Biomonitoring Summary

Pyrethroid Pesticides Overview

Pyrethroid pesticides are synthetic analogues of pyrethrins, which are natural chemicals found in chrysanthemum flowers. Pyrethroid pesticides are used to control a wide range of insects in public and commercial buildings, animal facilities, warehouses, agricultural fields, and greenhouses. They are also applied on livestock to control insects. In agriculture, cypermethrin, cyfluthrin, and deltamethrin have been used frequently on cotton. Pyrethroid insecticides are the most common active ingredient in commercially available insect sprays and are also used as structural termiticides. Certain pyrethroid insecticides (such as permethrin, resmethrin, and sumithrin) are also registered for use in mosquito-control programs in the United States. Outside the U.S., deltamethrin has been used for indoor protection against mosquitoes that carry malaria, in some situations replacing the use of DDT. About two million pounds of permethrin and one million pounds of cypermethrin have been applied annually (U.S. EPA, 2006a, 2006b). Permethrin is also used in skin lotions and shampoos as medical treatments for lice and scabies. Pyrethroid pesticides are generally formulated as complex mixtures of different chemical isomers, solvent oils, and synergists, such as piperonyl butoxide. Pyrethroid pesticides have low volatility, bind to soils, and are rarely detected in ground waters (USGS, 2007). Generally, they are not persistent in the environment due to their rapid degradation within days to several months. This class of pesticides has low toxicity in birds and mammals, but pyrethroids are highly toxic to fish and some aquatic invertebrates, so usage is restricted near water (U.S.EPA, 2012).

The general population may be exposed to pyrethroid insecticides primarily from the ingestion of food or from residential use. Estimated intakes from diet and drinking water are below recommended limits. Dermal exposure with the potential for inadvertent ingestion may occur when lotions or shampoos are applied to treat lice or scabies. Pesticide applicators can be exposed to pyrethroid pesticides via dermal and inhalation routes from powders and liquid formulations. Pyrethroids are not well absorbed through the skin (ATSDR, 2003; Woollen et al., 1992). After absorption from inhalation or ingestion, pyrethroids are rapidly metabolized, by either ester hydrolysis or hydroxylation, followed by conjugation, and then eliminated over several days in urine and bile (Kuhn et al., 1999; Leng et al., 1997; Soderlund et al., 2002; Woollen et al., 1992). Unmetabolized pyrethroids have been measured in breast milk, but may be poorly transferred across the placenta (ATSDR, 2003; WHO, 2005).

Human health effects from pyrethroid pesticides at low environmental doses or at biomonitored levels from low environmental exposures are unknown. Compared with other classes of insecticides such as organochlorines, organophosphorus, or carbamate pesticides, pyrethroid pesticides have less acute toxicity in animals and people. They are ranked as having moderate acute oral toxicity. Adverse effects from large doses are related to the action of pyrethroids on the nervous system, where these chemicals prolong sodium channel opening when a nerve cell is depolarized (Shafer et al., 2005; Soderlund et al., 2002). Possible other additional actions on neuroreceptors and other ion channels may also explain some pyrethroid effects. Human cases of systemic poisoning are rare and usually result from accidental exposure or intentional ingestion of pyrethroid insecticides. Signs and symptoms of acute pyrethroid poisoning after massive ingestions include agitation, hypersensitivity, tremor, salivation, choreoathetosis, and seizures (ATSDR, 2003; Ray et al., 2000; Soderlund et al., 2002). Concomitant exposure to organophosphorus insecticides may increase pyrethroid toxicity by slowing metabolic clearance of the pyrethroid. In California, cyfluthrin was the most frequent pyrethroid associated with symptomatic effects (irritant respiratory and dermal effects, paresthesias) reported in agricultural workers from 1996 to 2002 (Spencer and O'Malley, 2006). Transient dermal paresthesias have been reported among pesticide applicators after direct contact with certain types of pyrethroid pesticides. No relationship of indoor air or housedust concentrations of permethrin and irritant symptoms was found in a study of urban residents in 80 private homes (Berger-Preiss et al., 2002).

