this metabolite in this study. Environmental medicine requires a lower LOD. Moreover, our analytes are more specific for the individual pyrethroids than 3-PBA. We used the SPSS A statistical package from SPSS, Inc., Chicago (www.spss.com) that runs on PCs, most mainframes and minis and is used extensively in marketing research. It provides over 50 statistical processes, including regression analysis, correlation and analysis of variance. program, version 8 (SPSS GmbH Software, Munchen, Germany) for statistical analysis. [ILLUSTRATION OMITTED] Results Tables 1 and 2 show the results for [Br.sub.2]CA, cis-[Cl.sub.2]CA, trans-[Cl.sub.2]CA, and F-PBA in all 1,177 urine samples, listed according to different age groups (Table 1 [micro]g/L; Table 2 [micro]g/g creatinine creatinine /cre·at·i·nine/ (kre-at´i-nin) an anhydride of creatine, the end product of phosphocreatine metabolism; measurements of its rate of urinary excretion are used as diagnostic indicators of kidney function and muscle mass. ). The levels of trans-[Cl.sub.2]CA were above the LOD in 65% of the urine samples; cis-[Cl.sub.2]CA was detected in 29% of the urine specimens. The levels of [Br.sub.2]CA and F-PBA were above the detection limit in 19% and 16% of all urine samples, respectively (Table 3). No significant correlation was found between the levels of pyrethroid metabolites in urine and the age of the persons tested. A significant seasonal variation in the excretion excretion, process of eliminating from an organism waste products of metabolism and other materials that are of no use. It is an essential process in all forms of life. In one-celled organisms wastes are discharged through the surface of the cell. of pyrethroid metabolites in urine was not found either, but in the relatively small group of 38 persons tested between October and December 1998, there was a tendency for the concentrations of trans-[Cl.sub.2]CA in urine to be lower (Table 4). The correlation coefficients Correlation Coefficient A measure that determines the degree to which two variable's movements are associated. The correlation coefficient is calculated as: for the relationship between the permethrin contamination in household dust and the specific metabolites in the urine samples of the inhabitants
The game is based loosely on the concepts from SameGame. were low and insignificant (Spearman spear·man n. A man, especially a soldier, armed with a spear. rank correlations In statistics, rank correlation is the study of relationships between different rankings on the same set of items. It deals with measuring correspondence between two rankings, and assessing the significance of this correspondence. two-tailed; p [much greater than] 0.5).
Table 1. Pyrethroid metabolites in urine samples
([micro]g/L) listed according to age group.
Metabolite/
age (years) No. Mean [+ or -] SD Range
[Br.sub.2]CA
< 6 331 0.08 [+ or -] 0.55 < LOD-9.19
6 to < 12 247 0.09 [+ or -] 0.65 < LOD-9.19
12 to < 20 108 0.14 [+ or -] 0.67 < LOD-6.14
[is greater than or 483 0.07 [+ or -] 0.32 < LOD-4.76
equal to] 20
All (0-65) 1,177 0.08 [+ or -] 0.50 < LOD-9.19
cis-[Cl.sub.2]CA
< 6 331 0.06 [+ or -] 0.17 < LOD-1.16
6 to < 12 247 0.11 [+ or -] 0.29 < LOD-2.67
12 to < 20 108 0.13 [+ or -] 0.27 < LOD-1.51
[is greater than or 483 0.14 [+ or -] 0.57 < LOD-9.76
equal to] 20
All (0-65) 1,177 0.11 [+ or -] 0.41 < LOD-9.76
trans-[Cl.sub.2]CA
< 6 331 0.31 [+ or -] 0.50 < LOD-3.40
6 to < 12 247 0.41 [+ or -] 0.69 < LOD-6.15
12 to < 20 108 0.48 [+ or -] 0.63 < LOD-3.99
[is greater than or 483 0.47 [+ or -] 1.37 < LOD-17.82
equal to] 20
All (0-65) 1,177 0.41 [+ or -] 0.99 < LOD-17.82
F-PBA
