Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment

Figures & data

FIG. 1  Chemical structure of chlorpyrifos.

TABLE 1  Formulations containing chlorpyrifos and alternate chemical names

Bonidel	Dursban*	Lorsban*	Stipend
Brodan	Empire	Lorsbanv	Suscon*
Cequisa	ENT 27,311	NA 2783	Terial*
Coroban	Equity	OMS-0971	Tricel 20%
Detmol U.A.	Eradex	Pageant	XRM*
D(h)anusban	Ethion, Dry	Piridane
Dorsan	Killmaster	Pyrinex	Dowco 214**
Dowco 179	Lentrek	Radar	Reldan**
Durmet	Lock-on	Spannit	ENT 27,520**

*Several products with different numbers or other additions are mentioned.

**Chlorpyrifos-methyl: O,O-dimethyl analogue of chlorpyrifos.

TABLE 2  Chlopyrifos—Physical/chemical properties

CAS no.	2921-88-2
Chemical formula	C9H11Cl3NO3PS
Molecular weight	350.57
Melting point	41–42°C
Boiling point	Decomposes at ∼ 160°C
Density at 43.5°C	1.398 g/cm^3
Water solubility at 20°C	0.7 mg/L
Water solubility at 25°C	2.0 mg/L
Organic solvent solubility	79% w/w in isooctane
	43% w/w in methanol
	readily in others
Partition coefficients	Log Kow4.82
	Log Koc3.73
Vapor pressure at 20°C and 25°C	1.87 × 10^− 5 mm Hg
Henry's law constant at 25°C	1.23 × 10^− 5 atm-m^3/mol
Conversion factors at 25°C	1 ppm = 14.3 mg/ m^3
	1 mg/ m^3 = 0.07 ppm

FIG. 2  Distribution of chlorpyrifos uses before and after the restriction of indoor application. (Data provided by Dow AgroSciences.)

FIG. 3  U.S. Share in global agricultural and non-agricultural uses of chlorpyrifos from 2002–2006. Values are given as annual averages, in kg active ingredient (Data provided by Dow AgroSciences.)

FIG. 4  Former use of chlorpyrifos in nonagricultural settings in the U.S. during the period of 1998–2001, i.e., prior to restriction of home use. (Data provided by Dow AgroSciences.)

FIG. 5  Percentage of agriculturally applied chlorpyrifos used on crops in the United States. during 1998–2001 (left) and 2002–2006 (right). Major use crops are shown on the top, and minor use crops are shown on the bottom. (Data provided by Dow AgroSciences.)

FIG. 6  Degradation pathways for chlorpyrifos. Dashed arrows show theoretical metabolites that have not been rigorously identified as environmental degradation products.

FIG. 7  Environmental degradation pathways of chloropyrifos.

FIG. 8  Biotransformation of chlorpyrifos.

TABLE 3  Theoretical human brain chlorpyrifos-oxon levels utilizing Monte Carlo simulation for the QQ, QR, and RR PON1 polymorphism following a single exposure to different doses of chlorpyrifos

	Chlorpyrifos dose
PON1	0.005 mg/kg	0.05 mg/kg	0.5 mg/kg	5.0 mg/kg
QQ (low)	0.06 (1.2)	0.63 (1.31)	11.6 (1.63)	616 (1.72)
QR (med)	0.05 (1.0)	0.57 (1.19)	9.37 (1.31)	492 (1.38)
RR (high)	0.05	0.48	7.11	358

Note. Vlaues in table are theoretical brain chlorpyrifos-oxon, as AUC (area-under-curve) [(μ mol/L/h) × 10^{− 6}]. Values in parentheses represent the ratio of AUC for the QQ and QR relative to the RR polymorphism.Adapted from Timchalk et al. (2002a).

TABLE 4  Acute oral LD50 values in different species

Species	LD50 (mg/kg)	Reference
Dow-Wistar rats
Male	163	McCollister, 1974
Female	135
Sherman rats
Male	118	Gaines, 1969
Female	155
Mice	60	El-Sebae, 1978
Guinea pigs, male	504	McCollister, 1974
Chicken	32	McCollister, 1974

TABLE 5  Summary of genotoxicity studies with TCPy (from Dow, 2002)

Endpoint	Test object	Concentration	Purity (%)	Results
In vitro
Reverse mutation	S. typhimurium TA98, 100, 535, 1537, and 1538	3.16, 10, 31.6, 100, or 316 μ g/plate in DMSO	99.7	Negative
Unscheduled DNA synthesis	Rat hepatocyte (Fischer CDF 344)	1–100 mg/ml in DMSO	99.7	Negative
CHO/HGPRT forward mutation	Chinese hamster ovary cells	62.5, 125, 250, 500, or 750 μ g/ml	99.7	Negative
In vivo
Micronucleus (bone marrow cells)	Mouse (CD-1)	0, 1000 mg/kg bw, PO in corn oil (250–3000 mg/kg bw in range-finding test)	99.9	Negative
Micronucleus (bone marrow cells)	Mouse (CD-1)	0, 24, 76, or 240 mg/kg bw, PO in corn oil	99.7	Negative

TABLE 6  Controlled primate studies: Single dose and repeated dose

					Threshold dosage
Species	Author	Purity	Dosing	Type	AChE	BuChE	[Chlorpyrifos] in blood
Human adult	Kisicki et al., 1999	99.8%	Oral capsule	Single	2 mg/kg
Human adult male	Nolan et al., 1984	99.8%	Oral 0.5 mg/kg	Single	ND	0.5 mg/kg	< 30 ng/ml
Human adult male	Nolan et al., 1984	99.8%	Dermal 5.0 mg/kg	Single	ND	NM	< 30 ng/ml
Human adult male	Coulston et al., 1972	99.5%	Oral tablet	Daily	0.1 mg/kg-day	0.01 mg/kg-day
Rhesus monkey adult	Coulston et al., 1971	99.5%	Oral	6 months	> 0.08 mg/kg-day*	Depressed at all dosages

Note. ND: no change detected. NM: not measurable. Chlorpyrifos: Concentration of chlorpyrifos in blood.

TABLE 7  Summary of reports of the effects of uncontrolled exposures to chlorpyrifos

