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

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Review of the Toxicology of Chlorpyrifos with an Emphasis on Human Exposure and Neurodevelopment Critical Reviews in Toxicology ISSN: 1040-8444 (Print) 1547-6898 (Online) Journal homepage: http://www.tandfonline.com/loi/itxc20 Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment David L. Eaton, Robert B. Daroff, Herman Autrup, James Bridges, Patricia Buffler, Lucio G. Costa, Joseph Coyle, Guy McKhann, William C. Mobley, Lynn Nadel, Diether Neubert, Rolf Schulte-Hermann & Peter S. Spencer To cite this article: David L. Eaton, Robert B. Daroff, Herman Autrup, James Bridges, Patricia Buffler, Lucio G. Costa, Joseph Coyle, Guy McKhann, William C. Mobley, Lynn Nadel, Diether Neubert, Rolf Schulte-Hermann & Peter S. Spencer (2008) Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment, Critical Reviews in Toxicology, 38:sup2, 1-125, DOI: 10.1080/10408440802272158 To link to this article: https://doi.org/10.1080/10408440802272158 Published online: 21 Oct 2008. Submit your article to this journal Article views: 6285 Citing articles: 245 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=itxc20 Critical Reviews in Toxicology, S2:1–125, 2008 Copyright c 2008 Informa UK Ltd. ISSN: 1040-8444 print / 1547-6898 online DOI: 10.1080/10408440802272158 Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment David L. Eaton Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA Robert B. Daroff Department of Neurology, Case Western Reserve University School of Medicine, USA Herman Autrup Department of Environmental Medicine, University of Aarhus, Aarhus, Denmark James Bridges Professor Emeritus of Toxicology and Environmental Health, University of Surrey, Surrey, United Kingdom Patricia Buffler Department of Epidemiology, University of California-Berkeley, Berkeley, California, USA Lucio G. Costa Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA Joseph Coyle Department of Psychiatry and Neuroscience, Harvard Medical School, Boston, Massachusetts, USA Guy McKhann Department of Neurology and Neuroscience, The Johns Hopkins University Medical School, Baltimore, Maryland, USA William C. Mobley Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA Lynn Nadel Department of Psychology, University of Arizona, Tucson, Arizona, USA Diether Neubert Professor Emeritus of Clinical Pharmacology and Toxicology, Charite´ Berlin Campus Benjamin Franklin, Berlin, Germany Rolf Schulte-Hermann Department of Toxicology, Medical University of Vienna, Vienna, Austria Peter S. Spencer Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon, USA 1 2 D. L. EATON ET AL. This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10- to 20-fold because of the widespread presence of both TCPy and chlorpyrifos- methyl in the food supply. Current “background” (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase. However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association. Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms. Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized. Keywords Cholinesterase inhibition, chlorpyrifos, epidemiology, mechanism, neurobehavior, neu- rodevelopment, organophosphorous insecticide, review, toxicology, trichloropyridinol Table of Contents EXECUTIVE SUMMARY ............................................................................................................................................ 4 I. BACKGROUND AND GENERAL CHARACTERISTICS OF CHLORPYRIFOS ................................................ 9 I.A. Purpose ..................................................................................................................................................... 9 I.B. Introduction ..............................................................................................................................................10 I.C. Chemical and Physical Properties ...............................................................................................................10 I.D. Uses of Chlorpyrifos .................................................................................................................................10 I.E. Overview of Metabolic and Environmental Degradation of Chlorpyrifos ........................................................11 I.E.1. Environmental Distribution ...........................................................................................................12 I.E.2. Stability and Environmental Fate ...................................................................................................12 II. ABSORPTION, METABOLISM, DISTRIBUTION, EXCRETION, AND PHARMACOKINETICS OF CHLORPYRIFOS ...............................................................................................................................................12 II.A. Absorption ...............................................................................................................................................13 II.A.1. Oral Absorption ...........................................................................................................................13 II.A.2. Dermal Absorption .......................................................................................................................16 II.A.3. Absorption via Inhalation Exposure ...............................................................................................16 II.B. Distribution ..............................................................................................................................................17 II.B.1. Distribution Studies in Experimental Animals .................................................................................17 II.B.2. Distribution Studies in Humans .....................................................................................................17 II.C. Biotransformation of Chlorpyrifos ..............................................................................................................17 II.C.1. General Aspects of Biotransformation of Chlorpyrifos (Experimental Animals) .................................17 II.C.2. Influence of Animal Age and Characteristics of Dosing ...................................................................18 II.C.3. Overview of Active/Toxic Metabolites of Chlorpyrifos (Experimental Animals) .................................19 II.C.4. Biotransformation Studies in Humans ............................................................................................19 II.C.5. Paraoxonase (PON1) ....................................................................................................................23 II.C.6. Balance of Activation and Detoxication Pathways ...........................................................................25 II.C.7. Role of Cholinesterases in Chlorpyrifos Toxicity .............................................................................25 II.D. Excretion of Chlorpyrifos ..........................................................................................................................26 II.D.1. Urinary Excretion .........................................................................................................................26 TOXICOLOGY OF CHLORPYRIFOS 3 II.D.2. Biliary and/or Fecal Elimination ....................................................................................................26 II.D.3. Excretion in Milk .........................................................................................................................27 II.E. Comparison of Kinetics of Chlorpyrifos in Animals and Humans ..................................................................27 II.F. Summary of Conclusions Regarding ADME and PK of Chlorpyrifos in Animals and Humans .........................28 III. TOXICITY ASSESSMENT OF CHLORPYRIFOS .............................................................................................29
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