< 6 331 0.05 [+ or -] 0.15 < LOD-1.04
6 to < 12 247 0.04 [+ or -] 0.14 < LOD-1.35
12 to < 20 108 0.06 [+ or -] 0.19 < LOD-1.73
[is greater than or 483 0.05 [+ or -] 0.33 < LOD-5.11
equal to] 20
All (0-65) 1,177 0.05 [+ or -] 0.24 < LOD-5.11
All pyrethroids, sum
< 6 331 0.51 [+ or -] 0.94 < LOD-10.33
6 to < 12 247 0.66 [+ or -] 1.30 < L00-10.43
12 to < 20 108 0.82 [+ or -] 1.10 < LOD-6.83
[is greater than or 483 0.74 [+ or -] 2.10 < LOD-24.22
equal to] 20
All (0-65) 1,177 0.66 [+ or -] 1.59 < LOD-24.22
Percentile
Metabolite/
age (years) 25th 50th 75th 95th
[Br.sub.2]CA
< 6 < LOD < LOD < LOD 0.25
6 to < 12 < LOD < LOD < LOD 0.32
12 to < 20 < LOD < LOD 0.10 0.50
[is greater than or < LOD < LOD < LOD 0.29
equal to] 20
All (0-65) < LOD < LOD < LOD 0.30
cis-[Cl.sub.2]CA
< 6 < LOD < LOD 0.10 0.39
6 to < 12 < LOD < LOD 0.10 0.53
12 to < 20 < LOD < LOD 0.22 0.48
[is greater than or < LOD < LOD 0.10 0.65
equal to] 20
All (0-65) < LOD < LOD 0.10 0.51
trans-[Cl.sub.2]CA
< 6 < LOD 0.21 0.38 1.07
6 to < 12 < LOD 0.26 0.51 1.27
12 to < 20 0.10 0.31 0.61 1.52
[is greater than or < LOD 0.23 0.45 1.67
equal to] 20
All (0-65) < LOD 0.24 0.46 1.43
F-PBA
< 6 < LOD < LOD < LOD 0.39
6 to < 12 < LOD < LOD < LOD 0.27
12 to < 20 < LOD < LOD < LOD 0.37
[is greater than or < LOD < LOD < LOD 0.10
equal to] 20
All (0-65) < LOD < LOD < LOD 0.27
All pyrethroids, sum
< 6 < LOD 0.31 0.51 1.85
6 to < 12 < LOD 0.35 0.68 2.23
12 to < 20 0.23 0.52 1.01 2.87
[is greater than or < LOD 0.29 0.67 2.53
equal to] 20
All (0-65) < LOD 0.32 0.68 2.23
The age of eight participants was not known.
Table 2. Pyrethroid metabolites in urine samples
([micro]g/g creatinine) listed according to age group.
Metabolite/
age (years) No. Mean [+ or -] SD Range
[Br.sub.2]CA
< 6 331 0.10 [+ or -] 0.45 < LOD-6.56
6 to < 12 247 0.08 [+ or -] 0.57 < LOD-7.18
12 to < 20 108 0.10 [+ or -] 0.41 < LOD-3.57
[is greater than or 483 0.06 [+ or -] 0.24 < LOD-2.26
equal to] 20
All (0-65) 1,177 0.08 [+ or -] 0.40 < LOD-7.18
cis-[Cl.sub.2]CA
< 6 331 0.11 [+ or -] 0.32 < LOD-4.0
6 to < 12 247 0.11 [+ or -] 0.32 < LOD-3.34
12 to < 20 108 0.10 [+ or -] 0.19 < LOD-0.98
[is greater than 483 0.14 [+ or -] 0.61 < LOD-9.06
or equal to] 20
All (0-65) 1,177 0.12 [+ or -] 0.45 < LOD-9.06
trans-[Cl.sub.2]CA
< 6 331 0.47 [+ or -] 0.98 < LOD-14.70
6 to < 12 247 0.40 [+ or -] 0.66 < LOD-6.47
12 to < 20 108 0.32 [+ or -] 0.36 < LOD-1.86
[is greater than or 483 0.42 [+ or -] 1.22 < LOD-17.13
equal to] 20
All (0-65) 1,177 0.42 [+ or -] 0.99 < LOD-17.13
F-PBA
< 6 331 0.09 [+ or -] 0.24 < LOD-1.96
6 to < 12 247 0.04 [+ or -] 0.13 < LOD-1.17
12 to < 20 108 0.05 [+ or -] 0.15 < LOD-1.23
[is greater than or 483 0.07 [+ or -] 0.43 < LOD-5.74
equal to] 20
All (0-65) 1,177 0.07 [+ or -] 0.32 < LOD-5.74
All pyrethroids, sum
< 6 331 0.79 [+ or -] 1.44 < LOD-18.17
6 to < 12 247 0.63 [+ or -] 1.28 < LOD-12.08
12 to < 20 108 0.57 [+ or -] 0.67 < LOD-3.77
[is greater than or 483 0.69 [+ or -] 1.95 < LOD-20.92
equal to] 20
All (0-65) 1,177 0.69 [+ or -] 1.59 < LOD-20.92
Percentile
Metabolite/
age (years) 25th 50th 75th 95th
[Br.sub.2]CA
< 6 < LOD < LOD < LOD 0.51
6 to < 12 < LOD < LOD < LOD 0.22
12 to < 20 < LOD < LOD 0.05 0.39
[is greater than or < LOD < LOD < LOD 0.29
equal to] 20
All (0-65) < LOD < LOD < LOD 0.35
cis-[Cl.sub.2]CA
< 6 < LOD < LOD 0.09 0.60
6 to < 12 < LOD < LOD 0.10 0.61
12 to < 20 < LOD < LOD 0.12 0.59
[is greater than < LOD < LOD 0.07 0.53
or equal to] 20
All (0-65) < LOD < LOD 0.09 0.58
trans-[Cl.sub.2]CA
< 6 < LOD 0.30 0.55 1.82
6 to < 12 < LOD 0.23 0.50 1.44
12 to < 20 0.05 0.26 0.44 1.11
[is greater than or < LOD 0.17 0.39 1.28
equal to] 20
All (0-65) < LOD 0.22 0.47 1.40
F-PBA