Reference	Dosage/route	Laboratory studies^1	Clinical effects	Implications
Osterloh et al., J. Anal. Toxicol. 7:125, 1983. n = 1	Acute oral exposure Fatal ingestion of Dexol, which contains 2,4-D (10.8%), MCPP (11.6%) and chlorpyrifos (6.7%).	Plasma BuChE, RBC AChE and NTE inhibited in blood, peripheral nerve, and diaphragm but not in brain (perhaps chlorpyrifos-oxon not formed in brain or failed to reach brain)	Minimal cholinergic signs. Coma, myoclonus, miosis, diarrhea, cardiac arrythmias, downhill to death at 30 h.	Lymphocyte NTE inhibition correlated with peripheral nerve NTE inhibition. Chlorpyrifos found in frontal lobe, but not in cerebrospinal fluid.
Lotti et al., Arch. Toxicol. 59:176, 1986. Male (n = 1)	Acute oral exposure. ∼ 300 mg/kg of 41% commercial chlorpyrifos, I.D. confirmed	Chlorpyrifos – exponential decrease at 3–10 d BuChE ∼ 0 at 36 h AChE 60% at 30 d NTE 60% at 17 d	Cholinergic syndrome for 17 days. Mild axonal neuropathy from 43 days; advancing to 63 days; stable by 94 days.	Oral chlorpyrifos slowly dispersed. Humans relative to hens may require less NTE inhibition for neuropathy to occur.
Hodgson et al., J. Occup. Med. 28:434, 1986. Exposed (n = 5)	Acute inhalation exposure. Office workers Inhalation exposure over 5-h period prior to onset of acute symptoms	RBC AChE. Recovery of levels was not at a constant rate; rather it followed an exponential distribution over a period of 3 months.	No significant relationship between RBC AChE changes and muscarinic, nicotinic or CNS symptoms. One worker with complaints but no nerve conduction evidence of peripheral neuropathy.	Chlorpyrifos might redistribute after absorption to a second body compartment from which it is slowly released.
Aiuto et al., J. Pediatr. 122:658, 1993. Male, age 3 yr	Acute oral exposure. Accidental ingestion of Dursban treated with atropine and oxime.	Plasma BuChE WNL day 3. “Symptoms indicated that > 90% of the cholinesterase was inhibited.” Lymphocyte NTE measures not reported.	Areflexia and vocal cord paralysis during hospital days 11–18, improved days 23–31 and complete days 52. Normal NCS day 18 but absent F latencies.	Atypical age, pattern. and recovery for OP-induced peripheral neuropathy and no evidence of abnormal nerve conduction. Absent F latencies raised question of proximal axonopathy.
de Silva et al., Hum. Exp. Toxicol. 13:171, 1994 Male, aged 21 years	Acute oral exposure. Suicide intended-ingestion of chlorpyrifos treated with atropine (12 days) and oxime (3 days); later, 10 days of ventilation	Plasma BuChE, RBC AChE, and lymphocyte NTE measures not reported. WNL were [RBC], white cell count, RBC sedimentation rate, blood [glucose], [urea], serum [sodium], [potassium], [calcium].	Severe cholinergic toxicity, followed by intermediate syndrome requiring intubation and ventilation with recovery and normal cranial nerve function; followed by vocal cord paralysis 28 days, after exposure, when EMG and NCS of distal limb WNL.	Bilateral recurrent laryngeal paralysis (in the absence of clinical and electrophysiological evidence of a distal, symmetrical polyneuropathy) attributed to chlorpyrifos.
Moretto, Lotti. J. Neurol. Neurosurg. Psychiatry 64:463, 1998. chlorpyrifos (n = 2); total OP-exposed (n = 11)	Acute intoxication. Chlorpyrifos commercial formulation. Case 6. 78-year-old man. Case 9: 42-year-old man	[OP] GC-MS Plasma BuChE: 1, 3, 30 days < 0.5 [normal: 2.4–8.3 mU/L]. RBC AChE: 40 d 5.9 mU/L [normal 4.9–11.7]. Lymphocyte NTE: 5.9 (30 days) [normal: 6.5—16.5 mU/g protein]	Comatose for 5 days or 7 days; treated with 2-PAM & atropine; ventilated for 17 days or 21 days; antibiotics for 3 or 6 weeks. Case 6: No neuropathy. Case 9: Weakness & paresthesias at day 62	Case 6 had mild sensory component when symptoms and signs first and when the largely motor neuropathy fully developed. Argued that Kaplan et al. (1993) patients were not commercial chlorpyrifos-related.
Miranda et al.Int. J. Occup. Environ. Health 8:19, 2002a. Nicaraguan Exposed males (n = 59, with 17 chlorpyrifos), and referent males (n = 39)	Acute intoxication. 7/1/92–12/15/96 For chlorpyrifos, 15 workplace and 2 suicidal.	See Miranda et al., 2002b.	Hand, grip and pinch (3 trials) at hospital discharge (median 6 days) and follow-up (median 49 days) visit. Controls examined over whole period, with intervals of 66 days median.	Impaired motor function most marked among those exposed to neuropathic OPs, including chlorpyrifos. Severely poisoned, suicidal (chlorpyrifos = 2 of 16) cases had persistent motor weakness, consistent with motor neuropathy.
Miranda et al.Int. J. Occup. Environ. Health 8:212, 2002b. Nicaraguan Exposed males (n = 56, with 17 chlorpyrifos), and referent males (n = 39)	Acute intoxication. For chlorpyrifos, 15 workplace and 2 suicidal. Hospitalization and clinical classification of severity of poisoning	Control RBC AChE mean 28.0 IU/g hemoglobin; for all (including chlorpyrifos) moderately (n = 12) and severely (n = 9) poisoned, mean 11.6 and 8.0 IU/g, respectively.	Quantitative tactile vibration thresholds of index finger and big toes revealed no changes at 1^st (median 6 days) or 2^nd (49 days) exam for all (including chlorpyrifos-) poisoned subjects.	Suggestive of increased thresholds for severely (including chlorpyrifos-) poisoned subjects between first and second examinations; significant increase for toe threshold in intentionally poisoned group (chlorpyrifos = 2 of 16).
Meggs. Clin. Toxicol. 41:883, 2003. Male (n = 1) aged 61 yr	Acute intoxication. Carpenter with dermal and inhalation exposure to chlorpyrifos-containing insecticide.	Blood AChE (day 3 = 17 U/ml) 2 days after treatment with atropine and 2-PAM. EMG, nerve conduction, F-waves, hospital day 3, and day 31.	day 1: Acute illness and paralysis. day 2: Motor weakness in upper and lower (left) extremities; normal sensory and cranial nerve and mental function. days 3–83: motor and sensory nerve dysfunction leading to persistent motor weakness in hand; left ankle drop.	Rapid onset of motor > sensory peripheral neuropathy confirmed by EMG. Permanent paralysis and muscle atrophy of exposed hands and left legs/feet. Urinary retention. Mental status unimpaired throughout, up to 10-year follow-up.
Brenner et al., Br. J. Ind. Med. 46: 133, 1989. Exposed (n = 175). Comparison (n = 335).	Occupational exposure. Morbidity study of chlorpyrifos manufacturers, packers 1/1/77–12/31/85. Estimated TWA < 0.03–0.4 mg/m^3	Mean plasma ChE inhibition = 19.1–32.1%, which rough correlated with air monitoring data. Personnel measures = 0.016 to 0.23 mg/m^3	Dizziness, malaise, and fatigue nonsignificantly higher in exposed	No significant differences in illnesses or symptom prevalence between the two groups.
Ames et al., Am. Ind. Hyg. Assoc. J. 50:466, 1989. n = 68 (chlorpyrifos) of 696 (total)	Occupational exposure of Californian pet handlers.	Telephone survey of health symptoms (incidence and frequency) for 3-month period prior to interview.	Increased frequency of self-reported symptoms: blurred vision, skin flushing, and decreased frequency of urination	Blurred vision is consistent with miosis but decreased urination is the opposite effect of AChE inhibition. Suggests no systemic exposure; possible direct corneal exposure.
Kaplan et al., Neurology 43:2193, 1993. Male (n = 1) Female (n = 2) Family (n = 4) Unstated (n = 1)	Chronic exposure. Respiratory and dermal exposure after Dursban^2 fumigation (n = 7) or by applicator (n = 1)	RBC AChE low, normalizing after 2 months (n = 1). SNAP, CMAP, Late responses (tibial H reflex; peroneal and tibial F responses)	Acute symptoms (n = 5). Delay (1 month) onset of mild, mostly sensory neuropathy, with gradual, complete recovery (n = 8). Mild memory impairment in 5, reversible in 4.	Etiologic attribution to chlorpyrifos alone not certain; potential role of chlorpyrifos toxicity modifiers could not be ruled out. By authors (exact compositions of Dursban preparations not stated). Late responses not explained. Note: Chlorpyrifos has a low vapor pressure precluding acute toxicity by inhalation (Brenner et al., 1989).
Yeary et al., J. Toxicol. Environ. Hlth. 39:11, 1993. Workers (n = 1600–3800)	Chronic exposure. Applicators studied 1981–91.	> 200,000 plasma CHE and RBC AChE. Dropped to 79% from February to August, but rate declined with time	9/1000 workers removed in first 5–6 years because of RBC AChE drop. Recovery within 2 wk of removal.	No applicators required treatment for adverse medical effects.
Steenland et al., Am. J. Public Hlth. 84:731, 1994. Exposed (n = 191. Comparison (n = 189)	Chronic exposure. Applicators, current and former; mean 2.4 years chlorpyrifos + 2.5 years other	TCP: Mean = 629.5 [4.5 control mg/l] (n = 65 recently exposed applicators) Olfaction, NCV/amplitude, urinary TCP and paraoxonase genotyping	Exposed subjects more symptomatic and lower performance on pegboard and some postural sway tests, but in absence of clinical neurological findings.	NIOSH study of uncertain general applicability; subjects exposed to chlordane and other pesticides. Minimal neurological findings in chlorpyrifos-poisoned (n = 8) and chlorpyrifos-susceptible (n = 18)
Burns et al., Occup. Environ. Med. 55:65,1998. Exposed (n = 496) Comparison (n = 911)	Chronic exposure. Morbidity study of chlorpyrifos manufacturers, formulators, packers between 1/1/77–12/31/94	Plasma ChE tests monthly for exposed	Dizziness, pyrexia, malaise, fatigue, nausea, vomiting, heartburn more common in exposed not “dose-related” or to plasma ChE records.	No significant increase in peripheral neuropathy in presence of increased ear and mastoid diseases, and ill-defined respiratory and gastrointestinal conditions.
Dick et al., Neurotoxicol. Teratol. 23:381, 2001. Exposed (n = 106) Referents (n = 52)	Chronic exposure of applicators with current use of chlorpyrifos-containing product in past week; others not exposed in past week; unexposed to chlorpyrifos	Urinary TCP: Mean 200 mg/g creatinine for applicators on day of clinical testing—below levels associated with inhibition of plasma AChE (not measured)	Sensory and motor testing, Some significant postural differences when anchored to [TCP]	NIOSH study. Twelve subjects above urinary TCP of 461 mg/g creatinine, which equals the NOAEL for plasma ChE inhibition. Possibility of proprioceptive or vestibular differences in exposed vs. referents.
Dyer et al., Toxicology 169:177, 2001. Exposed (n = 39) Referents (n = 34)	Chronic exposure. Australian pest control operators	Plasma ChE RBC AChE. Lymphocyte NTE mean level higher in exposed than unexposed.	None. Three dibucaine (DN) phenotypes: most (n = 66) homozygous for typical ChE enzyme (DN 83–91); 6 heterozygous (66–75) and 1 homozygous (22).	Australian controls and British controls have similar values for AChE activity but dissimilar for NTE (∼ 50% lower) and plasma ChE (23% lower) activities.
Albers et al., Muscle Nerve 29:677, 2004a. Cross-sectional study of exposed (n = 53) and referents (n = 60)	Chronic exposure in manufacture: chlorpyrifos workers (9.72 years chlorpyrifos exposure) and controls (0.01 years)	Urinary TCP: Exposed vs. controls (108.6 vs. 4.3 mg/g creatinine); exposed results unrelated to BuChE levels: Exposed vs. controls (7281 vs. 8176 mU/ml). Motor nerve conduction.	Neurological exam, sensory and motor nerve conduction studies with limb temperature-recordings – no significant group differences.	Carefully performed analyzed study. No evidence of chlorpyrifos-related sensory neuropathy, subclinical neuropathy, or isolated nerve abnormalities despite long-term exposure of chlorpyrifos workers. Critical of Kaplan et al. (1993).
Albers et al., Occup. Environ. Med. 61:201, 2004b. Prospective study of exposed (n = 53) and controls (n = 60) aged 18–65, mostly male and white., 47% obese.	Chronic exposure during manufacture. Baseline studies on 53 of chlorpyrifos subjects and 60 matched controls at baseline and 111/113 subjects 1 year later.	Urinary TCP 0 and 1 year (192.2 vs. 6.2 mg/g creatinine); BuChE monthly (7155 vs. 8183 mU/ml). AChE 0 and 1 year showed no group differences at either time point.	Upper-and lower-extremity motor and sensory nerve conduction studies, temperature-recorded and adjusted (1 year).	Carefully performed and analyzed study. No clinical or subclinical neuropathy or temporal deterioration in subjects with chronic chlorpyrifos exposures that depress BuChE activity.
Albers et al., Toxicol. Sci. 97:196, 2007. Masked longitudinal study of group (n = 113)	Chronic exposure of chemical workers. Air monitoring and biological measures of chlorpyrifos.	Urinary TCP BuChE (see results for Albers et al., 2004.	See Albers et al., 2004. Subjects with more education showed adverse electrophysiology with increasing chlorpyrifos exposure.	Data not suggestive of causal relationships between long-term chlorpyrifos exposure at levels sufficient to cause chronic mild inhibition of BuChE and subclinical neuropathy

