Grantee Research Project Results
2002 Progress Report: Biomarkers and Neurobehavioral Effects of Perinatal Exposure to Chlorpyrifos and Other Organophosphate Insecticides
EPA Grant Number: R828611Title: Biomarkers and Neurobehavioral Effects of Perinatal Exposure to Chlorpyrifos and Other Organophosphate Insecticides
Investigators: Wilkins, John R. , Moeschberger, Melvin L. , Lindsay, Ronald L. , Weghorst, Christopher M. , Dietrich, Kim , Nishioka, M.
Current Investigators: Wilkins, John R. , Moeschberger, Melvin L. , Weghorst, Christopher M. , Dietrich, Kim , Nishioka, M.
Institution: The Ohio State University , Battelle Memorial Institute , University of Cincinnati
EPA Project Officer: Hahn, Intaek
Project Period: February 12, 2001 through February 11, 2004 (Extended to February 11, 2006)
Project Period Covered by this Report: February 12, 2002 through February 11, 2003
Project Amount: $1,126,463
RFA: Biomarkers for the Assessment of Exposure and Toxicity in Children (2000) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The main objective of this research project is to evaluate the putative relationship between adverse neurobehavioral effects among infants and young children and perinatal exposure to chlorpyrifos (CP), diazinon (DZ), other organophosphate (OP) insecticides, and, as an important addition to the study protocol, pyrethroid insecticides, while employing biomarkers of exposure and susceptibility in a longitudinal design. Cohort ascertainment requires the recruitment of 176 women in their second trimester of a low-risk pregnancy into the longitudinal study, which will follow only healthy full-term newborns for 2 years.
Progress Summary:
Overview of Data Collection. For each pregnancy, the following data are obtained: (1) maternal exposure to the OP and pyrethroid insecticides of interest; (2) maternal exposure to other neurodevelopmental toxicants likely to be factors in the target population (e.g., lead [Pb] and nicotine); (3) maternal demographics and other potentially confounding family-based factors (e.g., socioeconomic status [SES]); and (4) relevant clinical information pertaining to the pregnancy and birth event (e.g., activity, pulse, grimace, appearance, and respiration [APGAR] scores). Maternal exposures to the OPs and pyrethroids of interest are assessed by analyses of urine obtained from the mother prior to birth. At regular intervals throughout the follow-up period, urine samples are collected from the infants and analyzed for dialkylphosphates and 3,5,6-trichloro-2-pyridinol (TCP). Levels of 2-isopropyl-6-methyl-4-pyrimidinol (IMP) also are determined. Proposed analyses of pyrethroid urinary metabolites are discussed below. In addition, two postnatal blood samples are obtained from the youth (one at 12 months, one at 24 months) to determine blood Pb levels. Blood also is used to determine the infant’s paraoxonase (PON1) genotype, a biomarker of susceptibility to OP toxicity. Because vulnerability to the adverse effects of neurodevelopmental toxicants begins shortly after conception, blood obtained from the expectant mothers is used to determine the mother's PON1 genotype.
After birth, relevant data are obtained from the mother-child dyads at 3, 12, and 24 months. At 3 months, neurobehavioral/neurodevelopmental data are obtained from the infant by administration of the Bayley Scales of Infant Development-II (BSID-II). At 12 months, control data on potential confounders are obtained in addition to data on breast-feeding and parental IQ. At 24 months, the primary neurobehavioral/neurodevelopmental data will be obtained by repeat administration of the BSID-II, in addition to a one-time administration of Ireton's Child Development Inventory (CDI). Multiple regression modeling will be used to evaluate the relationship between the indicators of neurobehavioral development obtained and OP exposure.
This approach to analysis of the data permits control of the potentially confounding (and interactive) effects of Pb and other factors (e.g., maternal IQ), and also allows examination of the potential influence of PON 1 genotype (of the mother and/or child) as an effect modifier.