< 6 < LOD < LOD < LOD 0.61
6 to < 12 < LOD < LOD < LOD 0.27
12 to < 20 < LOD < LOD < LOD 0.32
[is greater than or < LOD < LOD < LOD 0.20
equal to] 20
All (0-65) < LOD < LOD < LOD 0.40
All pyrethroids, sum
< 6 < LOD 0.42 0.93 3.12
6 to < 12 < LOD 0.31 0.61 2.06
12 to < 20 0.14 0.36 0.78 2.22
[is greater than or < LOD 0.27 0.61 2.04
equal to] 20
All (0-65) < LOD 0.32 0.73 2.30
The age of eight participants was not known.
Table 3. Percentage of urine samples in which
pyrethroid metabolites were detected.
(% > LOD)
Urine cis trans-
samples [Br.sub.2] [Cl.sub.2] [Cl.sub.2]
Age (years) (n) CA CA CA F-PBA
< 6 331 16.6 21.0 51.3 16.1
6 to < 12 247 14.8 26.9 59.7 12.7
12 to < 20 108 25.6 36.4 68.6 18.2
[is greater 483 16.8 28.0 61.7 13.3
than or
equal to] 20
All 1,177 19.3 29.4 65.3 16.4
Table 4. Pyrethroid metabolites found in urine specimens
([micro]g/L) in different months of 1998.
Metabolite/
months No. Mean [+ or -] SD Range
[Br.sub.2]CA
Feb-March 537 0.07 [+ or -] 0.27 < LOD-4.03
April-May 286 0.12 [+ or -] 0.88 < LOD-9.19
June-July 227 0.07 [+ or -] 0.34 < LOD-4.76
Aug-Sept 88 0.09 [+ or -] 0.40 < LOD-2.88
Oct-Dec 38 0.08 [+ or -] 0.06 < LOD-0.30
cis-[Cl.sub.2]CA
Feb-March 537 0.10 [+ or -] 0.31 < LOD-3.94
April-May 286 0.13 [+ or -] 0.62 < LOD-9.76
June-July 227 0.12 [+ or -] 0.40 < LOD-5.01
Aug-Sept 88 0.05 [+ or -] 0.13 < LOD-0.55
Oct-Dec 38 0.08 [+ or -] 0.06 < LOD-0.25
trans-[Cl.sub.2]CA
Feb-March 537 0.43 [+ or -] 1.00 < LOD-17.82
April-May 286 0.46 [+ or -] 1.05 < LOD-14.27
June-July 227 0.40 [+ or -] 1.11 < LOD-14.45
Aug-Sept 88 0.31 [+ or -] 0.40 < LOD-1.78
Oct-Dec 38 0.23 [+ or -] 0.27 < LOD-1.26
F-PBA
Feb-March 537 0.08 [+ or -] 0.33 < LOD-5.11
April-May 286 0.03 [+ or -] 0.18 < LOD-1.83
June-July 227 0.02 [+ or -] 0.05 < LOD-0.43
Aug-Sept 88 0.02 [+ or -] 0.15 < LOD-1.37
Oct-Dec 38 0.07 [+ or -] 0.04 < LOD-0.10
Pyrethroids, sum
Feb-March 537 0.68 [+ or -] 1.48 < LOD-21.76
April-May 286 0.76 [+ or -] 1.89 < LOD-24.03
June-July 227 0.61 [+ or -] 1.80 < LOD-24.22
Aug-Sept 88 0.49 [+ or -] 0.75 < LOD-4.52
Oct-Dec 38 0.47 [+ or -] 0.34 < LOD-1.69
Percentile
Metabolite/
months 25th 50th 75th 95th
[Br.sub.2]CA
Feb-March < LOD < LOD < LOD 0.34
April-May < LOD < LOD < LOD 0.27
June-July < LOD < LOD < LOD 0.26
Aug-Sept < LOD < LOD < LOD 0.84
Oct-Dec < LOD 0.10 0.10 0.11
cis-[Cl.sub.2]CA
Feb-March < LOD < LOD 0.10 0.51
April-May < LOD < LOD 0.15 0.63
June-July < LOD < LOD 0.10 0.59
Aug-Sept < LOD < LOD < LOD 0.39
Oct-Dec < LOD 0.10 0.10 0.23
trans-[Cl.sub.2]CA
Feb-March < LOD 0.25 0.46 1.52
April-May < LOD 0.27 0.57 1.47
June-July < LOD 0.21 0.40 1.39
Aug-Sept < LOD 0.24 0.48 1.23
Oct-Dec 0.10 0.10 0.26 1.26
F-PBA
Feb-March < LOD < LOD < LOD 0.48
April-May < LOD < LOD < LOD 0.10
June-July < LOD < LOD < LOD 0.10
Aug-Sept < LOD < LOD < LOD 0.10
Oct-Dec < LOD 0.10 0.10 0.10
Pyrethroids, sum
Feb-March < LOD 0.36 0.72 2.36
April-May < LOD 0.32 0.69 2.81
June-July < LOD 0.26 0.63 2.00
Aug-Sept < LOD 0.25 0.61 2.10
Oct-Dec 0.40 0.40 0.54 1.29
Discussion All synthetic pyrethroids are rapidly metabolized by hydrolytic hy·drol·y·sis n. Decomposition of a chemical compound by reaction with water, such as the dissociation of a dissolved salt or the catalytic conversion of starch to glucose. cleavage cleavage, tendency of many minerals to split along definite smooth planar surfaces determined by their crystal structure. The directions of these surfaces are related to weaknesses in the atomic structure of the mineral and are always parallel to a possible crystal to form their corresponding metabolites, [Br.sub.2]CA or cis-[Cl.sub.2]CA and trans-[Cl.sub.2]CA. The alcohol moiety moiety: see clan. is