Note. AChE: AChE enzyme activity. BuChE: Plasma butyryl cholinesterase enzyme activity. CMAP: Compound muscle action potential. 2,4-D: 2,4-Dichlorophenoxyacetic acid. EMG: electromyography. MCPP: 2-(2-Methyl-4-chlorphenoxy)propionic acid. NCS: Nerve conduction studies. NIOSH: National Institute for Occupational Safety and Health. NOAEL: no-observable-adverse-effect level. [OP]: Organophosphate concentration; NS: Not significant. Organophosphate concentration. NTE: Neurotoxic esterase enzyme activity. 2-PAM: Pralidoxime chloride. SNAP: Sensory nerve action potential. TCP: 3,5,6-Trichloro-2-pyridinol. WNL: Within normal limits. ¹Reference values (X ± SD). Blood AChE, EC 3.1.1.7: 5.1 ± 1.0 mmol-min^{− 1}-ml^{− 1}; Plasma BuChE, EC 3.1.1.8: 3.0 ± 0.8 mmol-min^{− 1}-ml^{− 1}; Lymphocyte NTE: 11.5 ± 2.5 nmol-min^{− 1}-mg protein^{− 1 −}(Lotti et al., 1986). ²Exact composition not stated but Dow Dursban TC Temiticide Concentrate contains: 44.9% chlorpyrifos; 55.1% aromatic 100, xylene, 1,2,4-trimethylbenzene, cumene, and ethyltoluene.

TABLE 8  In vivo developmental neurotoxicity studies with chlorpyrifos (Chambers et al.)

Treatment	Effect	Brain AChE	Reference
3, 5, 7 mg/kg-day oral in c.o. with vanilla wafer (GD6–20)	Decreased ChAT (13%) on PND12 (high dose only)	26–45% decrease on PND1	Richardson and Chambers, 2003
3, 7 mg/kg-day oral in c.o. with vanilla wafer (GD6–20)	Decreased MR (18–27%) on PND1–6 (high dose) Decreased ChAT (11%) on PND12 (high dose only) Decreased HC-3 binding (∼ 25%) on PND6 (both doses) Decreased vesicular Ach transporter on PND3 (high dose)	15–30% decrease on PND1	Richardson and Chambers, 2004
100, 150, 200 mg/kg, sc in c.o. to dams on PND1	ND (purpose of the study was to determine exposure of pups via maternal milk)	12–26% decrease on PND6 (NS) [72–83% decrease in dams on PND1]	Tang et al., 1999
A. 3 mg/kg PND1–21 B. 3 mg/kg (PND1–5) and 6 mg/kg (PND7–21) C. 3 mg/kg (PND1–5), 6 mg/kg (PND7–13, 12 mg/kg (PND15–21). Oral in c.o., every other day	Decreased MR	20–60% decrease on PND22	Tang et al., 1999
Same as above	Hypoactivity on PND25 and PND30 at medium and high dosages (B,C)	26–50% decrease on PND20	Carr et al., 2001
A. 1.5 mg/kg-day (PND1–21) B. 1.5 mg/kg-day (PND1–5), 3.0 mg/kg-day (PND6–13), 6.0 mg/kg-day (PND14-21). Oral by gavage in c.o.	Decreased MR (10–17% on PND12–22 (both doses) Decreased ChAT on PND30 (high dose) Decreased HC-3 binding on PND6 (both doses) Decreased vesicular Ach transporter on PND30 (high dose)	40–60% decrease on PND22	Richardson and Chambers, 2005
A. 1 mg/kg-day (PND1–8) B. 1 mg/kg-day (PND1–5), 2 mg/kg-day (PND6–8) C. 1.5 mg/kg-day (PND1–5), 3.0 mg/kg-day (PND6–8). Oral by gavage in c.o.	Decreased MR	20–60% decrease on PND8	Guo-Ross et al., 2007

Note. Abbreviations: Ach, acetylcholine; MR, muscarinic receptors, ChAT, choline acetyltransferase; HC-3, hemicholinium-3; c.o., corn oil; ND, not determined.

TABLE 9  In vivo developmental neurotoxicity studies with chlorpyrifos (Pope et al.)

Treatment	Effect	Brain AChE	Reference
40 mg/kg, s.c. in p.o. Oral every 4 days from PND7	Decreased MR (7–12%) 4–14 days after last treatment	55–60% decrease 4d after last treatment	Chakraborti et al., 1993
200 mg/kg s.c. on GD12	Decreased MR on GD20 (16%) and on PND3 (11%)	> 40% decrease on GD16-20; 30% decrease on PND3	Chanda et al., 1995
5, 10 mg/kg-day (PND1–7 or PND1–14), s.c. in p.o.	Decreased MR (M2) (10–21%)	40–70% decrease on PND8, 15	Liu et al., 1999
0.15–15 mg/kg-day (PND 7–21). Oral by gavage in p.o.	Decreased MR and NR at 7.5 and 15 mg/kg-day on PND21	20–90% decrease on PND21	Zheng et al., 2000
7.5, 15 mg/kg on PND7 or 23.5, 47 mg/kg on PND17. Oral by gavage in p.o.	Changes in Ach release	40–80% decrease on PND7, 17	Won et al., 2001
13.5, 45 mg/kg-day on PND7–14, s.c. in p.o.	Decreased MR on PND 15–19. Changes in basal and stimulated AC. No change in IP accumulation	∼ 50% decrease on PND14	Zhang et al., 2002
13.5, 45 mg/kg-day on PND7–14, s.c. in p.o.	No effects on Ach synthesis	40–80% decrease on PND15–18	Karanth and Pope, 2003

Note. Abbreviations: Ach, acetylcholine; AChE, acetylcholinesterase; MR, muscarinic receptors; NR, nicotinic receptors; AC, adenylate cyclase; IP, inositol phosphates; p.o., peanut oil.

TABLE 10  In vivo developmental neurotoxicity studies with chlorpyrifos (Abou-Donia et al.)

Treatment	Effect	Brain AChE	Reference
30 mg/kg, dermal, between GD14 and 18 (single administration)	ND	67% decrease in fetal brain 24h after dosing	Abu-Qare et al., 2001
5.0 mg/kg between GD11 and 13, iv (single injection)	No chlorpyrifos or TCPy detected in fetuses, but low level of radioactivity was detected	ND	Abdel-Rahman et al., 2002
50 mg/kg on GD18 (oral in c.o.)	Faster recovery of AChE in fetus than in dam	∼ 90% decrease in fetuses on GD19	Ashry et al., 2002
0.1 mg/kg-day, GD4–20, dermal in ethanol	No histopathological changes	Increase in brainstem, cerebellum on PND30	Abdel-Rahman et al., 2003
0.1 mg/kg-day, GD4–20, dermal in ethanol	No effect on MR and NR. No histopathological changes. No effect on GPAP.	Increase (20%) in brainstem on PND60. No change in other brain areas.	Abdel-Rahman et al., 2004
1.0 mg/kg, GD4–20, dermal in ethanol	Decreased grip strength and performance on inclined plane (PND90). Decreased Purkinje cells. Increased GFAP.	Increase (∼ 20%) in brainstem on PND90 (female only)	Abou-Donia et al., 2006

Note. Abbreviations: GFAP, glial fibrillary acidic protein; MR, muscarinic receptors; NR, nicotinic receptors; iv, intravenous; c.o., corn oil; ND, not determined.

TABLE 11  In vivo studies with chlorpyrifos (1 mg/kg-day on PND 1–4) (Slotkin et al.)

Effect	Reference
Changes in DNA, protein levels. High mortality at a higher dose (5 mg/kg)	Campbell et al., 1997
Decreased AC. Decreased AChE (see text for details)	Song et al., 1997
Decreased RNA in forebrain, brainstem	Johnson et al., 1998
Decreased DNA synthesis on PND5. No effect on protein, RNA synthesis	Dam et al., 1998
Decreased HC-3 binding and ChAT in brainstem. Decreased HC-3 binding in forebrain	Dam et al., 1999
Decreased locomotor activity (male only). Changes in reflex righting, negative geotaxis (female only). Decreased AChE (see text for details)	Dam et al., 2000
Effects on nuclear transcription factors Sp1 and AP-1	Crumpton et al., 2000
Changes in ChAT and HC-3 binding	Slotkin et al., 2001
Decreased 5-HT transporter	Raines et al., 2001
Decreased norepinephrine turnover. Desensitization to nicotine.	Slotkin et al., 2002
Changes in GFAP	Garcia et al., 2002
No effect on MPB, NF68, NF200	Garcia et al., 2003
Increase of c-fos; no change in p53	Dam et al., 2003
Increase of 5-HT receptors	Aldridge et al., 2003
Increase of 5-HT receptors	Aldridge et al., 2004
Decreased nicotinic receptors in cerebellum on PND10 (only α 4β 2)	Slotkin et al., 2004
Changes in AC	Meyer et al., 2004
Behavioral changes related to the 5-HT system	Aldridge et al.,2005b
Increased 5-HT turnover	Aldridge et al., 2005c
Increased 5-HT receptors and 5-HT transporter on PND60	Slotkin et al., 2005
Microarray on PND5 showed changes in > 150 genes. No follow-up by PCR	Slotkin and Seidler, 2007
Decreased FGF gene expression in forebrain on PND5	Slotkin et al., 2007
No effect on AChE splice variants expression	Jameson et al., 2007

Note. Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); ChAT, choline acetyltransferase; HC-3, hemicholinium-3; AC, adenylate cyclase; GFAP, glial fibrillary acidic protein; FGF, fibroblast growth factor; MPB, myelin basic protein.

