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Biomonitoring Summary

Chlorpyrifos

CAS No. 2921-88-2

Chlorpyrifos-methyl

CAS No. 5598-13-0

General Information

The chemical 3,5,6-trichloro-2-pyridinol (TCPy) is a metabolite of chlorpyrifos and chlorpyrifos-methyl. Chlorpyrifos is a broad spectrum organophosphorus insecticide that has been widely used to control insects on food crops such as corn. It also has been applied directly on animals to kill mites, applied to structures to kill termites, and sprayed to kill mosquitoes. Approximately 21-24 million pounds per year were used domestically from 1987-1998. After 2001, chlorpyrifos was no longer registered for indoor residential uses in the United States; pre- and post-construction structural applications for termite control were to be phased out by 2005 (U.S.EPA, 2002). Chlorpyrifos-methyl is an organophosphorus insecticide also used in agriculture and not registered for residential use. Approximately 80,000 pounds are used per year. Chlorpyrifos is degraded in agricultural soils with a half-life of several months, and on plants for days to several weeks. It has low leachability, staying bound to soil particles, and is infrequently detected in ground water (IPCS, 1999; USGS, 2007), but can be detected in streams receiving runoff from application sites. Chlorpyrifos is very toxic to fish and aquatic invertebrates and shows modest degrees of bioconcentration.

The general population may be exposed to chlorpyrifos via oral, dermal, and inhalation routes. Estimated intakes from diet and water have not exceeded recommended intake limits, although some tolerances for specific food crops have been reduced in the past to avoid exceeding recommended intake limits for total dietary intake in special groups (U.S.EPA, 2002). Exposure can also result from contact with contaminated surfaces, air, and dust. For instance, in 142 urban homes and preschools in North Carolina, chlorpyrifos and TCPy were detected in all indoor air and dust samples (Morgan et al., 2005). Chlorpyrifos is not well absorbed through the skin but dermal exposure can be significant when other routes of exposure are low. Inhalational and dermal routes of exposure are important in pesticide formulators and applicators. Chlorpyrifos is rapidly absorbed following ingestion. Once absorbed, phosphorothioates such as chlorpyrifos are metabolically activated to the "oxon" form which has greater toxicity than the parent insecticide. Metabolic hydrolysis leads to the formation of TCPy, dialkyl phosphate metabolites, and other metabolites. Chlorpyrifos is eliminated from the body primarily in the urine with a half-life of approximately 27 hours (Nolan et al., 1984). In addition to being a metabolite of chlorpyrifos and chlorpyrifos-methyl in the body, TCPy can also occur in the environment from the breakdown of the parent compounds. TCPy is more persistent in the environment than chlorpyrifos itself (U.S.EPA, 2002). Thus, the detection of TCPy in a person's urine may reflect exposure to the environmental degradates.

Human health effects from chlorpyrifos or chlorpyrifos-methyl at low environmental doses or at biomonitored levels from low environmental exposures are unknown. Chlorpyrifos and chlorpyrifos-methyl both demonstrate moderate acute toxicity in animal studies. These organophosphorus insecticides share a mechanism of toxicity: inhibition of the activity of acetylcholinesterase enzymes in the nervous system, resulting in excess acetylcholine at nerve terminals, and producing acute symptoms such as nausea, vomiting, cholinergic effects, weakness, paralysis, and seizures. The metabolite TCPy does not inhibit acetylcholinesterase enzymes. Overt cholinergic toxicity from chlorpyrifos has been described following suicidal ingestion and unintentional high level occupational exposure. Based on animal data and human cholinesterase monitoring during occupational exposure, ubiquitous low-level environmental exposures in humans would not be expected to result in inhibition of cholinesterase activity. Recent in vitro and in vivo animal studies suggest that effects on neuronal morphogenesis, neurotransmission, and behavior may occur at systemically nontoxic doses or at doses of chlorpyrifos that do not result in cholinergic signs (Aldridge et al., 2005; Betancourt et al., 2006; Howard et al., 2005; Ricceri et al., 2006; Roy et al., 2005; Slotkin et al., 2006a, 2006b). In pesticide applicators, chronic exposure to chlorpyrifos may be associated with slight alterations in some components of neurophysiologic testing (Steenland et al., 2000). Two observational studies of pregnant women and their offspring exposed to chlorpyrifos at environmental levels have found inconsistent relationships with birth outcomes of weight and length (Eskenazi et al., 2004; Perera et al., 2003; Whyatt et al., 2004).

Some reproductive and teratogenic effects in animal testing were only observed at high doses of chlorpyrifos that caused overt maternal toxicity. Chlorpyrifos is not considered to be mutagenic or carcinogenic (NTP, 1992; U.S.EPA, 2002). Additional information about external exposure (i.e., environmental levels) and health effects is available from ATSDR at http://www.atsdr.cdc.gov/toxprofiles/index.asp and from U.S. EPA at http://www.epa.gov/pesticides/.