oxidized oxidized having been modified by the process of oxidation. oxidized cellulose see absorbable cellulose. to F-PBA or 3-PBA. Cis- and trans-[Cl.sub.2]CA are the specific metabolites of permethrin, cypermethrin, and cyfluthrin, whereas deltamethrin is transformed to [Br.sub.2]CA. Most pyrethroids are metabolized to form 3-PBA, but some fluoro-substituted pyrethroids such as cyfluthrin are transformed to F-PBA. Pyrethroids may produce markedly different metabolite patterns after oral and dermal dermal /der·mal/ (der´mal) pertaining to the dermis or to the skin. der·mal or der·mic adj. Of or relating to the skin or dermis. administration. After dermal administration of cypermethrin, the ratio of tran:cis cyclopropane cyclopropane, C3H6, a gaseous hydrocarbon. It is a cyclic alkane, its three carbon atoms being joined together in a ring. The angle between successive carbon-carbon bonds in the ring is only 60°, much less than that between successive acids is approximately 1:1, compared to 2:1 after oral administration (10). After inhalation exposure of volunteers to cyfluthrin, the ratio of trans:cis-cyclopropane was approximately 2:1 (5). Almost 20 years ago, the first study of permethrin metabolites in urine was carried out with samples from occupationally exposed forestry workers in Sweden (11). In all but one person the levels of permethrin metabolites were below the LOD of the method (i.e., [is less than] 0.5-0.1 mg/L urine). The person subjected to the highest level of exposure (85 [micro]g/[m.sup.3]) excreted 0.26 mg permethrin metabolite/L urine the following morning, but in the afternoon the amount excreted was [is less than] 0.5 mg/L urine (11). In several later studies with field workers and greenhouse workers exposed to permethrin and cypermethrin, the urinary metabolite [Cl.sub.2]CA was analyzed (1,11,12). [Br.sub.2]CA was found in the urine of workers exposed to deltamethrin by inhalation and dermal contact (13-16). In 2 of 10 greenhouse workers exposed to deltamethrin, 3-PBA was detected, with a range of [is less than] 2-52 [micro]g/L (17). Analyses of the levels of pyrethroids excreted by pest control pest control n → control m de plagas pest control n → lutte f contre les nuisibles pest control pest n workers using a method with an improved LOD (0.5-1 [micro]g/L urine) showed the pyrethroid levels in urine samples to be in the range of [is less than] 0.5-277 [micro]g/L (18). The metabolites were detectable in urine for up to 3.5 days after exposure to cyfluthrin (19). Data on occupational exposure are, however, scarce, as are data from the biomonitoring of pyrethroid exposure in the population (i.e., in an environmental setting). In our environmental, population-based study we used an improved method with an LOD of 0.1-0.2 [micro]g metabolite/L urine. A total of 1,177 urine samples from persons who had stated that they were neither occupationally exposed nor had used pyrethroids in their homes were tested for F-PBA, [Br.sub.2]CA, and the [Cl.sub.2]CA-isomers. trans-[Cl.sub.2]CA was detected in [is greater than] 60% of the urine samples, and cis-[Cl.sub.2]CA was found in about 30%. The trans.cis ratio was about 2:1. This ratio indicated oral or inhalation exposure, with no evidence of dermal uptake. The other metabolites were detected in [is less than] 20% of the urine samples. Although trans-[Cl.sub.2]CA was found in the highest amounts, in some cases [Br.sub.2]CA and F-PBA were excreted in high concentrations as well. There was no correlation between the excretion of pyrethroid metabolites and age; the levels of pyrethroid metabolites in the urine of adults did not differ from those in children. Our data may be compared with two other recently published studies. In 1998, Butte Butte, city, United States Butte (by  t), city (1990 pop. 33,336), seat of Silver Bow co., SW Mont.; inc. 1879. It is a trade, ranching, and industrial center. et al. (20) published data on the levels of [Cl.sub.2]CA