TABLE 12  In vivo studies with chlorpyrifos (5 mg/kg-day on PND 11–14) (Slotkin et al.)

Effect	Reference
Decreased DNA and protein levels. Body weight loss at a higher dose (25 mg/kg)	Campbell et al., 1997
Decreased adenylate cyclase activity in forebrain. Decreased AChE (see text for details)	Song et al., 1997
Decreased RNA levels in brainstem, forebrain	Johnson et al., 1998
Decreased ChAT, no effect on HC-3 binding (forebrain). No effects in brainstem	Dam et al., 1999a
Increased rearing (male only). Decreased AChE (see text for details)	Dam et al., 2000
Effects on nuclear transcription factors Sp1 and AP-1	Crumpton et al., 2000
Changes in ChAT activity and HC-3 binding	Slotkin et al., 2001
Decreased 5-HT transporter	Raines et al., 2001
Changes in GFAP	Garcia et al., 2002
Decreased norepinephrine turnover. Desensitization to nicotine.	Slotkin et al., 2002
Decreased 5-HT receptors	Aldridge et al., 2003
Decreases of MPB, NF68	Garcia et al., 2003
Decreased c-fos, no change in p53	Dam et al., 2003
Decreased number of glial cells in hippocampus	Roy et al., 2004
Changes of 5-HT receptors	Aldridge et al., 2004
Decreased nicotinic receptors in cerebellum, brainstem, forebrain on PND15,20	Slotkin et al., 2004
Decreases of ChAT activity, HC-3 binding, M2 MR on PND15,60 Decreased DNA content	Rhodes et al., 2004
Changes in adenylate cyclase	Meyer et al., 2004
Decreased number of neurons and glial cells	Roy et al., 2005
Decreased adenylate cyclase signaling	Meyer et al., 2005
Changes in 5-HT system	Aldridge et al., 2005a
No effect on 5-HT turnover	Aldridge et al., 2005c
Increased 5-HT turnover	Slotkin and Seidler, 2007

Note. Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); ChAT, choline acetyltransferase; HC-3, hemicholinium-3; MR, muscarinic receptor; MPB, myelin basic protein; GFAP, glial fibrillary acidic protein.

TABLE 13  Summary of studies on effects of prenatal exposures to chlorpyrifos PND 17–20 (Slotkin et al.)

Treatment*	Effect	Reference
1 or 5 mg/kg-day (GD17–20)	Hyperactivity in females. Working memory errors in radial arm maze. (both doses)	Levin et al., 2002
1, 2, 5 mg/kg GD9-12	Decreased protein/DNA ratio.	Qiao et al., 2002
1, 2, 5, 10, 20, 40 mg/kg-day (GD17–20)	Decreased M2 MR (from 5 mg/kg-day). Decreased AChE activity (see text for details)
1–40 mg/kg-day (GD17–20)	Changes in GFAP (only at 20, 40 mg/kg-day)	Garcia et al., 2002
1, 2, 5 mg/kg-day (GD9–12)	Changes in 5-HT receptors (GD17,21, all doses)	Aldridge et al., 2003
1–40 mg/kg-day (GD17–20)	Increased 5-HT receptors. Increased AC response to 5-HT (all doses)
1, 5 mg/kg-day (GD17–20)	Decreased HC-3 binding (both doses)	Qiao et al., 2003
1, 2, 5, 10, 20, 40 mg/kg-day (GD17–20)	Increase of MBP and NF68 (from 5 mg/kg)	Garcia et al., 2003
1, 2, 5 mg/kg-day (GD9–12)	No change in AC. Increased β AR at 2, 5 mg/kg-day	Meyer et al., 2003
1, 2, 5, 10, 20, 40 mg/kg-day (GD17–20)	Changes in AC (from 2 mg/kg). Decreased β AR at 1, 2 mg/kg, not at higher doses
1, 5 mg/kg-day (GD9–12)	Decreased HC-3 binding. Increased ChAT activity	Qiao et al., 2004
1, 5 mg/kg-day (GD9–12)	Increased 5-HT receptors (both doses)	Aldridge et al., 2004
1, 5 mg/kg-day (GD17–20)	Increased 5-HT receptors (from 1 mg/kg-day)
1, 5 mg/kg-day (GD9–12)	Hyperactivity. Decreased learning and memory in 16-arm maze	Icenogle et al., 2004
1, 5 mg/kg-day (GD9–12)	Changes in AC (high dose)	Meyer et al., 2004
1, 5 mg/kg-day (GD17–20)	Changes in AC (both doses)
1, 5 mg/kg-day (GD17–20)	Increased 5-HT and dopamine turnover (both doses)	Aldridge et al., 2005c
1, 5 mg/kg-day (GD9–12)	Increased 5-HT and dopamine turnover.	Slotkin and Seidler, 2007b
1, 5 mg/kg-day (GD17–20)	Increased 5-HT and dopamine turnover (both doses)

*Chlorpyrifos was dissolved in DMSO and given by sc injection.

Note. Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); AC, adenylate cyclase; β AR, beta adrenergic receptors, ChAT, choline acetyltransferase; HC-3, hemicholinium-3; GPAP, glial fibrillary acidic protein; MBP, myelin basic protein; MR, muscarinic receptors.

TABLE 14  Summary of in vitro effects of chlorpyrifos and chlorpyrifos metabolites

