David Otto's History of EPA Research in Behavioral Toxicology Background/Role at EPA After completing graduate studies in Physiological Psychology at Stanford University, I was hired by EPA in 1972 to study the neurobehavioral effects of air pollutants, focussing first on carbon monoxide. Since that time I have investigated the neurobehavioral effects of lead, organophosphorus pesticides, volatile organic compounds and arsenic in drinking water. I have worked throughout this time in the Chapel Hill Human Studies Facility, although I have been assigned administratively to three different divisions–Inhalation Toxicology (1972-1980), Neurotoxicology (1981-1988), and Human Studies (1989-present). I also served two years as a Special Assistant to the Associate Director for Health (1997-98) on the US-Mexican Border XXI Program. Relationship of Research to the Mission of EPA I was hired (with Vernon Benignus) to establish a Neurobehavioral Research Laboratory to conduct controlled exposure inhalation studies in humans. Our first assignment was to replicate a classical study (1) on the behavioral effects of carbon monoxide exposure. Beard and Wertheim reported impaired vigilance performance in humans at 5% carboxyhemoglobin, an important finding that the agency wanted to use as a basis for the CO exposure standard, but the data required independent confirmation. This study was also an early and important stimulus for the fledgling field of Human Behavioral Toxicology. We failed to replicate the Beard and Wertheimer results (2) and unequivocally demonstrated that there are no reliable neurobehavioral effects of CO below 20% carboxyhemoglobin level. Although negative findings are as important as positive findings in setting air quality standards, our early work on the health effects of carbon monoxide did not endear us in the hearts of behavioral toxicologists! One of the objectives of EPA is to identify subgroups in the general population who are most susceptible to pollutant exposure. Children are often considered to be a susceptible subgroup due to immature nervous systems and high risk behavior such as putting inappropriate things in their mouths. One of the goals of my work has been to identify or develop methods to study the effects of chemical exposure in young children. EPA’s need to establish ambient air quality standards for lead exposure provided the impetus for my initial efforts. I developed a mobile testing laboratory (3) and innovative electrophysiological methods (4) to study the effects of lead exposure in North Carolina children. A series of collaborative studies with the University of North Carolina (5) contributed to EPA’s regulatory needs and CDC’s successive lowering of the level of concern from 30 ug/dl when we initiated the studies in 1978 to the present level of 10 ug/dl. In the first study, I devised a slow potential conditioning paradigm that could be used with children as young as one year old. A follow-up study (6) provided the first evidence that low-level lead exposure impairs auditory function in children. This study also demonstrated the feasibility of using brainstem auditory and pattern-reversal evoked potentials to evaluate the sensory effects of chemical exposure in young children. Joel Schwartz and I later extended our understanding of the auditory effects of lead using data from NHANES II (7) and HISPANIC HANES (8) to show that hearing thresholds increase systematically with blood lead levels. These findings have been replicated by several other investigators (9). Amendments to the Clean Air Act (10) authorized EPA to study the health effects of indoor air. In 1986 I was asked to develop methods to study the neurobehavioral effects of controlled exposure to a complex mixture of volatile organic compounds commonly found in new buildings. My initial objective was to replicate the important study by Lars Molhave (11) which reported eye, nose and throat irritation and impaired memory after controlled exposure to a mixture of VOCs equivalent to 7 ppm toluene. With the consultation of Dr. Molhave, a VOC generator was constructed in the Human Studies Facility (HSF) and a rigorous replication study was carried out. We confirmed the subjective irritation findings, but did not find any evidence of memory impairment or other objective performance decrement (12). A follow-up study demonstrated the differential time course of odor threshold and other sensory symptoms elicited by VOC mixtures (13). This finding contributed significant evidence that eye and nose irritation, headache and drowsiness could not be explained simply as an aversive response to odor, a popular hypothesis at the time. A third study (14) showed that women do not express more discomfort than men when exposed to VOCs under controlled conditions, contrary to symptom reports from occupants of “sick” buildings. With the demise of Communism in Eastern Europe, interesting opportunities for environmental health studies emerged. In 1990 EPA initiated a multidisciplinary collaborative project with the Czech government to study the health effects of exposure to air pollutants resulting from the combustion of soft brown coal in Northern Bohemia. Monitoring data from the coal mining district of Teplice indicated high concentrations of fine particles, SO2, NOx, genotoxic organic compounds and toxic trace metals. Existing data also suggested