and 3-PBA in 254 urine specimens from healthy adults from
Schleswig-Holstein, in the northern part of Germany. Due to a different
analytical method, they were not able to differentiate between the cis-
and trans- isomers isomers (ī´sōmurz),n.pl 1. organic compounds having the same empirical formula–i.e. of [Cl.sub.2]CA. The median, maximum, and 95th percentile values for [Cl.sub.2]CA in the urine tested were below the LOD (0.2 [micro]g/L), 11.5 [micro]g/L, and 0.51 [micro]g/L, respectively, and thus lower than in our study. The differences may be due to differences in the analytical approach or may be caused by different external exposure in different regions in Germany. Because we did not find seasonal differences in the levels of pyrethroid metabolites determined in urine, the time of urine sampling can be excluded as an influencing factor. In the study conducted by Hardt et al. (21), 45 adult volunteers who were not occupationally exposed to pyrethroids were studied in the same laboratory as in our study, using the same analytical method, so that methodologic differences may be disregarded dis·re·gard tr.v. dis·re·gard·ed, dis·re·gard·ing, dis·re·gards 1. To pay no attention or heed to; ignore. 2. To treat without proper respect or attentiveness. n. . The data on the excretion of [Cl.sub.2]CA was comparable to our data from more than 1,000 persons, but the levels of [Br.sub.2]CA and F-PBA excreted were lower (21). To date, there are no other data available on the pyrethroid metabolites excreted in the urine of children. The indoor exposure of our study area, calculated on the basis of the pyrethroid levels in household dust, was lower than the general exposure evaluated in the representative environmental survey in Germany, 1990-1991. No correlations were detected in our study between the indoor exposure (permethrin in household dust or cupboard dust) and the levels of pyrethroid metabolites excreted in the urine of the inhabitants. This is also true for the study published by Butte et al. (20), although rather high permethrin levels were found in household dust (95th percentile, 73 mg/kg). It may be concluded, therefore, that the internal pyrethroid exposure detected in the general population in Germany for children and adults is mainly caused by dietary exposure. To test this hypothesis, duplicate diet studies combined with biomonitoring should be conducted, preferably pref·er·a·ble adj. More desirable or worthy than another; preferred: Coffee is preferable to tea, I think. pref with a representative design. Toxicologic evaluations have been drawn up for several synthetic pyrethroids by the Food and Agriculture Organization of the United Nations/World Health Organization Joint Meeting on Pesticide Residues Pesticide residue refers to the pesticides that may remain on or in food after they are applied to food crops.