System/endpoint	Effect	Chlorpyrifos	Chlorpyrifos-oxon	TCPy	Reference
Cytotoxicity
PC12 cells and C6 rat glioma cells	MTT reduction	ND	290 μ M (IC50, PC12) 267 μ M (IC50, C6)	ND	Li and Casida, 1998
Rat cortical neurons	Induction of apoptosis	30 μ M	50 μ M	No effect (up to 130 μ M)	Caughlan et al., 2004
Rat cortical neurons	MTT reduction	15 μ M	20 μ M	150 μ M	Caughlan et al., 2004
Human astrocytes	Induction of apoptosis	100 μ M	ND	ND	Mense et al., 2006
Human astrocytes	Increased LDH release	0.2 μ M	ND	ND	Mense et al., 2006
Mouse CGNs	MTT reduction	12 μ M (IC50)	2.5 μ M (IC50)	95 μ M (IC50)	Giordano et al., 2007
Mouse CGNs [Gclm (−/−)]	MTT reduction	0.8 μ M (IC50)	0.1 μ M (IC50)	15.6 μ M (IC50)	Giordano et al., 2007
Human astrocytoma cells (1321N1)	Trypan blue exclusion	50 μ M	50 μ M	ND	Guizzetti et al., 2005
Rat hippocampal slices	Increased PI fluorescence	ND	0.1–10 μ M	ND	Prendergast et al., 2007
Inhibition of macromolecule synthesis
PC12 cells	DNA synthesis	1.5 μ g/ml	ND	ND	Song et al., 1998
PC12 cells	RNA synthesis	15 μ g/ml	ND	ND	Song et al., 1998
PC12 cells	Protein synthesis	No effect at 50 μ g/ml	ND	ND	Song et al., 1998
Rat C6 glioma cells	DNA synthesis	2 μ g/ml	ND	ND	Garcia et al., 2001
Rat C6 glioma cells	Protein synthesis	50 μ g/ml	ND	ND	Garcia et al., 2001
PC12 cells and C6 glioma cells	DNA synthesis	30 μ M	30 μ M	30 μ M	Qiao et al., 2001
PC12 cells	DNA synthesis	5 μ M	ND	ND	Qiao et al., 2003
Rat cortical astrocytes	DNA synthesis	56 μ M (IC50)	51 μ M (IC50)	129 μ M (IC50)	Guizzetti et al., 2005
Human astrocytoma cells (1321N1)	DNA synthesis	53 μ M (IC50)	45 μ M (IC50)	108 μ M (IC50)	Guizzetti et al., 2005
Human astrocytoma cells (1321N1)	Muscarinic receptor-stimulated DNA synthesis	51 μ M (IC50)	8 μ M (IC50)	94 μ M (IC50)	Guizzetti et al., 2005
Human astrocytoma cells (1321N1)	EGF-stimulated DNA synthesis	22 μ M (IC50)	11 μ M (IC50)	139 μ M (IC50)	Guizzetti et al., 2005
PC12 cells	DNA synthesis	5 μ M	ND	ND	Jameson et al., 2006
Neurotransmitter receptors
Muscarinic M2 receptors (rat striatum)	Inhibition of ^3H-CD binding	∼ 20μ M (IC50)	22 nM (IC50)	ND	Huff et al., 1994
Muscarinic receptors (rat striatum)	Inhibition of ^3H-QNB binding	No effect at 1 mM	No effect at 1 mM	ND	Huff et al., 1994
Muscarinic M2 receptors (rat heart)	Binding of ^3H-chlorpyrifos-oxon	ND	∼ 200nM (IC50)	ND	Bomser and Casida, 2001
Muscarinic M2 receptors (rat heart)	Inhibition of ^3H-oxotremorine binding	No effect at 10 μ M	7–15 nM (IC50). Max 50% inhibition	ND	Howard and Pope, 2002
Muscarinic receptors (rat heart)	Inhibition of ^3H-QNB binding	No effect at 10 μ M	No effect at 10 μ M	ND	Howard and Pope, 2002
Nicotinic autoreceptors (rat brain)	Inhibition of nicotinic receptor function	ND	1–10 μ M	ND	Wu et al., 2003
Cannabinoid CB1 receptors	Inhibition of ^3H-CP55,940 binding	35 μ M (IC50)	14 nM (IC50)	ND	Quistad et al., 2002
Signal transduction pathways
Adenylate cyclase (rat heart)	Inhibition	ND	155 nM (IC50)	ND	Huff et al., 1994
Forskolin-stimulated adenylate cyclase (rat brain slices)	Inhibition	ND	15 nM (IC50, PND 7) 135 nM (IC50, PND90)	ND	Olivier et al., 2001
Adenylate cyclase (rat C6 glioma cells)	Inhibition or activation depending on time, stimulus	5 μ g/ml	ND	ND	Garcia et al., 2001
Adenylate cyclase (PC12 cells)	Inhibition of basal, fluoride-and forskolin-stimulated activity	30 μ M	ND	ND	Slotkin et al., 2007
MAPK (Erk1/2) (CHOK1 cells)	Activation	ND	50 μ M	ND	Bomser and Casida, 2000
Diacylglycerol-induced MAPK (Erk1/2) activation (CHOK1 cells)	Potentiation	ND	5 μ M	ND	Bomser et al., 2002
Nuclear transcription factors AP-1 and Sp1 (C6 rat glioma cells)	Inhibition of DNA binding	AP-1: no effect Sp1: 5 μ g/ml	ND	ND	Garcia et al., 2001
Nuclear transcription factors AP-1 and Sp1 (PC12 cells)	Inhibition of DNA binding	AP-1: 50 μ g/ml Sp1: no effect	ND	ND	Crumpton et al., 2000
Neuronal differentiation^a
PC12 cells (NGF)	Inhibition of neurite outgrowth	ND	10 μ M	ND	Li and Casida, 1998
PC12 cells (NGF)	Inhibition of neurite outgrowth	10 μ g/ml	10 ng/ml	No effect at 10 μ g/ml	Das and Barone, 1999
Mouse NB2a cells (dibutyryl cAMP)	Inhibition of neurite outgrowth	3 μ M	ND	ND	Sachana et al., 2001a
Mouse NB2a cells (dibutyryl cAMP)	Inhibition of neurite outgrowth	26 μ M (IC50)	ND	ND	Axelrad et al., 2002
Mouse NB2a cells (dibutyryl cAMP)	Inhibition of neurite outgrowth	3 μ M	ND	ND	Sachana et al., 2005
Superior cervical ganglia (BMP-7)	Decreased axonal length	0.1–1.0 nM	0.001 nM	No effect	Howard et al., 2005
Superior cervical ganglia (BMP-7)	Increased denditic length	1 μ M	1 nM	1 μ M	Howard et al., 2005
Dorsal root ganglia	Decreased axonal length	1 nM	0.01 nM	ND	Yang et al., 2008
Enzymes
Fatty acid amid hydrolase (FAAH)	Inhibition	ND	40 nM (IC50)	ND	Quistad et al., 2001
Diacylglycerol (DAG) lipase	Inhibition	ND	1.3, 3 μ M (IC50s)	ND	Quistad et al., 2001; Bomser et al., 2002
Acylpeptide hydrolase (APH)	Inhibition	ND	82 nM (IC50)	ND	Casida and Quistad, 2004
NTE-Lysophospholipase (NTE-LysoPLA)	Inhibition	ND	180 nM (IC50)	ND	Casida and Quistad, 2004
Monoacylglycerol (MAG) lipase	Inhibition	ND	34 nM (IC50)	ND	Quistad et al., 2006a
Serine hydrolase KIAA1363	Inhibition	ND	8 nM	ND	Nomura et al., 2006; Quistad et al., 2006b
Glutamine synthetase in aggregating brain cultures	Decrease	No effect	10 μ M	ND	Monnet-Tschudi et al., 2000
Other neurochemical endpoints
Cerebral cortex synaptosomes	Inhibition of high affinity choline uptake	ND	200 μ M (IC50)	ND	Liu and Pope, 1996
Rat brain synaptosomes	Stimulation of norepinephrine release	50 μ g/ml	ND	ND	Dam et al., 1999
Aggregating brain cultures	Decrease of ChAT	10 μ M	0.1 μ M	ND	Monnet-Tschudi et al., 2000
Aggregating brain cultures	Decrease of GAD	10 μ M	0.1 μ M	ND	Monnet-Tschudi et al., 2000
Potassium-evoked release of acetylcholine in rat striatal slices	Inhibition	ND	1–10 μ M	ND	Liu et al., 2002
Human astrocytes	Inhibition of glutamate uptake	1 μ M	ND	ND	Mense et al., 2006
PC12 cells	Decrease of ChAT	5 μ M	ND	ND	Jameson et al., 2006
AChE-R, AChE-S splice variants in PC12 cells	Increase of gene expression	30 μ M (both AChE-R and-S)	30 μ M (only AChE-R)	ND	Jameson et al., 2007
Other
Rat embryos (9.5 d)	Dysmorphogenesis	5 μ g/ml	ND	ND	Roy et al., 1998
Aggregating brain cell cultures	Decrease of CNP	No effect	10 μ M	ND	Monnet-Tschudi et al., 2000
Aggregating brain cell cultures	Decreased protein content	No effect	1 μ M	ND	Monnet-Tschudi et al., 2000
Oxidative stress in C6 glioma cells	Increase in ROS	50 μ g/ml	ND	ND	Garcia et al., 2001
Oxidative stress in mouse CGNs	Increase in ROS. Increased lipid peroxidation	1 μ M	1 μ M	ND	Giordano et al., 2007
Human astrocytes	Changes in gene expression (microarray)	25 μ M	ND	ND	Mense et al., 2006
Rat cortical neurons	Increase in pCREB	0.06 nM (IC50)	30 fM (IC50)	30 pM (IC50)	Schuh et al., 2002
Rat hippocampal neurons	Increase in pCREB	1–10 nM	0.01–0.1 nM	ND	Schuh et al., 2002
Rat cortical astrocytes	Increase in pCREB	No effect at 10 μ M	ND	ND	Schuh et al., 2002
Rat hippocampal slices	Decrease of microtubule-related proteins MAP-2 and α-tubulin	ND	0.1–10 μ M (MAP-2). No effect on α-tubulin	ND	Prendergast et al., 2007
Purified bovine tubulin	Decreased polymerization	ND	0.1–10 μ M	ND	Prendergast et al., 2006
Microtubules motility assay (bovine brain)	Increased microtubule detachment	1 μ M (IC50 = 9 μ M)	1 μ M (IC50 = 2 μ M)	ND	Gearhart et al., 2007

Note. Abbreviations: CD, cis-methyldioxolane; QNB, quinuclidinyl benzilate; MAP, microtubule-associated protein; EGF, epidermal growth factor; CGNs, cerebellar granule neurons; Gclm (−/−), mice lacking the modifier subunit of glutamate cysteine ligase (display very low glutathione levels); CHOK1, Chinese hamster ovary K1 cells; MAPK, mitogen-stimulated protein kinase; NGF, nerve growth factor; cAMP, cyclic adenosine monophosphate; BMP-7, bone morphogenetic factor-7; GAD, glutamic acid decarboxylase; ChAT, choline acetyltransferase; CNP, 2′,3′-cyclic nucleotide-3′-phosphohydrolase; ROS, reactive oxygen species; pCREB, phosphorylated Ca^{2 +}/cAMP response element binding protein.

^aCompounds used to differentiate cells are indicated in parentheses.

TABLE 15  Major cohort studies on chlorpyrifos, with summary of authors' reported finding

Authors	Test type	Correlations between chlorpyrifos or TCPy and outcomes	Correlations between nonspecific metabolites and outcomes
Perera et al., 2003	BW, BL, OFC	Increased chlorpyrifos with decreased BW, BL
Whyatt et al., 2004a	BW, BL, OFC	Increased chlorpyrifos with decreased BW, BL; chlorpyrifos level dose-related to decreased BW and BL.
		No evident significant relationships for infants born after January 1, 2001
Rauh et al., 2006	BW, BL, OFC	Increased chlorpyrifos with decreased BW.
		No significant negative association of chlorpyrifos with BL or OFC
Eskenazi et al., 2004	BW, BL, PI, OFC	No significant negative association between TCPy and fetal growth or gestational age at birth.	• No significant negative association between values for total DAPs, summed DEP or summed DMP metabolites.
			• Increased OFC with increased total DAPs.
			Reduced gestational age for DMP metabolites only.
Berkowitz et al., 2004	BW, BL, OFC	No significant negative association between TCPy(ur) and these measures.
		Increased OFC when interaction of PON1 activity increased level of TCPy considered.
		No significant interaction between PON1 activity and TCPy level for BW and BL.
Wolff et al., 2007	BW, BL, PI, OFC		• Total DAPs with decreased OFC.
			• Significant decrease in BW comparing low PON1 activity and high DEP metabolites versus high PON1 activity and low DEP metabolites.
			• Similar findings for PON 1 genotype.
			• Increased DEP metabolites with decreased BW in mothers with fast/fast PON1 alleles.
			• Significant negative association for DMP metabolites and PON1 activity for BL.
Young et al., 2005	BNBAS		• During pregnancy, total DAPs, summed DEP metabolites and summed DMP metabolites with increased number of abnormal reflexes.
			• During pregnancy, total DAPs, summed DEP metabolites and summed DMP metabolites with presence of 3 or more abnormal reflexes.
			• No significant negative association with the other six clusters of the BNBAS.
Engel et al., 2007	BNBAS		• Increased total DAPs, summed DEP metabolites and summed DMP metabolites with increased proportion of abnormal reflexes.
			• Increased summed DEP metabolites with increased number of abnormal reflexes.
			• Increased summed DEP metabolites with abnormal crawling reflex.
			• No interaction of summed DEP metabolites with maternal PON1 activity
			Significant interaction for summed DMP metabolites and PON1 activity for risk of abnormal reflexes.
Rauh et al., 2006	BSID-II and CBCL	ˆ At 36 months, increased chlorpyrifos with decreased mean PDI, increased percent with cognitive and motor problems, increased risk of mental and motor delay, increased problems with attention and ADHD and PDD.
		ˆ Decreased levels of chlorpyrifos levels after January 2001 associated with improved scores on MDI and PDI.
Eskenazi et al., 2007	BSID-II and CBCL	ˆ No significant association of TCPy with MDI or PDI.