Pesticides of Concern for Residential Exposure. The OPs DZ and CP have been used widely in both the residential and agricultural arenas (Gordon, et al., 1999). For example, in 1997, CP use by category was: 9-13 million pounds active ingredient in agriculture, 4-7 million pounds for commercial application, and 2-4 million pounds in the residential environment (Aspelin and Grube, 1999; Kiely, 1999). With 17 million pounds of insecticides used per year in the residential environment, approximately 10 million pounds of other insecticides are used there, and these figures ignore the 30 million pounds of insecticides used in the industrial and commercial sector, which includes residential treatment by licensed applicators. These data suggest that there may be as much as 10 pounds of insecticide active ingredient used per year per U.S. resident in and around homes.
The residential insecticide market changed significantly in 2000-2001 as a result of announcements made in June and November 2000 that the OPs CP and DZ will be phased out of indoor-use products. The market clearly is moving in the direction of pyrethroid (PYRE) insecticides, as evidenced by the Minnesota household pesticide inventory study (Adgate, et al., 2000). However, the PYRE market itself also is undergoing a dramatic shift in product formulation. Earliest PYREs were botanicals, derivatives of chysanthemic acid, and had the advantages of low mammalian toxicity and very short environmental half life (Pesticide Profiles, 1997). However, formulations had poor shelf stability, especially when formulated as an aqueous spray. The search for more potent and longer lived products led to the introduction of the synthetic PYREs based on a diphenyl ether and a terminal dichlorovinyl group separated by a dimethyl cyclopropanecarboxylate group in the late 1970s (Elliott, 1977; Itaya, et al., 1977). Further development led to the introduction of a cyano group (CN), alpha () to the diphenyl ether, and a halogenated aromatic group in place of the halogenated vinyl group (e.g., esfenvalerate). Both of these changes led to an increase in toxicity, increased resistance to degradation (either enzymatic or by hydrolysis), decrease in water solubility (Pesticide Profiles, 1997; Elliott, 1977; Itaya, et al., 1977), and by extension, enhanced solubility in the lipid membranes of the blood-brain barrier and axonal myelin sheath (Marei, et al., 1982; Staatz, et al., 1982a; Staatz, et al., 1982b).
The presence or absence of the -CN group distinguishes the two major classes of synthetic PYREs: Type I have no -CN group; Type II have the -CN group (HSDB–Permethrin, 2000; HSDB–Tralomethrin, 2000; HSDB–Cyfluthrin, 2000). The oral LD50 toxicities in rats of representative Type I and II PYREs, together with the toxicities of DZ and CP, indicate that many PYREs approach the toxicities of the Ops (Pesticide Profiles, 1997; Miyamoto, 1976; Elliott, 1976; The Pesticide Manual, 1983). The active ingredient(s) of major insecticide products for in-home use are either Type I or Type II PYREs, and many high-volume products (e.g., Raid with 23 percent market share, Hot Shot with 16 percent market share (Market Share Reporter, 2001; MMR, 2001) contain Type II PYREs. Interestingly, many current products for outdoor use are convenient-to-use aerosols and sprays that may be used indoors, and these products contain both OPs and PYREs.
Population-based studies of pesticide metabolites in urine have suggested increased exposures for the U.S. population over the last 30 years: detectable levels in 6-7 percent of the population in 1976-1980 National Health and Nutrition Examination Survey (NHANES) II (Murphy, et al., 1983), detectable levels in 82 percent of the population in 1988-1994 NHANES III (Hill, et al., 1995), with some of this due to enhanced method sensitivity, 96 percent detects in the Maryland National Human Exposure Assessment Survey (NHEXAS) in 1995-1996 (MacIntosh, et al., 1999), and 92 percent detects in Region V NHEXAS Children's Pesticide Study (Quackenboss, et al., 1998). A similar study by Battelle researchers showed a similarly high detection rate for TCPy in the urine of children 0-6 years of age (Iachan, et al., 1999). Based on these results and the sustained market for insecticides, it is reasonable to expect that PYRE metabolites will be found with this same frequency in the present and near future. Similarly, the occurrence of PYRE insecticides in indoor air and house dust is expected to supplant that of the OPs (Gordon, et al., 1999), especially given that the major suppliers to the residential market produce "fogger" formulations, which, in OP studies, are associated with the highest indoor air levels (Fenske, et al., 1990). Changes in levels of OPs in food commodities (with the exception of levels in apple juice, grape juice, and tomato sauces) may not change appreciably in this time frame, though, as many agricultural uses may continue.
