CAS No. 2921-88-2
CAS No. 5598-13-0
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 https://www.atsdr.cdc.gov/toxprofiles/index.asp and from U.S. EPA at https://www.epa.gov/pesticides/.
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.
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