TABLE 16  Summary of mean chlorpyrifos concentration in air and blood of Columbia cohort maternal–child pairs

Parameter	Arithmetic mean (SD)	Range	Geometric mean (95%CI)	Correlation
Personal air (ng/m^3; n = 394) 1998–2002	14.3 (30.7)	0.1–345	6.3 (5.6, 7.1)
1999 (n = 123)	17.2 (23.4)	0.7–156	9.5 (7.9, 11.5)
2000 (n = 126)	14.3 (31.6)	0.8–274	6.6 (5.5, 8.0)
2001 (n = 90)	13.1 (39.0)	0.1–345	4.7 (3.7, 6.1)
2002 (n = 49)	4.8 (5.9)	0.4–27	3.0 (2.3, 3.9)
Maternal blood (pg/g; n = 326) 1998–2002	3.8 (4.8)	0.3–35	1.7 (1.4, 2.0)	0.21
Cord blood (pg/g; n = 341) 1998–2002	3.7 (5.7)	0.5–63	1.5 (1.2, 1.7)	0.19
1999 (n = 109)	6.9 (7.8)	0.5–63	3.7 (2.9, 4.7)
2000 (n = 104)	3.5 (4.2)	0.5–33	2.0 (1.6, 2.5)
2001 (n = 67)	0.9 (2.1)	0.5–16	0.4 (0.3, 0.5)
2002 (n = 9)	1.3 (0.9)	0.5–2.6	1.1 (0.7, 1.7)

Note. Data kindly provided by Robin Whyatt, Columbia University. Portions of these data have been presented in Whyatt et al. (2003, 2004a, 2005).

TABLE 17  Urinary TCPy Concentrations (μ ug/L, or ppb)

Study	Type of study population	Number of subjects	Number of samples	Age range (years)	% > DL	Mean (SD) or median (UCL)	Geometric mean (SD)	Range
Kutz et al., 1992	NHANES II study	6,990	6,990	20–59	6%	NR	NR	< 5–104
Hill et al., 1995	Subset of NHANES III	993	993	20–59	82%	4.5 (8.5)	NR	< 1–77
Adgate et al., 2001	MNCPES: urban/non-urban children	90	266	3–13	93%	9.2 (0.5)	6.4 (1.1)	< 0.3–45
Fenske et al., 2002b	Applicator children, WA, 49 families	72	72	< 6	20%	4.5 (15)	NR	< 8–100
Fenske et al., 2002b	Farm worker children, WA, 12 families	12	19	< 6	33%	6.4 (15)	NR	< 8–53
Fenske et al., 2002b	Agricultural children, WA, 61 families	61	91	< 6	23%	4.9 (15)	NR	< 8–100
Fenske et al., 2002b	Reference children, WA, 12 families	18	18	< 6	29%	4.6 (9.2)	NR	< 8–27
Berkowitz et al., 2003	Mother–child pair cohort, 404 families	404	404	35% < 20	43%	7.6	NR	1.6–32.5 (interquartile)
Clayton et al., 2003	NHEXAS-MN—children; day 1	87	87	3–13	93%	7.2	NR	NR
Clayton et al., 2003	NHEXAS-MN—children; day 5	87	87	3–13	87%	6.7	NR	NR
Clayton et al., 2003	NHEXAS-MN—children; day 7	89	89	3–13	97%	8.3	NR	NR
Wilson et al., 2003	NHEXAS-MN—children	18	108	2–5	100%	8.5	NR	3.8–17.7
NHANES III	U.S. population samples, 1999–2000	481	481	6–12	> 95%	2.7 (4.8))	2.9 (4.2)	1–26 (UCLt)
NHANES III	U.S. population samples, 2000–2001	573	573	6–12	> 95%	3.1 (4.2)	2.7 (3.6)	1–24 (UCL)
NHANES III	U.S. population samples, 1999–2000	681	681	12–19	> 95%	2.1 (2.9)	2.4 (3.0)	1–24 (UCL)
NHANES III	U.S. population samples, 2000–2001	823	823	12–19	> 95%	3.6 (4.3)	2.7 (3.6)	1–24 (UCL)
NHANES III	U.S. population samples, 1999–2000	832	832	20–65	> 95%	1.5 (1.7)	1.5 (1.8)	1–11 (UCL)
NHANES III	U.S. population samples, 2000–2001	1113	1113	20–65	> 95%	1.5 (2.3)	1.5 (1.7)	1–12 (UCL t)
Hore et al., 2005	CPPAES—baseline—before C&C use	10	9	2–5	94%	7.3 (5.2)	NR	< 1–18
Hore et al., 2005	CPPAES–child; after C&C use	10	70	2–5	94%	7.7 (4.5)	NR	NR
Morgan et al., 2005	CTEPP: children in homes and day care	128	128	1.5–5	NR	7.3 (10.3)	5.2 (NR)	< MDL–104
Meeker et al., 2004a,b, 2005,2006a,b	Males from infertility clinic (incl. 2004)	322	322	36 ± 5	95	2.53 (8.95)	2.12	< 0.25–32.2
*Curwin et al., 2005a	Nonfarmers, chlorpyrifos not sprayed	45	45	adults	89%	NR	3.3 (3.2)	2.2–5.2 (UCL)
*Curwin et al., 2005a	Farmers, chlorpyrifos not sprayed	45	45	adults	89%	NR	3.5 (3.5)	2.3–5.5 (UCL)
*Curwin et al., 2005a	Farmers, chlorpyrifos self-sprayed	2	2	adults	100%	NR	5.9 (5.3)	0.9–20 (UCL)
*Curwin et al., 2007b	Father, nonfarm	23	89	adults	94%	NR	13 (11–15)	3. 8–47
*Curwin et al., 2007b	Father, farm	24	92	adults	100%	NR	17 (15–20)	6.5–58
*Curwin et al., 2007b	Mother, nonfarm	24	93	adults	95%	NR	11 (9.6–14)	1.8–35
*Curwin et al., 2007b	Mother, farm	24	94	adults	100%	NR	14 (12–17)	5.6–52
*Curwin et al., 2007b	Child, nonfarm	51	182	< 16	100%	NR	15 (13–18)	5.4–54
*Curwin et al., 2007b	Child, farm	65	235	< 16	100%	NR	17 (15–19)	6. 1–87
Lu et al., 2006	urban children—conventional diet	23	87	3–11	78%	7.2 (5.8)	NR	< 0.2–31.1
Lu et al., 2006	urban children—'organic foods' diet	23	116	3–11	50%	1.7 (2.7)	NR	< 0.2–17.1
Lu et al., 2006	urban children—conventional diet	23	155	3–11	78%	5.8 (5.4)	NR	< 0.2–25.3
Alexander et al., 2006	Farm families—Applicators pre-appl.	34	34	adult	100%	6.6	7.8 (2.3)	1.6–44.1
Alexander et al., 2006	Farm families—Applicators post-appl**	34	34	adult	100%	15.3	19.0 (2.8)	4.1–293
Alexander et al., 2006	Farm families—Spouses pre-appl	34	34	adult	100%	4.4	4.7 (1.9)	1.7–19.3
Alexander et al., 2006	Farm families—Spouses post-appl**	34	34	adult	100%	4.7	5.0 (2.0)	1.2–34.7
Alexander et al., 2006	Farm families—Children pre-appl	50	50	4–18	100%	6.5	7.6 (1.8)	1.9-31.5
Alexander et al., 2006	Farm families—Children post-appl**	50	50	4–18	100%	6.7	7.6 (2.2)	1.1–77.1
Eskenazi et al., 2007	CHAMACOS: Pregnant Women, Ag	445	838	18–35+	91%	3.5 (NR)	NR	NR
Lu et al., 2008	CPES-WA—Urban children–summer	23	243	3–11	90%	6.4 (5.9)	NR	< 0.2–31
Lu et al., 2008	CPES-WA—Urban children–fall	21	156	3–11	90%	2.6 (3.1)	NR	< 0.2–22
Lu et al., 2008	CPES-WA—Urban children–Winter	20	157	3–11	> 95%	5.1 (4.9)	NR	< 0.2–32
Lu et al., 2008	CPES-WA—Urban children–Spring	19	145	3–11	> 95%	5.6 (4.0)	NR	< 0.2–19

*The Curwin et al. (2005) study measured TCPy in urine by an HPLC method, and reported the results only for fathers. The Curwin et al. (2007a) study measured TCPy by an immunoassay, and reported levels in the same farm fathers, but also nonfarm fathers, and mothers and children from both farm and nonfarm households. The ELISA method gave TCPy values that were 3–4 times greater than the HPLC method.