[1] Regulation of pesticide residue in the US (22). The acceptable daily intake acceptable daily intake the amount of a drug or chemical residue to which an animal can be exposed daily for a lifetime without suffering a deleterious or injurious effect, on the basis of all of the facts known at the time. (ADI) has been estimated for various synthetic pyrethroids. The ADI values are in the range of 10 [micro]g/kg body weight (e.g., deltamethrin) up to 50 [micro]g/kg body weight (e.g., permethrin, cypermethrin) (22). The level of background exposure reported here is therefore orders of magnitude lower than the ADI values. Summary In this study, spot urine samples from 1,177 persons with neither occupational nor recent indoor exposure were analyzed using a method shown to be precise, accurate, specific, sensitive, and suitable for routine analysis. With this method, the most important pyrethroid metabolites can be determined in one run. Background exposure to pyrethroids was found in the general population: trans-[Cl.sub.2]CA was detected in 60% of the urine samples tested, cis-[Cl.sub.2]CA was detected in 30%, and [Br.sub.2]CA and F-PBA were detected in 16-19%. The urinary metabolite concentrations in children did not differ from those in adults, and there was no correlation with the indoor exposure, assessed by determining the levels of permethrin in household dust. The month in which the urine samples were taken had no influence on the levels of pyrethroids in urine. As long as representative data are lacking, the rounded 95th percentile values obtained in our study may be used as reference values in the population, for both children and adults: [Br.sub.2]CA, 0.3 [micro]g/L; cis-[Cl.sub.2]CA, 0.5 [micro]g/L; trans-[Cl.sub.2]CA, 1.5 [micro]g/L; and F-PBA, 0.3 [micro]g/L. REFERENCES AND NOTES (1.) WHO. Permethrin. Environmental Health Criteria 94. Geneva Geneva, canton and city, Switzerland Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. :World Health Organization, 1990. (2.) Friedrich C, Becker K, Hoffmann G, Hoffmann K, Krause C, Nollke P, Schulz C, Schwabe R, Seiwert M. Pyrethroide im Hausstaub der deutschen Wohnbevolkerung-Ergebnisse zweier bundesweiter Querschnittstudien. Gesundheitswesen 60:95-101 (1998). (3.) Walker G, Hostrup O, Hoffmann W, Butte W. Biozide im Hausstaub. Gefahrstoffe -- Reinhaltung der Luft 59:33-41 (1999). (4.) Landesamt fur Natur und Umwelt des Landes Schleswig-Holstein. Bodenbelastungen in Hausgarten und Hausstaubbelastungen aus vier Regionen in Schleswig-Holstein. Kiel, Germany:Landesamt fur Natur und Umwelt des Landes Schleswig-Holstein, 1997. (5.) Leng G, Leng A, Kuhn K-H, Lewalter J, Pauluhn J. Human dose-excretion studies with the pyrethroid insecticide insecticide Any of a large group of substances used to kill insects. Such substances are mainly used to control pests that infest cultivated plants and crops or to eliminate disease-carrying insects in specific areas. cyfluthrin: urinary metabolite profile following inhalation. Xenobiotica 27:1273-1283 (1997). (6.) Heudorf U, Peters M, Angerer J. Coal tar pitch coal tar pitch a cause of severe hepatic necrosis in pigs that nibble at pitch-coated pens and floors. The syndrome includes anemia, jaundice and emaciation. parquet glue glue: see adhesive. glue Adhesive substance resembling gelatin, extracted from animal tissue, particularly hides and bones, or from fish, casein (milk protein), or vegetables. : a problem of old houses in Germany including former US-Housing. Umweltmed Forsch Prax 4:202-203 (1999). (7.) Hardt J, Heudorf U, Peters M, Angerer J. External and internal exposure of inhabitants of former US-Housing to organophosphates. Umweltmed Forsch Prax 4:202 (1999). (8.) Angerer J, Ritter rit·ter n. pl. ritter A knight. [German, from Middle High German riter, from Middle Dutch ridder, from r A. Determination of metabolites of pyrethroids in human urine Urine is liquid waste product of the body secreted by the kidneys by a process of filtration from blood and excreted through the urethra. This waste is eventually expelled from the body in a process