In developing rodents, neurochemical changes in cholinergic, dopaminergic, and catecholaminergic pathways and behavioral changes have been demonstrated at subacute and subchronic doses for some pyrethroid pesticides (Aziz et al., 2001; Elwan et al., 2006; Eriksson and Fredriksson, 1991; Lazarini et al., 2001; Shafer, et al., 2005). The pyrethroids in general use are not considered teratogenic or to have significant reproductive toxicity (ATSDR, 2003; WHO, 2005), though a few pyrethroid pesticides and some metabolites have shown weak or inconsistent estrogenic effects on standardized assays (ATSDR, 2003; Garey and Wolff, 1998; Go et al., 1999; Hu et al., 2003; Kim et al., 2004; Kunimatsu et al., 2002; McCarthy et al., 2006; Moniz et al., 2005). Generally, the pyrethroids are not considered genotoxic in in vitro testing or carcinogenic in animal testing (WHO, 2005). IARC considers deltamethrin and permethrin as not classifiable as to their human carcinogenicity. Additional information about pesticides is available from U.S. EPA at https://www.epa.gov/pesticides and from ATSDR at https://www.atsdr.cdc.gov/toxprofiles/index.asp#H.

There are about 30 different pyrethroid pesticides in use. The table shows the urinary pyrethroid metabolites measured in the National Biomonitoring Program.

Phthalates and Urinary Metabolites Measured in the National Biomonitoring Program

Table of Phthalates and Urinary Metabolites Measured in the National Biomonitoring Program
Pyrethroid (CAS number)	Urinary metabolite (CAS number)
Cyfluthrin (68359-37-5)	4-Fluoro-3-phenoxybenzoic acid (77279-89-1)
Cypermethrin (52315-07-8) Cyfluthrin (68359-37-5) Permethrin (52645-53-1)	cis-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (63597-73-9) trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (59042-50-1)
Deltamethrin (52918-63-5)	cis-3-(2,2-Dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (59042-49-8)
Cyhalothrin (68359-37-5) Cypermethrin (52315-07-8) Deltamethrin (52918-63-5) Fenpropathrin (39515-41-8) Permethrin (52645-53-1) Tralomethrin (66841-25-6)	3-Phenoxybenzoic acid (3739-38-6)

Cyhalothrin

CAS No. 68359-37-5

Cypermethrin

CAS No. 52315-07-8

Deltamethrin

CAS No. 52918-63-5

Fenpropathrin

CAS No. 39515-41-8

Permethrin

CAS No. 52645-53-1

Tralomethrin

CAS No. 66841-25-6

General Information

The chemical 3-phenoxybenzoic acid is a metabolite and an environmental degradate of the six pyrethroid pesticides listed above. Thus, the presence of 3-phenoxybenzoic acid in urine not only reflects the metabolic transformation of any of the six pesticides listed above, but can reflect direct exposure to 3-phenoxybenzoic acid formed in the environment from the degradation of these pesticides.

Biomonitoring Information

Urinary levels of 3-phenoxybenzoic acid reflect recent exposure to the parent pyrethroid pesticides. In an analysis of 217 urine specimens from a nonrandom sample of United States residents, Baker et al. (2004) reported geometric mean levels of 3-phenoxybenzoic acid that were approximately sixfold higher than levels for adults in the NHANES 2001-2002 subsample (CDC, 2009). Median levels of urinary 3-phenoxybenzoic acid were 67-fold higher in 307 pregnant New York City women who used indoor pesticides compared with the median levels for adults in the NHANES 2001-2002 subsample (Berkowitz et al., 2003; CDC, 2009). In the New York City study, a temporal variation in levels was observed and considered to correspond to seasonal spraying of pesticides. A study of 396 German children (Becker et al., 2006) showed that urinary levels of 3-phenoxybenzoic acid at the 95th percentile were similar to levels at the 95th percentile for children in the U.S. representative NHANES 2001-2002 subsample (CDC, 2009). Urinary levels of 3-phenoxybenzoic acid in children were found to be related to residential pesticide use and house dust levels (Lu et al., 2006; Becker et al., 2006). A small sample of occupationally unexposed Italian residents had median levels of urinary 3-phenoxybenzoic acid that were about fourfold higher than for adults in the NHANES 2001-2002 subsample (CDC, 2009; Saieva et al., 2004). In one study of 145 urban residents in 80 private homes in Germany, urinary 3-phenoxybenzoic acid levels at the 95th percentile were about threefold lower than the levels at the 95th percentile in the 2001-2002 NHANES subsample (Berger-Preiss et al., 2002; CDC, 2009).