Biomonitoring Information

Urinary TCPy levels reflect recent exposure. Levels of TCPy in the U.S. subsamples of NHANES 1999-2000 and 2001-2002 (CDC, 2009) appear roughly similar to values reported for a nonrandom subsample of NHANES III (1988-1994) participants (Hill et al., 1995) and were similar to levels reported in studies of healthy adults in Germany (Koch et al., 2001) and Italy (Aprea et al., 1999). In a probability-based sample of 102 Minnesota children aged 3-13 years, the weighted population mean of TCPy measurements was approximately three times higher (Adgate, 2001) than the corresponding values reported for the group aged 6-11 years from the NHANES 1999-2000 subsample (CDC, 2009). MacIntosh et al. (1999) reported mean urinary TCPy levels in a sample of Maryland adults that were about three times higher than adults in the U.S. population (CDC, 2009). Of 482 pregnant women living in an agricultural community, 76% had detectable levels of TCPy and levels were similar to those reported for NHANES 1999-2000 (Eskenazi et al., 2004). Other small studies of environmentally-exposed persons have shown a high frequency of detecting low levels of TCPy.

Following crack-and-crevice application of chlorpyrifos in their homes, urinary TCPy levels in children were reported not to have increased (Hore et al., 2005). Chlorpyrifos levels in house dust and hand rinses did not correlate with levels of TCPy in urine (Lioy et al., 2000). Replacing conventional diets with organic diets in 23 children led to about a fourfold decrease in urinary levels of chlorpyrifos; median urinary levels on the conventional diet were several times higher than those in the NHANES 1999-2000 subsample (Lu et al., 2006). Measurements of urinary TCPy in single spot urine collections show variability over time in environmentally exposed individuals and are poorly correlated between collections, suggesting changing low-level exposure and variance in collection timing with respect to exposure (Meeker et al., 2005). Estimation of dose or intake based on the urinary excretion of TCPy indicates that environmental doses are generally below recommended limits (Hore et al., 2005; Koch et al., 2001).

In Iowa farm families using several different pesticides, but not chlorpyrifos, the geometric mean urinary TCPy levels were similar in parents and children, but levels were roughly four to six times higher than the geometric means in the U.S. representative subsample of NHANES 1999-2000 (CDC, 2009; Curwin et al., 2007). In Minnesota and South Carolina farmers who used chlorpyrifos, urinary TCPy levels averaged about sixfold higher than those in the NHANES 1999-2000 subsample (Mandel et al., 2005; CDC, 2009). Urinary levels of TCPy have been found to be hundreds of times higher in chlorpyrifos manufacturing workers (Burns et al., 2006) and episodically, many times higher in pesticide applicators compared to median levels from NHANES 1999-2000 (CDC, 2009).

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

References

Adgate JL, Barr DB, Clayton CA, Eberly LE, Freeman NC, Lioy PJ, et al. Measurement of children's exposure to pesticides: analysis of urinary metabolite levels in a probability-based sample. Environ Health Perspect 2001;109(6):583-590.

Aldridge JE, Meyer A, Seidler FJ, Slotkin TA. Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure. Environ Health Perspect 2005;113(8):1027-1031.

Aprea C, Betta A, Catenacci G, Lotti A, Magnaghi S, Barisano A, et al.Reference values of urinary 3,5,6-trichloro-2-pyridinol in the Italian population--validation of analytical method and preliminary results (multicentric study). J AOAC Int 1999;82(2):305-312.

Betancourt AM, Burgess SC, Carr RL. Effect of developmental exposure to chlorpyrifos on the expression of neurotrophin growth factors and cell-specific markers in neonatal rat brain. Toxicol Sci 2006;92(2):500-506.

Burns CJ, Garabrant D, Albers JW, Berent S, Giordani B, Haidar S, et al. Chlorpyrifos exposure and biological monitoring among manufacturing workers. Occup Environ Med 2006;63(3):218-220.

Centers for Disease Control and Prevention (CDC). Fourth National Report on Human Exposure to Environmental Chemicals. 2009. [online] Available at URL: http://www.cdc.gov/exposurereport/. 1/24/13

Curwin BD, Hein MJ, Sanderson WT, Striley C, Heederik D, Kromhout H, et al. Urinary pesticide concentrations among children, mothers and fathers living in farm and non-farm households in Iowa. Ann Occup Hyg 2007;51(1):53-65.

Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, et al. Association of in utero organophosphate pesticide exposure and fetal growth and length of gestation in an agricultural population. Environ Health Perspect 2004;112(10):1116-1124.

Hill RH Jr, Head SL, Baker S, Gregg M, Shealy DB, Bailey SL, et al. Pesticide residues in urine of adults living in the United States: reference range concentrations. Environ Res 1995;71:99-108.

Hore P, Robson M, Freeman N, Zhang J, Wartenberg D, Ozkaynak H, et al. Chlorpyrifos accumulation patterns for child-accessible surfaces and objects and urinary metabolite excretion by children for 2 weeks after crack-and-crevice application. Environ Health Perspect 2005;113(2):211-219.

