A review of the reference dose for chlorpyrifos

Toxicology Excellence for Risk Assessment (TERA), 2300 Montana Avenue, Suite 409, Cincinnati, OH 45211, USA.
Regulatory Toxicology and Pharmacology (Impact Factor: 2.03). 04/2006; 44(2):111-24. DOI: 10.1016/j.yrtph.2005.10.003
Source: PubMed


Chlorpyrifos is an inhibitor of cholinesterase (ChE) and inhibition of ChE is believed to be the most sensitive effect in all animal species evaluated and in humans from previous evaluations. Recent literature, in particular epidemiology studies reporting associations between chlorpyrifos levels and fetal birth weight decreases, suggest the need to reevaluate the basis of the reference dose (RfD) for chlorpyrifos, however. In this paper, we evaluated newly available publications regarding chlorpyrifos toxicity and discuss the choice of critical effect--whether cholinesterase inhibition or developmental effect, the choice of appropriate species and study, the appropriate point of departure, and choice of uncertainty factors--including a discussion of the FQPA safety factor. We conclude that RBC cholinesterase inhibition is the critical effect, that human studies form the best choice of species--supported by a wealth of experimental animal data, that a NOAEL of 0.1 mg/kg/day is the most appropriate point of departure, and that a 10-fold factor for within human variability is sufficient to characterize the overall uncertainty in this rather large database. The resulting RfD is 0.01 mg/kg/day.