an unusually high prevalence of learning disabilities in school children from Teplice. I coordinated a series of neurobehavioral studies of Czech school children over the next five years, comparing the performance and prevalence of learning disabilities in children from three different districts–Teplice, Prachatice--an agricultural control district in Southern Bohemia, and Znojmo-- a city in Southern Moravia where natural gas is used for heating and power generation (control district 2). Assessments included computerized neurobehavioral tests and visual tests of acuity and contrast sensitivity. Cohorts of children in the 2nd, 4th, 7th and 8th grades were tested. Hair and urine samples were obtained and used to assess exposure to arsenic and mercury. Teacher questionnaires confirmed that more than twice as many students were referred for assessment of learning disabilities in Teplice than in Prachatice or Znojmo. Although district differences in neurobehavioral performance were found in the 7th and 8th grade cohorts (15)–i.e., the worst performance was found in children from the highly polluted district of Teplice, no consistent association of performance and biological measures of arsenic or mercury was found because the levels of these neurotoxicants were very low. While we were unable to link neurobehavioral performance to any specific pollutant, the results indicate that living in an environment containing high levels of air pollutants is associated with increased prevalence of learning disabilities and reduced cognitive performance. Impact and Recognition of Research I have been invited to speak at more than 60 local, national and international meetings about research on lead, indoor air and neurobehavioral assessment methods (see vita). I was a contributing author on the Air Quality Criteria for Lead document and the Neurotoxicity Risk Assesment Guidelines, served as an EPA advisor to the National Center for Health Statistics on NHANES III and IV, and have served on study sections for EPA, DVA and NIOSH. I have organized and edited proceedings of international (4th Int Conf on Event-Related Slow Potentials of the Brain, 1976) (16) and national (Workshop on Neurotoxicity Testing in Human Populations, 1983) (17) meetings and served on the organizing committee and co-edited proceedings of other international (1st Int. Neurotoxicol Assoc Meeting, 1987; Symposium on Computerized Behavioral Testing of Humans in Neurotoxicity Research, 1995) and national (Workshop on the Assessment of Health Effects of Pesticide Exposure in Young Children, 1997) (18) meetings. My pioneering efforts in applying sensory evoked potential methods in the study of pediatric lead poisoning have been emulated in German, Danish, Israeli and Mexican studies of lead, mercury and other chemicals. I was invited to speak on the use of sensory evoked potentials in neurotoxicity testing at the first meeting of the International Neurotoxicology Association in 1987 (19) and at the 4th Int. Symposium on Neurobehavioral Methods and Effects in 1991 (20). In 1991 I assisted the Agency for Toxic Sunstances and Disease Registry in developing the Pediatric Environmental Neurobehavioral Test Battery (PENTB) (21) and have served as an advisor on the implementation of this battery. My work during the next decade focussed on the application of computer-assisted neurobehavioral tests in neurotoxicology, particularly in pediatric populations. A description of the Neurobehavioral Evaluation System (NES) in the proceedings of the Quail Roost Workshop (22) introduced this test battery to the occupational and environmental health community. Since then, NES has become the most widely used computer-assisted neurotoxicity test battery in the world. In preparation for NHANES III, we demonstrated the feasibility of using computerized tests to assess psychomotor function in children (23). NCHS included three NES2 tests in the adult portion of NHANES III. Many other computer-assisted batteries have been introduced during the past 15 years. Most of these batteries are described in the proceedings of the Portland Symposium (24) which is a basic source document for the current state-of-the art in computer-assisted neurotoxicity testing. I received three Scientific and Technological Achievement Awards from EPA: (1) 1982 “in recognition of excellent scientific accomplishments in environmental health research”; (2) 1988 for “enhancing knowledge of lead effects on hearing thresholds and neurobehavioral development in children”; and (3) 1992 for “contributions in understanding the health effects of indoor air pollutants/volatile organic compounds”. I also received Special Achievement Awards from EPA for editing the EPIC IV proceedings (1980); contributions to MTBE research (1993), Northern Bohemia Health /Studies (1993), and contributions to the US-Mexican Border XXI Program (1997, 1998). In 2000 I received an EPA Silver Medal “in recognition of scientific expertise and national leadership in developing the EPA Guidelines for Neurotoxicity Risk Assessment” and in 2004 I received an EPA Bronze Medal for neurobehavioral contributions in the Czech Air Pollution Studies. Current Research (1) Neurobehavioral Effects of Arsenic Exposure. Peripheral neuropathy is a classical symptom of arsenic poisoning. The usual method of evaluating peripheral nerve function is to measure nerve