known as urination. using solid-phase extraction and gas chromatography-mass-spectrometry. J Chromatogr 695:217-226 (1997). (9.) Angerer J, Schaller KH. Analyses of Hazardous Substances in Biological Materials, Vol 6. Weinheim: Wiley-VCH, 1999. (10.) Wilkes MF, Woollen woollen fabrics such as tweeds, felts, flannels, blankets, knitwear made of wool with a shorter fiber length than that used for worsted. BH, Marsh JR, Batten bat·ten 1 v. bat·tened, bat·ten·ing, bat·tens v.intr. 1. To become fat. 2. PL, Chester G. Biological monitoring for pesticide exposure--the role of human volunteer studies. Int Arch Occup Environ Health 65(suppl):189-192 (1993). (11.) Kolmodin-Hedman B, Swensson A, Akerblom M. Occupational exposure to some synthetic pyrethroids (permethrin and fenvalerate). Arch Toxicol 50:27-33 (1982). (12.) Eadsford CV, Bragt PC, van Sittert NJ. Human-dose excretion studies with pyrethroid insecticides cypermethrin and alphacypermethrin: relevance for biological monitoring. Xenobiotica 18:803-614 (1988). (13.) He F, Sun J, Hen Hen, in the Bible, man who was to have a memorial in the temple. K, Wu Y, Yao P, Wang S, Liu L. Effects of pyrethroid insecticides on subjects engaged in packing pyrethroids. Br J Ind Med 45:548-551 (1988). (14.) He F, Deng H, Ji X, Zhang Z, Sun J, Yao P. Changes of nerve excitability excitability readiness to respond to a stimulus; irritability. and urine deltamethrin in sprayers. Int Arch Occup Environ Health 62:587-590 (1991). (15.) He F. Biological monitoring of occupational pesticides exposure. Int Arch Occup Environ Health 65(suppl):69-76 (1993). (18.) Zhang Z, Sun J, Chen S, Wu Y, He F. Levels of exposure and biological monitoring of pyrethoids in spraymen. Br J Ind Med 48:82-86 (1991). (17.) Tuomainen A, Kangas J, Liesivuori J, Manninen A. Biological monitoring of deltamethrin exposure in greenhouses. Int Arch Occup Environ Health 69:62-64 (1996). (18.) Leng G, Kuhn K-H, Idel H. Biological monitoring of pyrethroids in blood and pyrethroid metabolites in urine: applications and limitations. Sci Total Environ 199:173-181 (1997). (19.) Leng G, Kuhn K-H, Idel H. Biological monitoring of pyrethroid metabolites in urine of pest control operators. Toxicol Lett 88:215-220 (1996). (20.) Butte W, Walker G, Heinzow B. Referenzwerte der Konzentrationen von Permethrinmetaboliten Cl2-CA (3-(2,2-Dichlorvinyl)-2,2-dimethylcyclopropancarbonsaure und 3-PBA (3-Phenoxybenzoesaure) im Urin. Umweltmed Forsch Prax 3:21-26 (1998). (21.) Hardt J, Heudorf U, Angerer J. Zur Frage der Belastung der Allgemeinbevolkerung durch Pyrethroide. Umweltmed Forsch Prax 4:54-55 (1999). (22.) Pesticide Residues in Food: Joint Report of the FAO FAO, n See Food and Agriculture Organization. Working Party on Pesticide Residues and the WHO Expert Committee on Pesticide Residues. Series. Rome:Food and Agriculture Organization of the United Nations Noun 1. Food and Agriculture Organization of the United Nations - the United Nations agency concerned with the international organization of food and agriculture FAO, Food and Agriculture Organization , 1964-1995. Ursel Heudorf(1) and Juergen Angerer(2) (1) Public Health Department of the City of Frankfurt am Main, Frankfurt, Germany; (2) Institute for Occupational, Social, and Environmental Medicine, University Erlangen-Nurnberg, Erlangen, Germany Address correspondence to U. Heudorf, Public Health Department, Braubachstr. 18-22, D-60311 Frankfurt/Main, Germany. Telephone: 49-69-21236980. Fax: 49-69-21230475. E-mail: ursel.heudorf@stadt-frankfurt.de Received 27 July 2000; accepted 11 October 2000. |
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