Extensive mammalian studies of OP toxicity, in general, and chlorpyrifos toxicity, in particular, have demonstrated that neurotoxic effects can be expected from low dose/chronic exposures. In addition to acetylcholine esterase inhibition at the nerve synapse, OPs also interfere in the acquisition of new brain cells and the proper functioning of cell signaling intermediates involved in brain cell differentiation, inhibit DNA synthesis and axonogenesis, and inhibit synapse formation (Whitney, et al., 1995; Dam, et al., 1998; Li and Cassida, 1998). These functions are critical to proper neurological development, especially in the cognitive realm (Rice and Barone, 2000; Weiss, 2000).
Synthetic PYREs act directly on the axon, causing the Na+ activation gate to remain in a modified open position, resulting in sustained excitability of the nerve, both in the central and peripheral systems (WHO, 1989; WHO, 1990; Vijverberg and VanDenBerken, 1982; Wouters and VanDenBerken, 1978; Vijverberg, et al., 1983). The action on the peripheral nervous system is remarkably similar to the action of dichlorodiphenyltrichloroethane (DDT), though DDT has no central nervous system (CNS) component (Lund and Narahashi, 1983; Hong, et al., 1986). Type I PYREs generate toxic effects in the CNS through stimulation of membrane bound enzymes of the brain; they significantly decrease K+ uptake at the neuronal junction, inhibit dopamine transmission, and overall, impair neurotransmitter homeostatsis in the hypothalamus, brain stem, and hippocampus (Bhatnagar and Kataria, 1997; Vaeswara and Jagannatha, 1997; Vaccari and Saba, 1995; Hudson, et al., 1986; Gammon, et al., 1982). In addition to axonal action, the Type II PYREs inhibit the gamma-aminobutyric acid neurotransmitter receiving complex in the postsynaptic junction (Gammon and Casida, 1983).
The toxic responses in rats from Type I and II PYRE exposures include generalized hyperexcitability, increased sensitivity to external stimuli, incoordination, tremors, salivation, increased burrowing (females) or aggressive sparring (males); the latter actions are tied to the regulation of hormonal systems by neurotransmitters (WHO, 1990; Vijverberg and VanDenBerken, 1982; Crofton and Reiter, 1988; Mitchell, et al., 1988). The impairment of neurotransmitter homeostatis begs the question of low-level effects in the susceptible human fetus and infant (Weiss, 2000; Experimental and Clinical Neurotoxicology, 1980; Wyburn, 1960).
In a manner analogous to the OPs, environmental hydrolysis and/or mammalian metabolism of PYREs yields two major fragments (Eadsforth and Baldwin, 1983; Gaughan, et al., 1977; Crawford, et al., 1981). Ester hydrolysis, followed by oxidation of the diphenyl ether portion, results in the formation of 3-phenoxybenzoic acid (3PBA) in many PYREs. Analysis of 3PBA and 4-fluoro-3-PBA (4F-3PBA) in urine provides two common biomarkers for a host of products.
Relatively few studies of PYRE excretion rates have been conducted to date. Elimination in urine occurs within a few days (Crawford, et al., 1981), but further elimination in feces can continue up to 12 days. The amount excreted in urine and feces depends on the cis or trans isomer conformation (WHO, 1990; Vijverberg and VanDenBerken, 1982). Two dosed humans excreted 18-39 percent of an oral permethrin dose in 24 hours (WHO, 1990).