conduction velocity. NCV testing requires expensive equipment, highly trained professionals, and is an invasive, painful procedure. Assessment of vibration thresholds with a vibrothesiometer is an alternative noninvasive, painless and sensitive method to assess peripheral nerve function. I have been using measures of vibration thresholds in the Inner Mongolian Arsenic Study (IMAS). Farmers exposed to arsenic in China also complained of visual and auditory problems. Three visual measures were used in the initial Inner Mongolian Study: acuity, contrast sensitivity, and color discrimination. Results of the Inner Mongolian Arsenic Study (P54,P55) showed that vibration thresholds increased significantly in subjects in the high arsenic exposure group. Regression analysis indicated that the threshold for the effect of arsenic in drinking water is about 140 µg/l, well below the 1000 µg/l threshold for neurological effects specified by the National Research Council (1999). Case reports of arsenic poisoning also include CNS symptoms such as impaired memory and attention, but only one psychometric study has been reported. Dr. Youxin Liang at the Shanghai Medical University has developed a Chinese version of the NES. I have proposed the use of either a modified version of NES-C3 or traditional psychometric tests to determine if arsenic in drinking water is associated with cognitive dysfunction for a later stage of IMAS. In 2000 EPA recommended lowering the current MAC for arsenic in drinking water from 50 to 10 µg/l. This action was controversial since it put many communities out of compliance. The arsenic team initiated studies in 2000 in Fallon, Nevada where arsenic levels in the municipal drinking water are about 100 mg/l (double the current U.S. standard) and levels in some rural homes are as high as 200 mg/l. A brief smell identification test was administered in the this study at my suggestion. A recent report of impaired cognitive function in Thai school children exposed to arsenic in drinking water (25) suggests the possibility that arsenic may affect children’s IQ in a manner similar to lead. If an appropriate population of arsenic exposed children in the U.S. can be identified, a replication of the Thai psychometric study will be undertaken. (2) Neurobehavioral Effects of Pesticide Exposure in Young Children. The Office of Children’s Health and the Environmental Health Work Group of the US-Mexican Border XXI Program have identified the health effects of pesticide exposure in children as a high priority research area. Unlike other neurotoxic chemicals, pesticides are specifically designed to impair nervous system function. Considerable information is available on the effects of acute, high-level exposure to pesticides, but little information is available about chronic, low-level exposure in humans, particularly in children. Investigation of the health effects of chronic, low-level multisource and multimedia exposure of young children to organophosphorus pesticides is the basic objective of the Border XXI Pesticides in Children Research Team (B21PCT). There are many challenges confronting this area of research including the difficulty of obtaining valid biological measures of exposure to chemicals with a very short half-life, the difficulty of assessing neurobehavioral function in young children, and the dearth of good methods to assess neurobehavioral function in this population. The first phase of the B21PCT was to assess existing data on pesticide exposure along the US-Mexican border and to hold a workshop to assess available methodology to study health effects from pesticide exposure in young children. I took the lead in organizing this workshop and editing the proceedings (18). I was also a member of the North Carolina Birth Cohort Team (led by Pauline Mendola) which will be conducting a longitudinal multidisciplinary study of children to determine the effects of air pollutants and pesticides on neurobehavioral, pulmonary and immunological function. Efforts of these three teams will all contribute to characterizing the neurotoxicological effects of chronic pesticide exposure in children. References (see CV) Px: Peer-reviewed publication Bx: Book chapter, proceeding, monograph Ox: Other reports 1. Beard RR, Wertheim GA. (1967). Behavioral impairment associated with small doses of carbon monoxide. AmJPubHlth, 57:2012-2022. 2. P7, P8, B9 3. P18, B25 4. P9, P12, P14, O3 5. P10-12, P14, P16-18, P21, P26; B12-B14, B17, B21-23, O3-O5 6. P9, B21 7. P23 8. P30 9. P38 10. Title IV of the Superfund Amendments and Reauthorization Act of 1986. 11. Molhave L, Bach B, Pedersen OF (1986). Human reactions to low concentrations of volatile organic compounds. EnvironIntl, 12:167-175. 12. P27, P32-35, B28, B29, O9 13. B32 14. B31 15. P41, PI43, P46, P48, B34 16. B6 17. B18-B20 18. Otto D, Calderon R, Hilborn E, Mendola P (eds). Assessment of health effects of pesticide exposure in young children: Proceedings of a workshop held in El Paso, Texas in December, 1997. EPA Report 600/R-99/086, May 2000. 19. P24 20. P37 21. P39 22. B18 23. P31, O6, O8 24. B33 25. Siripatayakunkit U. Association between chronic arsenic exposure and children’s intelligence in Thailand. In WR Chappell, CO Abernathy, RL Calderon (eds) Arsenic Exposure and Health Effects. Elsevier, New York, 1999, pp141-149. 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