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Jane Ellen Simmons

Publications and source records attributed to Jane Ellen Simmons.

9 recordsLinked to original sources
PubMed2006

Neurotoxicological interactions of a five-pesticide mixture in preweanling rats.

The estimation of risk following exposure to mixtures is an important feature of pesticide risk assessment. Also of concern is the potential for increased sensitivity of the young to pesticide toxicity. We have conducted interaction studies using a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion) in both adult (published previously) and preweanling rats using a fixed-ratio ray design. In the present study, cholinesterase inhibition and behavioral changes (motor activity, gait, and tail-pinch response) were measured in 17-day-old Long-Evans male rats following acute exposure to the OPs. The ratio of pesticides in the mixture reflected the relative dietary exposure estimates projected by the U.S. Environmental Protection Agency Dietary Exposure Evaluation Model. Dose-response data were collected for each OP alone, which were used (alone or in conjunction with the mixture data) to build an additivity model to predict the effects of the pesticide mixture along a ray of increasing total doses, using the same fixed ratio of components. The mixture data (full ray) were similarly modeled and statistically compared to the additivity model along the ray. Since malathion has been shown to produce synergistic interactions with certain OPs, it was of interest to evaluate the influence of malathion in this study. A second pesticide mixture, without malathion (reduced ray), was tested using the same dose levels of the remaining four OPs. Analysis of the full ray revealed significant greater-than-additive responses for all endpoints. The magnitude of this shift ranged from two- to threefold for estimates of the ED(20) and ED(50). The deviation from additivity was also detected in the reduced ray for all but two endpoints (motor activity and tail-pinch response); however, for all endpoints, the reduced ray was significantly different from the full ray. Thus, greater-than-additive responses were detected in preweanling rats with this OP mixture, and this effect can only partially be attributed to the malathion in the mixture.

Animals↗
PubMed2005

D-optimal experimental designs to test for departure from additivity in a fixed-ratio mixture ray.

Traditional factorial designs for evaluating interactions among chemicals in a mixture may be prohibitive when the number of chemicals is large. Using a mixture of chemicals with a fixed ratio (mixture ray) results in an economical design that allows estimation of additivity or nonadditive interaction for a mixture of interest. This methodology is extended easily to a mixture with a large number of chemicals. Optimal experimental conditions can be chosen that result in increased power to detect departures from additivity. Although these designs are used widely for linear models, optimal designs for nonlinear threshold models are less well known. In the present work, the use of D-optimal designs is demonstrated for nonlinear threshold models applied to a fixed-ratio mixture ray. For a fixed sample size, this design criterion selects the experimental doses and number of subjects per dose level that result in minimum variance of the model parameters and thus increased power to detect departures from additivity. An optimal design is illustrated for a 2:1 ratio (chlorpyrifos:carbaryl) mixture experiment. For this example, and in general, the optimal designs for the nonlinear threshold model depend on prior specification of the slope and dose threshold parameters. Use of a D-optimal criterion produces experimental designs with increased power, whereas standard nonoptimal designs with equally spaced dose groups may result in low power if the active range or threshold is missed.

Animals↗
PubMed2005

Momentary brain concentration of trichloroethylene predicts the effects on rat visual function.

The relationship between the concentration of trichloroethylene (TCE) in the brain and changes in brain function, indicated by the amplitude of steady-state pattern-elicited visual evoked potentials (VEP), was evaluated in Long-Evans rats. VEPs were recorded from visual cortex following stimulation of the eyes and, thus, reflect the function of the afferent visual pathway and, in broad terms, may be indicative of overall brain function. The concentration of TCE in the brain at the time of VEP testing (i.e., momentary brain concentration) was hypothesized to predict the amplitude of the VEP across a range of inhalation concentrations, both during and after exposure. Awake restrained rats were exposed to clean air or TCE in the following combinations of concentration and duration: 500 ppm (4 h), 1000 ppm (4 h), 2000 (2 h), 3000 ppm (1.3 h), 4000 ppm (1 h), and 5000 ppm (0.8 h). VEPs were recorded several times during the exposure session, and afterward for experimental sessions of less than 4 h total duration (i.e., concentrations from 2000 to 5000 ppm). The sample collection time for each VEP was about 1 min. Brain concentrations of TCE were predicted using a physiologically based pharmacokinetic (PBPK) model. VEP waveforms were submitted to spectral analysis, and the amplitude of the largest response component, occurring at twice the temporal stimulation rate (F2), was measured. Exposure to all air concentrations of TCE in the study reduced F2 amplitude. The reduction of F2 amplitude was proportional to momentary brain TCE concentration during and after exposure. A logistical function fit to the combined data from all exposure conditions described a statistically significant relationship with 95% confidence limits between brain TCE concentration and F2 amplitude. The results support the hypothesis that momentary brain concentration of TCE is an appropriate dose metric to describe the effects of acute TCE inhalation exposure on rat VEPs. The combination of the PBPK model predicting brain TCE concentration from the exposure conditions with the logistical function predicting F2 amplitude from the brain TCE concentration constitute a quantitative exposure-dose-response model describing an acute change in neurological function following exposure to an important hazardous air pollutant.

Animals↗
PubMed2005

Duration adjustment of acute exposure guideline level values for trichloroethylene using a physiologically-based pharmacokinetic model.

Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important. We employed an alternative approach to duration adjustments in which a physiologically-based pharmacokinetic (PBPK) model was used to predict the arterial blood concentrations [TCE(a)] associated with adverse outcomes appropriate for AEGL-1, -2, or -3-level effects. The PBPK model was then used to estimate the atmospheric concentration that produces equivalent [TCE(a)] at each of the AEGL-specific exposure durations. This approach yielded [TCE(a)] values of 4.89 mg/l for AEGL-1, 18.7 mg/l for AEGL-2, and 310 mg/l for AEGL-3. Duration adjustments based on equivalent target tissue doses should provide similar degrees of toxicity protection at different exposure durations.

Animals↗
PubMed2003

Dose-based duration adjustments for the effects of inhaled trichloroethylene on rat visual function.

Risk assessments often must consider exposures that vary over time or for which the exposure duration of concern differs from the available data, and a variety of extrapolation procedures have been devised accordingly. The present experiments explore the relationship(s) between exposure concentration (C) and time (t) to investigate procedures for assessing the risks of short-term solvent exposures. The first hypothesis tested was that the product of C x t would produce a constant health effect (Haber's rule). The second hypothesis tested was that exposure conditions produce effects in proportion to the tissue concentrations created. Awake, adult, male Long-Evans (LE) rats were exposed to trichloroethylene (TCE) vapor in a head-only exposure chamber while pattern onset/offset visual evoked potentials (VEPs) were recorded. Exposure conditions were designed to provide C x t products of 0 ppm/h (0 ppm for 4 h) or 4000 ppm/h created through four exposure scenarios: 1000 ppm for 4 h; 2000 ppm for 2 h; 3000 ppm for 1.3 h; or 4000 ppm for 1h (n = 9-10/concentration). The amplitude of the VEP frequency double component (F2) was decreased significantly by exposure; this decrease was related to C but not to t or to the C x t product, indicating that Haber's rule did not hold. The mean amplitude (+/- SEM in muV) of the F2 component in the control and treatment groups measured 4.4 +/- 0.5 (0 ppm/4 h), 3.1 +/- 0.5 (1000 ppm/4 h), 3.1 +/- 0.4 (2000 ppm/2 h), 2.3 +/- 0.3 (3000 ppm/1.3 h), and 1.9 +/- 0.4 (4000 ppm/1 h). A physiologically based pharmacokinetic (PBPK) model was used to estimate the concentrations of TCE in the brain achieved during each exposure condition. The F2 amplitude of the VEP decreased monotonically as a function of the estimated peak brain concentration but was not related to the area under the curve (AUC) of the brain TCE concentration. In comparison to estimates from the PBPK model, extrapolations based on Haber's rule yielded approximately a 6-fold error in estimated exposure duration when extrapolating across only a 4-fold change in exposure concentration. These results indicate that the use of a linear form of Haber's rule will not predict accurately the risks of acute exposure to TCE, nor will an estimate of AUC of brain TCE. However, an estimate of the brain TCE concentration at the time of VEP testing predicted the effects of TCE across exposure concentrations and durations.

Administration, Inhalation↗
PubMed2002

Development of a research strategy for integrated technology-based toxicological and chemical evaluation of complex mixtures of drinking water disinfection byproducts.

Chemical disinfection of water is a major public health triumph of the 20th century. Dramatic decreases in both morbidity and mortality of waterborne diseases are a direct result of water disinfection. With these important public health benefits comes low-level, chronic exposure to a very large number of disinfection byproducts (DBPs), chemicals formed through reaction of the chemical disinfectant with naturally occurring inorganic and organic material in the source water. This article provides an overview of joint research planning by scientists residing within the various organizations of the U.S. Environmental Protection Agency Office of Research and Development. The purpose is to address concerns related to potential health effects from exposure to DBPs that cannot be addressed directly from toxicological studies of individual DBPs or simple DBP mixtures. Two factors motivate the need for such an investigation of complex mixtures of DBPs: a) a significant amount of the material that makes up the total organic halide and total organic carbon portions of the DBPs has not been identified; and b) epidemiologic data, although not conclusive, are suggestive of potential developmental, reproductive, or carcinogenic health effects in humans exposed to DBPs. The plan is being developed and the experiments necessary to determine the feasibility of its implementation are being conducted by scientists from the National Health and Environmental Effects Research Laboratory, the National Risk Management Research Laboratory, the National Exposure Research Laboratory, and the National Center for Environmental Assessment.

Chemistry Techniques, Analytical↗
PubMedDate not supplied

Component-based and whole-mixture techniques for addressing the toxicity of drinking-water disinfection by-product mixtures.

Chemical disinfection of water is of direct public health benefit as it results in decreased water-borne illness. The chemicals used to disinfect water react with naturally occurring organic matter, bromide, and iodide in the source water, resulting in the formation of disinfection by-products (DBPs). Despite the identification of several hundred DBPs, more than 50% of the mass of total organic halide formed during chlorination remains unidentified. The toxic contribution of the DBPs that are formed and present but not yet chemically identified, the unidentified fraction, has been largely unexplored. A better understanding of the potential for adverse human health consequences associated with exposure to the DBPs present in drinking water will be gained by integration of knowledge on the toxicity of individual DBPs; simple, defined DBP mixtures; complex, environmentally realistic DBP mixtures with partial chemical characterization; and the unidentified fraction.

Chlorine Compounds↗
PubMedDate not supplied

Moving from external exposure concentration to internal dose: duration extrapolation based on physiologically based pharmacokinetic derived estimates of internal dose.

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C(n) (the ten Berge modification) x t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.

Computer Simulation↗