In 57 volunteers entering areas previously spot-sprayed with various pyrethroid pesticides, median urinary levels of 3-phenoxybenzoic acid were slightly less than median levels in the NHANES 2001-2002 subsample (Leng et al., 2003; CDC, 2009). Following residential spraying with deltamethrin for malaria protection in Mexico, mean peak urinary levels of 3-phenoxybenzoic acid in children increased at least sixtyfold over non-detectable background levels for several days and mean levels remained slightly above background levels 45 days after the spraying (Ortiz-Perez et al., 2005). The mean peak levels in these children were 83-fold higher than the geometric mean for children in the NHANES 2001-2002 subsample (CDC, 2009). In a small group of indoor pest-control operators, the post-application median urinary levels of 3-phenoxybenzoic acid were 24-fold higher than those for adults in the NHANES 2001-2002 subsample (CDC, 2009; Hardt and Angerer, 2003).

Finding a measurable amount in urine does not imply that the level will result in an adverse health effect. Biomonitoring studies of 3-phenoxybenzoic acid provide physicians and public health officials with reference values so that they can determine whether other people have been exposed to higher levels of pyrethroids than levels found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

References

Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for pyrethrins and pyrethroids. September 2003. Available from URL: https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=787&tid=153. 12/28/12

Aziz MH, Agrawal AK, Adhami VM, Shukla Y, Seth PK. Neurodevelopmental consequences of gestational exposure (GD14-GD20) to low dose deltamethrin in rats. Neurosci Lett 2001;300(3):161-5.

Baker SE, Olsson AO, Barr DB. Isotope dilution high-performance liquid chromatography-tandem mass spectrometry method for quantifying urinary metabolites of synthetic pyrethroid insecticides. Arch Environ Contam Toxicol 2004;46(3):281-8.

Becker K, Seiwert M, Angerer J, Kolossa-Gehring M, Hoppe HW, Ball M, et al. GerES IV pilot study: assessment of the exposure of German children to organophosphorus and pyrethroid pesticides. Int J Hyg Environ Health 2006;209(3):221-33.

Berger-Preiss E, Levsen K, Leng G, Idel H, Sugiri D, Ranft U. Indoor pyrethroid exposure in homes with woollen textile floor coverings. Int J Hyg Environ Health 2002;205(6):459-72.

Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, et al. Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort. Environ Health Perspect 2003;111(1):79-84.

Centers for Disease Control and Prevention (CDC). Fourth National Report on Human Exposure to Environmental Chemicals.2009. [online] Available at URL: https://www.cdc.gov/exposurereport/. 12/28/12

Elwan MA, Richardson JR, Guillot TS, Caudle WM, Miller GW. Pyrethroid pesticide-induced alterations in dopamine transporter function. Toxicol Appl Pharmacol 2006;211(3):188-97.

Eriksson P, Fredriksson A. Neurotoxic effects of two different pyrethroids, bioallethrin and deltamethrin, on immature and adult mice: changes in behavioral and muscarinic receptor variables. Toxicol Appl Pharmacol 1991;108(1):78-85.

Garey J, Wolff MS. Estrogenic and antiprogestagenic activities of pyrethroid insecticides. Biochem Biophys Res Commun 1998;251(3):855-9.

Go V, Garey J, Wolff MS, Pogo BG. Estrogenic potential of certain pyrethroid compounds in the MCF-7 human breast carcinoma cell line. Environ Health Perspect 1999;107(3):173-7.

Hardt J, Angerer J. Biological monitoring of workers after the application of insecticidal pyrethroids. Int Arch Occup Environ Health 2003;76(7):492-8.

Hu JY, Wang SL, Zhao RC, Yang J, Chen JH, Song L, et al. [Effects of fenvalerate on reproductive and endocrine systems of male rats] Zhonghua Nan Ke Xue 2002;8(1):18-21. (in Chinese)

Kim IY, Shin JH, Kim HS, Lee SJ, Kang IH, Kim TS, et al. Assessing estrogenic activity of pyrethroid insecticides using in vitro combination assays. J Reprod Dev 2004;50(2):245-55.

Kuhn K, Wieseler B, Leng G, Idel H. Toxicokinetics of pyrethroids in humans: consequences for biological monitoring. Bull Environ Contam Toxicol 1999;62:101-8.