Howard AS, Bucelli R, Jett DA, Bruun D, Yang D, Lein PJ. Chlorpyrifos exerts opposing effects on axonal and dendritic growth in primary neuronal cultures. Toxicol Appl Pharmacol 2005;207(2):112-124.

International Programme on Chemical Safety-INCHEM (IPCS). Environmental Health Criteria 198. Chlorpyrifos. 1999. Available at URL: http://www.inchem.org/documents/jmpr/jmpmono/v99pr03.htm. 1/24/13

Koch HM, Hardt J, Angerer J. Biological monitoring of exposure of the general population to the organophosphorus pesticides chlorpyrifos and chlorpyrifos-methyl by determination of their specific metabolite 3,5,6-trichloro-2-pyridinol. Int J Hyg Environ Health 2001;204(2-3):175-180.

Lioy PJ, Edwards RD, Freeman N, Gurunathan S, Pellizzari E, Adgate JL, et al. House dust levels of selected insecticides and a herbicide measured by the EL and LWW samplers and comparisons to hand rinses and urine metabolites. J Expo Anal Environ Epidemiol 2000;10(4):327-340.

Lu C, Toepel K, Irish R, Fenske RA, Barr DB, Bravo R. Organic diets significantly lower children's dietary exposure to organophosphorus pesticides. Environ Health Perspect 2006;114(2):260-263.

MacIntosh DL, Needham LL, Hammerstrom KA, Ryan PB. A longitudinal investigation of selected pesticide metabolites in urine. J Expo Anal Environ Epidemiol 1999;9(5):494-501.

Mandel JS, Alexander BH, Baker BA, Acquavella JF, Chapman P, Honeycutt R. Biomonitoring for farm families in the farm family exposure study. Scand J Work Environ Health 2005;31 Suppl 1:98-104.

Meeker JD, Barr DB, Ryan L, Herrick RF, Bennett DH, Bravo R, et al. Temporal variability of urinary levels of nonpersistent insecticides in adult men. J Expo Anal Environ Epidemiol 2005;15(3):271-281.

Morgan MK, Sheldon LS, Croghan CW, Jones PA, Robertson GL, Chuang JC, et al. Exposures of preschool children to chlorpyrifos and its degradation product 3,5,6-trichloro 2-pyridinol in their everyday environments. J Expo Anal Environ Epidemiol 2005;15(4):297-309.

Nolan RJ, Rick DL, Freshour NL, Saunders JH. Chlorpyrifos: pharmacokinetics in human volunteers. Toxicol Appl Pharmacol 1984;73:8-15.

National Toxicology Program (NTP). Executive summary of safety and toxicity information. chlorpyrifos. 2921-88-2. February 5, 1992. Available at URL: http://ntp.niehs.nih.gov/ntpweb/index.cfm?objectid=6F5E95EB-F1F6-975E-7C20F4211536F46F. 1/24/13

Perera FP, Rauh V, Tsai WY, Kinney P, Camann D, Barr D, et al. Effects of transplacental exposure to environmental pollution on birth outcomes in a multiethnic population. Environ Health Perspect 2003;111(2):201-5.

Ricceri L, Venerosi A, Capone F, Cometa MF, Lorenzini P, Fortuna S, et al. Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex specific behaviors at adulthood in mice. Toxicol Sci 2006;93(1):105-113.

Roy TS, Sharma V, Seidler FJ, Slotkin TA. Quantitative morphological assessment reveals neuronal and glial deficits in hippocampus after a brief subtoxic exposure to chlorpyrifos in neonatal rats. Brain Res Dev Brain Res 2005;155(1):71-80.

Slotkin TA, Levin ED, Seidler FJ. Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity. Environ Health Perspect 2006a;114(5):746-751.

Slotkin TA, Tate CA, Ryde IT, Levin ED, Seidler FJ. Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition. Environ Health Perspect 2006b;114(10):1542-1546.

Steenland K, Dick RB, Howell RJ, Chrislip DW, Hines CJ, Reid TM, et al. Neurologic function among termiticide applicators exposed to chlorpyrifos. Environ Health Perspect 2000;108(4):293-300.

U.S. Environmental Protection Agency (U.S. EPA). Interim registration eligibility decision for chlorpyrifos. EPA 738-R-01-007. February 2002. Available at URL: http://www.epa.gov/oppsrrd1/REDs/chlorpyrifos_ired.pdf. 1/24/13

U.S. Geological Survey (USGS). The Quality of Our Nation's Waters. Pesticides in the Nation's Streams and Ground Water, 1992-2001. March 2006, revised February 15, 2007 [online]. Available at URL: http://pubs.usgs.gov/circ/2005/1291/. 1/14/13

Whyatt RM, Barr DB, Camann DE, Kinney PL, Barr JR, Andrews HF, et al. Contemporary-use pesticides in personal air samples during pregnancy and blood samples at delivery among urban minority mothers and newborns. Environ Health Perspect 2003;111(5):749-56.


 
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