Disease relevance of chlorpyrifos

• Possible differences in susceptibility to chlorpyrifos toxicity therefore are unlikely to be predicted by the paraoxonase genotype alone [1].
• We report eight people who developed peripheral neuropathy after exposure to exterminator-applied commercial Dursban; five also experienced memory loss and cognitive slowing [2].
• The panel assessed the quality of the existing epidemiologic literature on chlorpyrifos and specific outcomes such as neuropathy (including organophosphate induced delayed neurotoxicity), behavior (cognition and affect), immunologic, and multiple complaints (also referred to as multiple chemical sensitivities) [3].
• The organophosphate pesticide chlorpyrifos affects form deprivation myopia [4].
• For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g [95% confidence interval (CI), -81.8 to -3.8, p = 0.03] and birth length decreased by 0.24 cm (95% CI, -0.47 to -0.01, p = 0.04) [5].

Psychiatry related information on chlorpyrifos

• Critical periods for chlorpyrifos-induced developmental neurotoxicity: alterations in adenylyl cyclase signaling in adult rat brain regions after gestational or neonatal exposure [6].
• These data suggest that early postnatal chlorpyrifos exposures will depress locomotor activity in juvenile rats, with the effects most pronounced after brain ChE activity has substantially recovered [7].
• In conclusion, chlorpyrifos decreased motor activity but had no effects on short-term memory (i.e., information retention capability) and on encoding/motivation/attention [8].
• Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination [9].
• A computer-assisted, three-dimensional video imaging system was used to measure spontaneous swimming and feeding behaviors in control and chlorpyrifos-exposed fish [10].

High impact information on chlorpyrifos

• Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos [11].
• The ratio of paraoxonase over that of chlorpyrifos oxonase provided an excellent method for genetic typing of the paraoxonase polymorphism, as did the substitution of phenylacetate for chlorpyrifos as the substrate [1].
• Chlorpyrifos is an extensively used organophosphate insecticide with numerous agricultural crop and urban pest control uses [12].
• There are no indications that chlorpyrifos caused delayed neurotoxicity at dose levels below twice the oral LD50 [12].
• A panel of toxicology and medical experts was convened on 7-9 April 1997 to consider the available scientific literature on chlorpyrifos, both published and unpublished, to determine the acute and chronic toxicology reference dose (RfD) [13].

Chemical compound and disease context of chlorpyrifos

• These results suggest that in the mouse, the acute toxicity of chlorpyrifos is mediated by extrahepatic production of oxon, whereas that of parathion is likely mediated by both hepatic and extrahepatic activation [14].
• Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (p < 0.05) [5].
• Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling [15].
• In catfish, the ki of chlorpyrifos-oxon was 22-fold greater than that of paraoxon, while in rats it was 9-fold greater, suggesting that target site sensitivity is an important factor in the higher toxicity of chlorpyrifos to catfish but not in the higher toxicity of parathion to rats [16].
• Developmental toxicity studies in rats and rabbits with 3,5,6-trichloro-2-pyridinol, the major metabolite of chlorpyrifos [17].

Biological context of chlorpyrifos

• Homozygotes for low paraoxonase activity ranged over almost the entire spectrum of chlorpyrifos oxonase activity [1].
• Computer analyses of the binding data revealed that chlorpyrifos and parathion each bound reversibly to a single class of binding sites on BSA, with apparent KD values of 3.4 +/- 0.1 and 11.1 +/- 0.3 microM, respectively [18].
• Kinetic constants determined for four insecticides, temephos, chlorpyrifos, fenitrothion and propoxur indicate the rates of acylation and the affinities of binding of the insecticides to this carboxylesterase are important [19].
• In embryo cultures, chlorpyrifos also evoked apoptosis during neurulation [20].
• Exposure from inhalation of indoor air accounted for 84.7% of aggregate daily exposure to chlorpyrifos on average [21].

Anatomical context of chlorpyrifos

• Chlorpyrifos inhibited DNA synthesis in undifferentiated PC12 cells, which have relatively few cholinergic receptors [20].
• Chlorpyrifos inhibited DNA synthesis in both cell lines but had a greater effect on gliotypic cells [22].
• Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting [23].
• Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling [24].
• Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure [25].

Associations of chlorpyrifos with other chemical compounds

• For the organophosphate pesticide chlorpyrifos, median inhalation noncancer, acute children's exposures in agricultural communities are elevated above reference doses; for diazinon, similar exposures are nearly elevated [26].
• MATERIALS AND METHODS: Homozygous reeler (RL), heterozygous (HZ), and wild-type (WT) mice were prenatally exposed to chlorpyrifos-oxon (CPF-O), the active metabolite of chlorpyrifos, or to vehicle (prenatal controls) on gestation days 14-16, that is, during a peak period of neurogenesis in the cerebral cortex [27].
• Potential uses of biomonitoring data: a case study using the organophosphorus pesticides chlorpyrifos and malathion [28].
• Phosphorothionate insecticides such as parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate) and chlorpyrifos (CPS; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate; Dursban) are metabolically converted by oxidative desulfuration into paraoxon and chlorpyrifos-oxon (CPO) [29].
• To determine whether these functional effects of DFP resulted from inhibition of ChE and downregulation of muscarinic cholinergic receptors, rats were dosed with chlorpyrifos (CPF), an OP pesticide which inhibits blood and brain ChE of rats for weeks after a single injection [30].

Gene context of chlorpyrifos

• Testosterone and the insecticide chlorpyrifos were used to assess the catalytic activities of the most common CYP3A4 allele (CYP3A4*1) and its allelic variants [31].
• Recombinant human CYP2B6 possessed the highest desulphuration activity for chlorpyrifos, whereas CYP2C19 had the highest dearylation activity [32].
• The unexpected finding that CYP2D6, as well as CYP3A4, catalysed oxidative biotransformation was confirmed for chlorpyrifos and parathion using microsomes prepared from a human lymphoblastoid cell line expressing CYP2D6 [33].
• The insecticidal action of chlorpyrifos stems from inhibition of acetylcholinesterase (AChE) by CPO, resulting in severe cholinergic toxicity [29].
• However, when the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference [34].

Analytical, diagnostic and therapeutic context of chlorpyrifos

• METHODS: Chickens, a well-established animal model for experimental myopia and organophosphate neurotoxicity, were dosed with chlorpyrifos (3 mg/kg per day, orally, from day 2 to day 9 after hatching) or corn oil vehicle (VEH) with or without monocular form deprivation (MFD) over the same period [4].
• An on-line multidimensional supercritical fluid extraction/microcolumn liquid chromatography/capillary gas chromatography system (SFE/LC/GC) has been developed and applied to the quantitative determination of trace levels (parts per billion) of chlorpyrifos insecticide in grass field samples [35].
• The samples collected at 4 hr and 7, 14, and 21 days after treatment in the nonshampoo protocol averaged 971, 157, 70, and 26 microg chlorpyrifos, respectively; in the shampoo protocol the samples averaged 459, 49, 15, and 10 microg, respectively [36].
• Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals 24 h or 7 days after a single subcutaneous injection of either 390 mg/kg or 70 mg/kg of chlorpyrifos, respectively [37].
• Automated sample clean-up and fractionation of chlorpyrifos, chlorpyrifos-methyl and metabolites in mussels using normal-phase liquid chromatography [38].

References