**In the Alexander et al. Farm Family Exposure Study, 24-h urine samples were collected before application, on the day of application, and daily for 3 days following application. The urinary TCPy concentrations shown for postapplication are for day 1 following application.

TABLE 19  Chlorpyrifos in source media—Soil, Housedust and food [mean, SD; (maximum or range)]

Study (author, year)	Population	Housedust, ng/g:	Soil, ng/g:	Food μ g/kg:	Surface loading, ng/cm^2
#Whitmore et al., 1994	NR	4700 (median)	NR	NR
Bradman et al., 1997	5 Farm-worker homes, CA	ND (2), 230 (2), 33000	NR	NR	ND (2), 1700, 5200, 14000
Bradman et al., 1997	1 Non-farm-worker home, CA	710	NR	NR	1100
#Muckerjee et al., 1997	Brownsville, TX, spring	300 (100–1700)	NR	NR	NR
#Muckerjee et al., 1997	Brownsville, TX summer	560 (200–1700)	NR	NR	NR
Simcox et al., 1995	Agricultural home exposure	NR	43 (20% > 11; 243)	NR	NR
Simcox et al., 1995	Non-Agricultural home	NR	36 (20% > 11; 39)	NR	NR
Gurunathan et al., 1998	Households after application	NR	NR	NR	20–50
Byrne et al., 1998	Households after C&C application	NR	NR	NR	< 2–23
Krieger et al., 2000^1	Carpet after fogger application	NR	NR	NR	3.6 ± 2.8
Gordon et al., 1999)	NHEXAS-AZ	160 (< 4–119,000)	NR	NR	NR
Pang et al., 2002	NHEXAS-MD: Largely urban	2400 ± 5000, 27,000	200 (950; 6,500)	0.75 ± 2.2; 24	NR
Fenske et al., 2002b	Applicator children, WA, 49 families	550 ± 580; 2600	NR	NR	NR
Fenske et al., 2002b	Farm worker children, WA, 12 families	270 ± 180; 560	NR	NR	NR
Fenske et al., 2002b	Agricultural children, WA, 61 families	500 ± 540, 2600	NR	NR	NR
Fenske et al., 2002b	12 reference households	90 ± 90; 290	NR	NR	NR
Clayton et al., 2003	NHEXAS-MNCPS-children	See surface loading	3% > DL	0.20; (57% > DL; 0.58 90th%ile)	1.15 (1.33, 90th%ile)
Lu et al., 2004	Farm worker children, WA	< 1000	< 50	12 (NR)	NR
Lu et al., 2004	Urban comparison, WA	< 1000	< 50	350 (NR)	NR
Wilson et al., 2003	NHEXAS-MN (MNCPES)—2 day-care centers	107 (32–271)	< 2	0.65 (0.2–6.5)	NR
Wilson et al., 2003	NHEXAS-MN (MNCPES)—Childrens' homes	1040 (34–6450)	1 (2–9)	0.8 (0.08–2.3)	NR
Hore et al., 2005	CPPAES—10 homes prior to application	See surface loading	NR	NR	0.4–0.5
Hore et al., 2005	CPPAES—7 ‘high’ homes 1 day post application	See surface loading	NR	NR	9.7 (10.7; 25)
Hore et al., 2005	CPPAES—3 ‘low’ homes 1 day post application	See surface loading	NR	NR	0.75 (0.8; 2.1)
Hore et al., 2006	CPPAES-MENTOR-SHEDS	See surface loading	NR	NR	1.0 (1.1; 3.2)
Morgan et al., 2005*	CTEPP-urban homes	310 ± 790, 6,860	3.6 (14.9, 111)	3.1 (2.8, 18.1)	NR
Morgan et al., 2005*	CTEPP-urban daycare	94 ± 100, 370	< DL, 1.7	3.8 (3.3, 17.5)	NR
Bradman et al., 2007	Rural agricultural, CA	49 ± NR; 1200	NR	< 1	NR

^#As cited in (Gordon et al., 1999) (table 7).

TABLE 18  Chlorpyrifos in source media–air, ng/m³ [mean (SD/range; maximum)]

Study	Population	Number of samples	Indoor air	Outdoor air
#Whitmore et al., 1994	Jacksonville, Fl, summer	NR	182 (< 2.5–2170)	9 (< 2.5–206)
#Whitmore et al., 1994	Jacksonville, Fl, summer	NR	69 (< 2.5–1043)	< 2.5 (< 2.5–26)
#Muckerjee et al., 1997	Brownsville, TX, spring	NR	7.6 (2.5–115)	2.1 (1.3–2.8)
#Muckerjee et al., 1997	Brownsville, TX summer	NR	24 (5.7–67)	2.7 (1.5–4.3)
Aston and Seiber, 1997	Sierra Nevada Mts, CA, summer	NR		0.1–100
Gurunathan et al., 1998	Households after application	2	4000–6000 peak	NR
Byrne et al., 1998	Households after C&C application	3	100–800 TWA: 1680	NR
Rawn and Muir, 1999	Southern Manitoba, Canada, following aerial or ground applications	Weekly air collected over 3 summers (1995–1997)		Peak conc, 10–103
Gordon et al., 1999	NHEXAS-AZ	122	8 (< 3.2–3280)	< 3.2 (< 3.2–22)
Pang et al., 2002	NHEXAS-MD: Largely urban	80 subjects over 10 years old	32 (89; 798)	NR
Lee et al., 2002	California—urban ambient air	21	8 > QL	15 (22)
Lee et al., 2002	California—rural ambient air	82	75 > QL	100 (150; < 9.4–910)
Clayton et al., 2003	NHEXAS-MNCPS—children	82 households	1.7 (16.2, 90%ile)	10% > DL;
Wilson et al., 2003	NHEXAS-MNCPS—children	Day cares of 9 children	14 (2–29)	1 (0.8–8)
Wilson et al., 2003	NHEXAS-MNCPS—children	Homes of 9 children	158 (3–1145)	1.7 (1–4)
Lu et al., 2004	Farm-worker children, WA	6 agricultural households	3 (4; 10)	NR
Lu et al., 2004	Urban comparison, WA	7 urban households	2 (2; 5)	NR
Harnly et al., 2005	SE Central Valley, CA	Outdoor air, late spring 2006	NR	33 (median)
Hore et al., 2005	CPPAES—child exposure	10 homes—prior to application	27 (35; 115)	NR
Hore et al., 2005	CPPAES—child exposure	7 “high” homes—day 1 (highest)	285 (257; 816)	NR
Hore et al., 2005	CPPAES—child exposure	3 “low” homes—day 1	15 (9.9; 29)	NR
Hore et al., 2006	CPPAES-MENTOR-SHEDS	7 homes C&C treated	66 (80; 338)	NR
Morgan et al., 2005*	CTEPP—urban homes	129, children 1.5–5	5 (13.3; 135)	0.5 (1; 9.1)
Morgan et al., 2005*	CTEPP—urban day care	13. children 1.5–5	2.6 (3.3; 9.8)	0.2 (0.2; 0.7)
Whyatt et al., 2002	Pregnant women, inner city	72 pregnant, 18–35 years old	21.1 (30.2; 193)	NR
Whyatt et al., 2003	Pregnant women, inner city	230 pregnant 18–35 yo	18.3 (36.8; 345)	NR
Whyatt et al., 2004b	Pregnant women, inner city	Before Jan 1, 2001	8.0	NR
Whyatt et al., 2004b	Pregnant women, inner city	After Jan 1, 2001	4.9	NR
Whyatt et al., 2005**	Pregnant women, inner city	394 pregnant, 18–35 years old	14.3 (30.7; 345)	NR
Whyatt et al., 2007**	Pregnant women, inner city	102 homes, 337 samples	6.9 (17; 171)	NR
Whyatt et al., 2007**	Pregnant women, inner city	32 homes	12.4 (29)	NR
Whyatt et al., 2007**	Pregnant women, inner city	16 homes	2.4 (1.9)	NR
Bradman et al., 2007	CHAMACOS, agricultural, CA	20 children, < 5 years old	11 (4–36)	6 (4–36)

#As cited in Gordon et al., 1999 (table 7).

**Data from this 2005 report include previously reported data in Perrera et al. (2002) and Whyatt et al. (2002, 2003, 2004b). Some Whyatt (2007) subjects were included in previous reports. Whyatt et al. (2007) samples included 2 homes for which recent chlorpyrifos use appears evident, since the levels reported over the first two weeks of monitoring were between 100–200 ng/m³, whereas the mean among 102 homes was 6.9, and was 2.4 for a subset of 16 homes.

^⁁The personal air monitoring data reported in Figure 1 of Whyatt et al. (2004b) represent arithmetic mean values, whereas the data reported in Table 1 of that same paper, and the summary data presented in Whyatt et al. (2005) represent geometric mean values. (R. Whyatt, personal communication).

FIG. 9  Pre-versus postapplication exposure to chlorpyrifos from residential use (from Kreiger et al., 2001).