Kunimatsu T, Yamada T, Ose K, Sunami O, Kamita Y, Okuno Y, et al. Lack of (anti-) androgenic or estrogenic effects of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) in the Hershberger and uterotrophic assays. Regul Toxicol Pharmacol 2002;35(2 Pt 1):227-37.

Lazarini CA, Florio JC, Lemonica IP, Bernardi MM. Effects of prenatal exposure to deltamethrin on forced swimming behavior, motor activity, and striatal dopamine levels in male and female rats. Neurotoxicol Teratol 2001;23(6):665-73.

Leng G, Leng A, Kuhn KH, Lewalter J, Pauluhn J. Human dose-excretion studies with the pyrethroid insecticide cyfluthrin: urinary metabolite profile following inhalation. Xenobiotica 1997;27(12):1273-83.

Leng G, Ranft U, Sugiri D, Hadnagy W, Berger-Preiss E, Idel H. Pyrethroids used indoors—biological monitoring of exposure to pyrethroids following an indoor pest control operation. Int J Hyg Environ Health 2003;206(2):85-92.

Lu C, Barr DB, Pearson M, Bartell S, Bravo R. A longitudinal approach to assessing urban and suburban children’s exposure to pyrethroid pesticides. Environ Health Perspect 2006;114(9):1419-23.

McCarthy AR, Thomson BM, Shaw IC, Abell AD. Estrogenicity of pyrethroid insecticide metabolites. J Environ Monit 2006;8(1):197-202.

Moniz AC, Cruz-Casallas PE, Salzgeber SA, Varoli FM, Spinosa HS, Bernardi MM. Behavioral and endocrine changes induced by perinatal fenvalerate exposure in female rats. Neurotoxicol Teratol 2005;27(4):609-14.

Ortiz-Perez MD, Torres-Dosal A, Batres LE, Lopez-Guzman OD, Grimaldo M, Carranza C, et al. Environmental health assessment of deltamethrin in a malarious area of Mexico: environmental persistence, toxicokinetics, and genotoxicity in exposed children. Environ Health Perspect 2005;113(6):782-6.

Ray DE, Forshaw PJ. Pyrethroid insecticides: poisoning syndromes, synergies, and therapy. J Toxicol Clin Toxicol 2000;38:95-101.

Shafer TJ, Meyer DA, Crofton KM. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environ Health Perspect 2005;113(2):123-36.

Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, et al. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology 2002;171:3-59.

Spencer J, O’Malley M. Pyrethroid illnesses in California, 1996-2002. Rev Environ Contam Toxicol 2006;186:57-72.

U.S. Environmental Protection Agency (U.S. EPA). Permethrin, resmethrin, d-phenothrin (Sumithrin): synthetic pyrethroids for mosquito control. Updated September 12, 2012. Available at URL: https://www.epa.gov/mosquitocontrol/Synthetic_Pyrethroids.htmlexternal icon. 12/28/12

U.S. Environmental Protection Agency (U.S. EPA). Permethrin Facts (Reregistration Eligibility Decision Fact Sheet). June 2006a. Available at URL: https://www.epa.gov/oppsrrd1/REDs/factsheets/permethrin_fs.htmexternal icon. 12/28/12

U.S. Environmental Protection Agency (U.S. EPA). Reregistration Eligibility Decision for Cypermethrin. June 2006b. Available at URL: https://www.epa.gov/oppsrrd1/REDs/cypermethrin_red.pdfpdf iconexternal icon. 12/28/12

U.S. Geological Survey (USGS). Pesticides in the Nation’s Streams and Ground Water, 1992–2001. March 2006, Revised February 15, 2007. Available at URL: https://pubs.usgs.gov/circ/2005/1291/external icon. 12/28/12

Woollen BH, Marsh JR, Laird WJ, Lesser JE. The metabolism of cypermethrin in man: differences in urinary metabolite profiles following oral and dermal administration. Xenobiotica 1992;22(8):983-991.

World Health Organization (WHO). Pesticide and Evaluation Scheme. Safety of pyrethroids for public health use. 2005. Available at URL: http://whqlibdoc.who.int/hq/2005/WHO_CDS_WHOPES_GCDPP_2005.10.pdfpdf iconexternal icon. 12/28/12

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Content source: Centers for Disease Control and Prevention