Important recent studies have demonstrated critical issues for neonate exposures to PYREs. Cantalamessa (1993) found permethrin and cypermethrin to be more toxic to the neonate compared with the adult rat (Cantalamessa, 1993). Sheets identified no difference between neonate and adult for Type I exposure, but threefold difference for Type II exposures, and attributes this neonatal susceptibility to limited metabolic detoxification capacity (Sheets, 2000). Higher lipid solubility for sequestration of Type II compounds also may play a part. Large potency enhancements of Type I and II PYREs following intracerebroventricular injection has been suggested as evidence for a primarily CNS site of action for these insecticides, rather than peripheral (Staatz, et al., 1982a; Staatz, et al., 1982b). Finally, in a study of a high-level exposure to permethrin following either habituation or nonhabituation to moderate doses, where both groups of rats showed no difference in retention of learned behaviors, the nonhabituated group showed significantly lower retention capacity, decreases in coordination and balance, and a higher incidence of conflict behavior (Sherman, 1979).
In discussing advances in PYRE synthesis and toxic action on the housefly, Miller and Adams noted, "These factors suggest that pyrethroids can be toxic by virtue of DDT-like action, but the modern synthetic pyrethroids as pioneered by Dr. Elliott owe their potency to an improved action at the central nervous system. In effect, there are two sites of action and the peripheral actions mask the more important effects in the central nervous system" (Miller and Adams, 1977). Because initial PYRE exposures may occur early in life, when metabolic systems have limited capacity, and toxic insult may have lifelong implications, it is important to understand the frequency and magnitude of early childhood exposures, the routes by which these exposures occur, and the outcomes of such exposures.
Given the rapid switch in residential insecticide formulations from OPs to PYREs and the fact that both OPs and PYREs have the potential to cause adverse neuromotor and neuropsychological outcomes in neonates and infants, we feel that it is critical and imperative to include measures of exposures to both OP and PYRE pesticides in this STAR Grant project.
The metabolism of the PYREs, and their excretion in urine, can be compared in many ways to the metabolism of the OPs. Hydrolysis of virtually any OP yields one of six different dialkyl phosphates and a compound-specific phenolic moiety. Thus, exposure to DZ and CP could be ascertained via measurement of pesticide-specific IMPy and TCPy, respectively, and the nonspecific alkyl phosphate, diethyl-thiophosphate, in the urine. The PYREs undergo hydrolysis at the ester linkage to generate a divinylcyclopropyl carboxylic acid, and a benzyl alcohol (from the diphenyl ether derived compounds), which is quickly metabolized further to a phenoxybenzoic acid. Given the similarity in the structure of many PYREs, relatively few numbers of compounds need to be analyzed in urine to obtain a global perspective on exposure to various classes of PYRE insecticides.
For six of the parent PYREs (notably, cypermethrin, cyfluthrin, deltamethrin, esfenvalerate, permethrin, and sumithrin), metabolite standards are available that would allow us to detect and quantify in urine the metabolite products that are formed from both halves of the parent insecticide. For population exposure studies, the analysis of one metabolite, which is broadly associated with one class of compounds (e.g., 3PBA for the synthetic pyrethroids and c/t-DMCA for the "natural" pyrethroids), may allow market trends to be followed. Given the relative difference in toxicity between these two classes of pyrethroids, this will be an especially important trend to note.
Progress to Date (Analytical Chemistry). The results detailed below come from the other EPA program. We present those results here to show the promise of this method and to show how we plan to leverage the results of the other program to enhance the value of this STAR grant program.