TABLE 20  Summary statistics for chlorpyrifos and chlorpyrifos-methyl residues in foods, FDA Total Diet Study, 1991–2003

Statistic	Chlorpyrifos	Chlorpyrifos-methyl
Total number of food types with 1 or more detects	149 (52.3%)	88 (31%)
Total number samples greater than / equal to QL	259 (4.3%)	1225 (37.4%)
Total number samples less than QL but greater than DL	795 (13.3%)	809 (24.7)
Total number samples with detectable residues	1054 (17.7%)	2034 (62.2%)
Number of samples below QL	4906 (82.3%)	1238 (37.8%)
Mean chlorpyrifos concentration (mean of means, with 0 used for nondetects)	0.9 μ g/kg (ppb)	4.4 μ g/kg (ppb)
Mean chlorpyrifos concentration in samples in which > 10% of samples in the food group had detectable residues (83 food groups, 3186 samples)	1.4 μ g/kg (ppb)	5.0 μ g/kg (ppb)
Average maximum chlorpyrifos concentration detected in samples with > 10% detectable (range of maximums)	18.6 (1–220) ppb	31.0 μ g/kg (ppb)

Note. There were 285 food types analyzed, with a total of 5960 individual food samples collected.Data from http://www.cfsan.fda.gov/∼acrobat/tds1byps.pdf.

TABLE 21  Estimates of daily chlorpyrifos/chlorpyrifos-methyl intake based on food intake rates and residue concentrations

	Chlorpyrifos			Chlorpyrifos-methyl			Combined (chlorpyrifos + chlorpyrifos-methyl)
	Adult	Toddler	Infant	Adult	Toddler	Infant	Adult	Toddler	Infant
Parameter	(70 kg)	(20 kg)	(10 kg)	(70 kg)	(20 kg)	(10 kg)	(70 kg)	(20 kg)	(10 kg)
Average daily intake, μ g/d	0.35	0.28	0.09	1.46	1.32	0.86	1.81	1.6	0.94
Average daily intake, adjusted for body weight μ g/kg-day	0.005	0.014	0.009	0.021	0.086	0.010	0.026	0.100	0.018
*Maximum daily intake, μ g/d (maximum residue level for each food group)	5.30	4.8	1.07	7.0	1.3	4.1	12.3	6.1	5.17
*Maximum daily intake, adjusted by body weight (μ g/kg-day)	0.077	0.242	0.113	0.100	0.412	0.066	0.176	0.652	0.176
Body burden at steady state, based on average daily intake (μ g/kg) and 70% absorption/urinary elimination	0.006	0.016	0.011	0.024	.098	.011	0.246	0.114	0.022
Body burden at steady state, based on maximum daily intake (μ g/kg) and 70% absorption/urinary elimination	0.087	0.275	0.128	0.113	0.467	0.075	0.2	0.742	0.203
Estimated urinary TCPy concentration (ppb) at steady state, based on average body burden	0.1	0.4	0.2	0.5	2.4	0.3	0.6	2.6	0.4
*Estimated urinary TCPy concentration (ppb) at steady state, based on maximum body burden	1.8	6.2	2.9	2.5	11.5	1.9	4.1	16.7	4.6

*“Maximum” is determined by taking the maximum chlorpyrifos residue concentration identified for each food item, multiplying by the average daily intake for that food item, then summing the amounts for all food items. This value is not a realistic intake rate, as the probability that all of the food items consumed by a given individual contained the maximum residue concentration is highly unlikely. However, it is certainly possible that an individual might consume much more of a given food item than is reflected by the average intake rate. This value perhaps represents the upper end of the range of possible dietary exposures to chlorpyrifos, and consequent predicted urinary concentrations. It should also be recognized that the urinary concentration values assume that the intake rate occurs on a daily basis, such that a steady-state body burden and 24-h urinary elimination rate is achieved.

TABLE 22  Urinary TCPy concentrations in children consuming conventional and “certified organic” diet (from Lu et al., 2006)

Study phase	Number of samples	Percent > DL (0.2 ppb)	Median (ppb)	Mean (ppb)	Maximum (ppb)
Phase I (conventional)	87	78%	6.0	7.2 ± 5.8	31.1
Phase II (organic diet)	116	50%	0.9	1.7 ± 2.7*	17.1
Phase III (conventional)	155	78%	4.3	5.8 ± 5.4	25.3

Note. A value of 0 was used for samples below the DL.

*Statistically different from phase I and phase III.

TABLE 23  Variability in urinary TCPy at different times of sample collection (from Kissel et al., 2005)

Child	Night	FMV	Lunch	Dinner	Average	SD
A	1	6	24	15	11.5	10.1
B	24	12	1	10	11.8	9.5
C	5	10	4	1	5.0	3.7
D	9	6	7	9	7.8	1.5
Mean	9.8	8.5	9.0	8.8	9.0
SD	10.0	3.0	10.3	5.8	7.1

FIG. 10  Urinary TCPy concentrations in children following Crack and Crevice treatment of homes with chlorpyrifos. Data from Hore et al. (2005).

TABLE 24  Comparison of exposure parameters for three epidemiology cohort studies evaluating potential neurodevelopmental effects of chlorpyrifos

Parameters	Columbia cohort	Berkeley cohort	Mount Sinai cohort
	Personal Air Sample (geometric mean)
	Source: Table 16:	Personal air sample (median)	Personal air sample: NA
	6.3 ng/m^3 (overall 1998–2002) (n = 394)	Source: Bradman et al., 2007: 11 ng/m^3
	9.5 ng/m^3 (1999)(n = 123)
	3.0 ng/m^3 (2002) (n = 49)
	Source: Whyatt et al., 2004:
	15.3 ng/m^3 (overall 1998–2002) (n = 271)
	8.0 ng/m^3 (pre-01/2001)
	4.9 ng/m^3 (post-01/2001)
	Personal Air Sample (arithmetic mean)
	Source: Table 16:
Chlorpyrifos exposure measure(s)	14.3 ng/m^3 (overall 1998–2002) (n = 394)
	17.2 ng/m^3 (1999) (n = 123)
	4.8 ng/m^3 (2002) (n = 49)
	Fetal cord blood (geometric mean)	Maternal/fetal cord blood: NA	Maternal/fetal cord blood: NA
	Source: Table 16:
	1.5 pg/g (overall 1998-2002) (n = 341)
	3.7 pg/g (1999) (n = 109)
	1.1 pg/g (2002) (n = 9)
	Source: Whyatt et al., 2004:
	4.0 pg/g (overall 1998 to 2002 (n = 256)
	2.5pg/g (pre-01/2001)
	0.6 pg/g (post-01/2001)
	Fetal cord blood (arithmetic mean)
	Source: Table 163
	1.5 pg/g (overall, i.e., 1998–2002)
	6.9 pg/g (1999) (n = 109)
	1.3 pg/g (2002) (n = 9)
	Urinary TCPy: NA	Urinary TCPy (median)	Urinary TCPy (median)
		Source: Eskanzi et al., 2004: 3.3 μ g/L	Source: Berkowitz et al., 2004: 7.6 μ g/L
Estimated mean daily inhalation exposure (geometric mean)*	Source: Table 16—Using:	Source: Bradman et al., 2007: median = 165 ng	NA
	Geometric mean (overall) = 94.5 ng
	Geometric mean (1999) = 142.5 ng
	Geometric mean (2002) = 33 ng
	Arithmetic mean (overall) = 214.5ng
	Arithmetric mean (1999) = 258 ng
	Arithemetric mean (2002) = 72 ng
Estimated contribution of inhaled chlorpyrifos to urinary TCPy **	Source: Table 16—Using: Geometric mean (overall) = 0.03 μ g/L	0.055 ug/L	NA
	Geometric mean (1999) = 0.05 μ g/L
	Geometric mean (2002) = 0.015 μ g/L
	Arithmetic mean (overall) = 0.07 μ g/L
	Arithmetic mean (1999) = 0.086 μ g/L
	Arithmetic mean (2002) = 0.024 μ g/L
Percent contribution of inhaled dose to total urinary TCPy	NA	1.7%	NA
Estimated dietary exposure to chlorpyrifos***	0.35 μ g/day	0.35 μ g/day	0.35 μ g/day
Estimated dietary exposure to chlorpyrifos-methyl	1.46 μ g/day	1.46 μ g/day	1.46 μ g/day
Estimated summed exposures to dietary chlorpyrifos and chlorpyrifos-methyl	1.81 μ g/day	1.81 μ g/day	1.81 μ g/day
Estimated intake of chlorpyrifos and chlorpyrifos methyl from inhalation and diet	Source: Table 16—Using:	Source: Bradman et al., 2007: 1.97 μ g/day	NA
	Geometric mean for inhalation:
	Overall = 1.90 μ g/day
	In 1999 = 1.94 μ g/day
	In 2002 = 1.84 μ g/day
	Arithmetic mean for inhalation
	Overall = 2.02 μ g/day
	In 1999 = 2.07 μ g/day
	In 2002 = 1.88 μ g/day
Estimated dose of chlorpyrifos and chlorpyrifos methyl with respect to body weight (70-kg adult)	Source: Table 16—Using:	Source: Bradman et al., 2007: 0.028 μ g/kg/day	NA
	Geometric mean for inhalation:
	Overall = 0.027 μ g/kg/day
	In 1999 = 0.028 μ g/kg/day
	In 2002 = 0.026 μ g/kg/day
	Arithmetic mean for inhalation:
	Overall = 0.028 μ g/kg/day
	In 1999 = 0.029 μ g/kg/day
	In 2002 = 0.027 μ g/kg/day

*Estimated mean daily inhalation for an average adult breathing 15 m³/day; 1 ng/m³ (15 m³/day) = 15 ng/day, assuming total absorption.**The conversion is as follows: 1 ng/m³ results in 0.005 μ g/L in urine.***From Table 22, using the data from studies that specifically assess chlorpyrifos levels in food eaten by adults. The estimated daily intake is 0.35 μ g/day for chlorpyrifos and 1.46 μ g/day for chlorpyrifos methyl.

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