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    • "BChE is more sensitive to inhibition by CPF than RBC AChE and thus, is considered a more sensitive biomarker (Farahat et al., 2011; Nolan et al., 1984). Inhibition of BChE is not known to cause detrimental health effects (Lotti, 1995; Zhao et al., 2006). Approximately 40% of the Egyptian workforce is employed in agriculture, making it the largest industrial sector in Egypt (Abdel Rasoul et al., 2008). "
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    ABSTRACT: Chlorpyrifos (CPF) and profenofos (PFF) are organophosphorus (OP) insecticides that are applied seasonally in Egypt to cotton fields. Urinary trichloro-2-pyridinol (TCPy), a specific CPF metabolite, and 4-bromo-2-chlorophenol (BCP), a specific PFF metabolite, are biomarkers of exposure, while inhibition of blood butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities are effect biomarkers that may be associated with neurotoxicity. Urinary TCPy and BCP and blood BChE and AChE activities were measured in 37 adult Egyptian Ministry of Agriculture workers during and after 9–17 consecutive days of CPF application followed by an application of PFF (9–11 days), and a second CPF application (5 days) in 2008. During the OP applications, urinary TCPy and BCP levels were significantly higher than baseline levels, remained elevated following the application periods, and were associated with an exposure related inhibition of blood BChE and AChE. Analysis of blood AChE levels before and after the PFF application period suggests that individual workers with peak BCP levels greater than 1000 μg/g creatinine exhibited further inhibition of blood AChE with PFF application, demonstrating that PFF exposure had a negative impact on AChE activity in this highly exposed worker population. While large interindividual differences in exposure were observed throughout this longitudinal study (peak urinary BCP and peak TCPy levels for individuals ranging from 13.4 to 8052 and 16.4 to 30,107 μg/g creatinine, respectively), these urinary biomarkers were highly correlated within workers (r = 0.75, p < 0.001). This suggests that the relative exposures to CPF and PFF were highly correlated for a given worker. The variable exposures between job classification and work site suggest that job title and work location should not be used as the sole basis for categorizing OP exposures when assessing neurobehavioral and other health outcomes in Egyptian cotton field workers. Together, these findings will be important in educating the Egyptian insecticide application workers in order to encourage the development and implementation of work practices and personal protective equipment to reduce their exposure to CPF and PFF.
    International Journal of Hygiene and Environmental Health 11/2014; 218(2). DOI:10.1016/j.ijheh.2014.10.005 · 3.83 Impact Factor
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    • "The mechanism of its toxicity is inhibition of acetylcholinesterase (AChE), a crucial enzyme for the functioning of the nervous system (Lassiter et al., 2003). Zhao et al. (2006) determined that the safe dosage of chlorpyrifos for humans is 0.01 mg CPF/kg/day. The acute oral LD50 for rats ranges from 135 to 163 mg CPF/kg body mass (Chattopadhyay, 1993). "
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    ABSTRACT: One of the most important issues in ecotoxicology is better understanding the effects of interactions between chemical pollutants and physical environmental factors on animals. To fill this knowledge gap, changes in the activity of acetylcholinesterase (AChE) in the brain samples of bank voles Myodes (Clethrionomys) glareolus due to temperature effects, and two chemical stressors were studied in a full factorial laboratory experiment (27 treatments). The experiment was divided into three phases: acclimatisation (3 days), intoxication (42 days) and elimination (21 days). During the intoxication phase, animals were orally exposed to different concentrations of either nickel (0, 300 or 800mg Ni/kg food), chlorpyrifos (CPF) (0, 50 or 350mg CPF/kg food) or a mixture of both chemicals. During the acclimatisation and elimination phases, the bank voles were given uncontaminated food. The experiment was conducted at three different temperatures (10, 20 or 30°C), and a 12h:12h light:dark regime. The animals were sacrificed at 0, 5, 10, 20, 42, 49 and 63 days after the beginning of the intoxication, and brain samples were obtained for chemical analysis. The nickel accumulation in the brain depended on the level of nickel exposure and on interactions between the temperature and other factors. Nickel exhibited no effect on AChE activity. In contrast, AChE was drastically inhibited by chlorpyrifos and low temperature, but interactions between all factors significantly influenced the enzyme activity during the elimination phase of the experiment. High mortality was observed in the groups exposed to high concentrations of nickel and chlorpyrifos.
    Ecotoxicology and Environmental Safety 05/2014; 106C:204-212. DOI:10.1016/j.ecoenv.2014.04.021 · 2.76 Impact Factor
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    • "The present review of the animal and epidemiologic studies on birth and growth outcomes differs from previous reviews (Clegg and van Gemert 1999a; Eaton et al. 2008; Weselak et al. 1999b; 2007; Zhao et al. 2005; 2006;) by contributing in-depth analyses of outcomes and including an additional study published in 2010 (Barr et al. 2010). The two 1999 expert panel reports (Clegg and van Gemert 1999a; 1999b) were written prior to publication of the epidemiologic studies included in this review. "
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    ABSTRACT: Chlorpyrifos (CPF) is one of the most widely used organophosphate insecticides in the United States. By December 2000, nearly all residential uses were voluntarily canceled, so that today, CPF is only used to control insect pests on a variety of crops. Periodic review of the potential effects of CPF on all developmental outcomes is necessary in the United States because the Food Quality Protection Act mandates special consideration of risk assessments for infants and children. This article reviews epidemiologic studies examining the association of potential CPF exposure with growth indices, including birth weight, birth length, and head circumference, and animal studies focusing on related somatic developmental endpoints. It differs from earlier reviews by including an additional cohort study and providing in-depth systematic evaluation of the patterns of association across different studies with respect to specificity of biomarkers for CPF, consistency, dose response, strength of association, temporality, and biological plausibility (Hill 1965), as well as consideration of the potential role of effect modification and bias. The review did not identify any strong associations exhibiting consistent exposure-response patterns that were observed in more than one of the four cohort studies evaluated. In addition, the animal data indicate that developmental effects occur at doses that produce substantial maternal toxicity and red blood cell (RBC) acetylcholinesterase (AChE) inhibition. Based on consideration of both the epidemiologic and animal data, maternal RBC AChE inhibition is a more sensitive endpoint for risk assessment than somatic developmental effects reviewed in this article.
    Journal of Toxicology and Environmental Health Part B 05/2012; 15(4):281-316. DOI:10.1080/10937404.2012.672150 · 4.97 Impact Factor
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