Initial analytical work involved the assessment of different extraction solvents and clean-up methods. This work is ongoing, with work continuing in refinements to the temperature program, the cleanup step, and the selective extraction of IMPy. This assessment involved fortification of a control human urine with all analytes at the level of 10 ng/mL in urine. As listed there, only TCPy was present in this urine, although there was one significant interference (to methylene chloride [DMCA]) and several minor chromatographic interferences that will be used to monitor the efficacy of cleanup steps. Recovery of most analytes was quite good; recoveries of IMPy and its SRS 13C4-IMPy are quite low at the pH required for extraction of the TCPy and PYRE metabolites. However, much of the IMPy and its SRS 13C4-IMPy, 64 and 59 percent, respectively, is recovered in a sequential extraction of the urine at pH=5. It appears that heterocyclic IMPy is ionic at the pH favored for extraction of the other metabolites.
The slight interferences to the two SRS compounds can be handled by changing the ions, which are monitored as the quantification and qualifier ions. The interferences to the analytes 3PBA, 4F-3PBA, and DMCA will have to be handled via a cleanup step. Two approaches have been identified for this, and they currently are undergoing tests. Once the method development activities are completed, we will validate the method for both free urine and urine collected on diapers at three different fortification levels and will begin analyses of collected samples.
Progress to Date (Recruiting). To date, study protocols and questionnaires have been written, piloted, and are actively being used. A total of 374 women have been approached for recruitment in clinics and 23 have signed consent forms. Because 263/374 (63.1 percent) were found ineligible for inclusion, the initial response rate so far has been 23/138 = 16.7 percent. Unfortunately, 16 women have dropped out since enrolling, making the effective participation rate among clinic-based subjects 5.1 percent.
The first 18 weeks of recruitment resulted in 19 women entering the study. After the recruitment strategy change of utilizing local physicians, flyers, and word of mouth, 40 women have entered the study. Thus, the rate of recruitment of stable subjects (subjects retained in the study long-term) prior to the changes in the recruitment process was 0.37 per week and the rate since then has been 0.63 per week—a 70 percent increase. Most of the women recruited since the protocol changes were made have remained in the study. All but seven women recruited before the changes have dropped out. More local physicians have agreed to help recruit women into the study and are just now beginning to recruit for us. The recruitment rate now is almost double the previous rate of recruitment, showing an almost fourfold increase in absolute numbers of women recruited. We do not know however, how many women have been approached by local physicians. Forty-five enrolled women have provided at least one urine specimen and 44 have provided blood specimens. Blood specimens have been centrifuged, aliquotted, and frozen. Urine specimens have been aliquotted and frozen for future batch analysis. Thirty-four of the recruited mothers have delivered their infants. Thirty-six women have provided second urine specimens and completed questionnaires. We have received 24 urine-soaked diapers from 2-month-old infants, and are expecting 8 more within the next month. We have performed 20 BSID-IIs on 3-month-old infants with 10 more BSID-IIs to be scheduled and performed by the end of July. We have received two urine soaked diapers from 9 month-old infants with the expectation of four more to be arriving by the end of July.
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Future Activities:
The last 6 months of 2003 will be devoted to aggressively recruiting women into the study and obtaining necessary biological specimens and questionnaire information. As infants are born, the effort will shift to receipt of biological specimens from infants as well as neurobehavioral assessments of infants. Analyses for insecticide metabolites will proceed as more samples are obtained.
Journal Articles:
No journal articles submitted with this report: View all 2 publications for this projectSupplemental Keywords:
infants, insecticides, children, biomarkers of exposure, susceptibility, organophosphate., RFA, Health, Scientific Discipline, Toxicology, Genetics, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Children's Health, genetic susceptability, Molecular Biology/Genetics, health effects, sensitive populations, infants, vulnerability, biomarkers, adolescence, health risks, chlorpyrifos, measuring childhood exposure, exposure, neurotoxicity, longitudinal study, endocrine disruptors, children, children's vulnerablity, assessment of exposure, insecticides, neurobehavioral effects, perinatanl exposure, biological markers, developmental disorders, genetic susceptibility, organophosphate pesticides, environmental hazard exposuresRelevant Websites:
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.