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Biomedical subjects

S Padilla

Publications and source records attributed to S Padilla.

At least 19 recordsLinked to original sources
PubMed2000

Gentamicin release from hydroxyapatite/poly(ethyl methacrylate)/poly(methyl methacrylate)composites.

In this work the release kinetics of gentamicin sulfate (GEN) in samples composed by hydroxyapatite, poly(methyl methacrylate), and poly(ethyl methacrylate) has been studied. The release study was performed by soaking three samples in simulated body fluid at 37 degrees C; the medium was periodically replaced during 70 days. The concentration of GEN was determined by the o-phtaldialdehyde method. The release profile shows three stages: the first stage, occurring during the first 10 h, corresponds to a fast release (nearly 30% of the drug is released in this period). The second stage is slower and includes from the first 10 h to 16 days, releasing 60% of the total amount of GEN. The final stage is the slowest and it takes from 16 to 70 days (10% of GEN is released). The fraction of released GEN versus square root of time can be fitted to a third order polynomial, corresponding with the model proposed by Cobby et al. (J Pharm Sci 1974;63:725-732). The characterization of the samples after the release study shows that a carbonate hydroxyapatite layer has grown on the whole surface of the composites.

Animals↗
PubMed2000

Physiological responses to a 6-d taper in middle-distance runners: influence of training intensity and volume.

PURPOSE: This study examined some physiological and performance responses to a 6-d taper, and the influence of training intensity and volume on these responses. METHODS: After 15 wk of training, 8 well-trained male middle-distance runners were randomly assigned to either a moderate volume taper (MVT, N = 4) or a low volume taper (LVT, N = 4), consisting of either a 50% or a 75% progressive reduction in pretaper low intensity continuous training (LICT) and high intensity interval training (HIIT). Blood samples were obtained and 800-m running performance was measured before and after taper. RESULTS: Performance was not significantly enhanced by either taper protocol (post- vs pre-taper times 124.9 +/- 4.5 vs 126.1 +/- 4.2 s with LVT, 126.2 +/- 8.0 vs 125.7 +/- 6.6 s with MVT). For the entire group of 8 subjects, red cell count, hemoglobin (Hb), mean corpuscular volume and mean corpuscular Hb concentration significantly decreased with taper, while reticulocyte count increased. Performance changes for all subjects correlated with changes in postrace peak blood lactate concentration (r = 0.87, P < 0.01). Taper LICT correlated with changes in Hb (r = 0.77), hematocrit (r = 0.81), reticulocyte count (r = 0.73), creatine kinase (r = 0.72), and total testosterone (r = -0.78), and with posttaper red cell distribution width (r = -0.75) and lymphocyte count (r = -0.82). Taper HIIT correlated nonsignificantly with changes in red cell count (r = -0.66) and total testosterone (r = 0.68). CONCLUSION: It is concluded that taper-induced physiological changes in trained middle-distance runners are mainly hematological, and that distinct physiological changes are elicited from LICT and HIIT during taper. Middle-distance runners can progressively reduce their usual training volume by at least 75% during a 6-d taper.

Adolescent↗
PubMed2000

Creatine supplementation and sprint performance in soccer players.

PURPOSE: This investigation examined the effects of creatine (Cr) supplementation on intermittent high-intensity exercise activities specific to competitive soccer. METHODS: On two occasions 7 d apart, 17 highly trained male soccer players performed a counter-movement jump test (CMJT), a repeated sprint test (RST) consisting of six maximal 15-m runs with a 30-s recovery, an intermittent endurance test (IET) consisting of forty 15-s bouts of high-intensity running interspersed by 10-s bouts of low-intensity running, and a recovery CMJT consisting of three jumps. After the initial testing session, players were evenly and randomly included in a CREATINE (5 g of Cr, four times per day for 6 d) or a PLACEBO group (same dosage of maltodextrins) using a double-blind research design. RESULTS: The CREATINE group's average 5-m and 15-m times during the RST were consistently faster after the intervention (0.95 +/- 0.03 vs 0.97 +/- 0.02 s, P < 0.05 and 2.29 +/- 0.08 vs 2.32 +/- 0.07 s, P = 0.07, respectively). Neither group showed significant changes in the CMJT or the IET. The CREATINE group's recovery CMJT performance relative to the resting CMJT remained unchanged postsupplementation, whereas it tended to decrease in the PLACEBO group. CONCLUSION: In conclusion, acute Cr supplementation favorably affected repeated sprint performance and limited the decay in jumping ability after the IET in highly trained soccer players. Intermittent endurance performance was not affected by Cr.

Adult↗
PubMed2000

Exercise intensity during competition time trials in professional road cycling.

PURPOSE: To estimate, upon competition heart rate (HR), exercise intensity during time trials (TT) in professional road cycling. METHODS: Eighteen world-class cyclists completed an incremental laboratory cycling test to assess maximal power output (Wmax), maximal HR (HRmax), onset of blood lactate accumulation (OBLA), lactate threshold (LT), and a HR-power output relationship. An OBLA(ZONE) (HR(OBLA) +/- 3 beats x min(-1)) and a LT(ZONE) (HR(LT) +/- 3 beats x min(-1)) were described. HR was monitored during 12 prologue (<10 km, PTT), 18 short (<40 km, STT), 19 long (>40 km, LTT), eight uphill (UTT), and seven team (TTT) time trials. A HR-power output relationship was computed to estimate each cyclist's power output during TT racing from competition HR. Competition training impulse (TRIMP) values were estimated from HR and race duration. RESULTS: %HRmax were 89+/-3%, 85+/-5%, 80+/-5%, 78+/-3%, and 82+/-2% in PTT, STT, LTT, UTT, and TTT, respectively. The amount of TRIMP were, respectively, 21+/-3, 77+/-23, 122+/-27, 129+/-14, and 146+/-6. Competition HR values relative to HR(OBLA) and HR(LT) were, respectively, 100+/-3%, 114+/-8% in PTT, 95+/-7%, 108+/-9% in STT, 89+/-5%, 103+/-8% in LTT, 87+/-2%, 101+/-5% in UTT, and 91+/-4%, 105+/-11% in TTT. CONCLUSIONS: %HRmax, TRIMP and time distribution around HR(OBLA) and HR(LT) reflected the physiological demands of different TT categories. HR(OBLA) and HR(LT) were accurate intensity markers in events lasting, respectively, < or =30 (PTT and STT) and > or =30 min (LTT, UTT, TTT).

Adult↗
PubMed2000

Scientific approach to the 1-h cycling world record: a case study.

The purpose of this study was to describe the physiological and aerodynamic characteristics and the preparation for a successful attempt to break the 1-h cycling world record. An elite professional road cyclist (30 yr, 188 cm, 81 kg) performed an incremental laboratory test to assess maximal power output (W(max)) and power output (W(OBLA)), estimated speed (V(OBLA)), and heart rate (HR(OBLA)) at the onset of blood lactate accumulation (OBLA). He also completed an incremental velodrome (cycling track) test (VT1), during which V(OBLAVT1) and HR(OBLAVT1) were measured and W(OBLAVT1) was estimated. W(max) was 572 W, W(OBLA) 505 W, V(OBLA) 52.88 km/h, and HR(OBLA) 183 beats/min. V(OBLAVT1), HR(OBLAVT1), and W(OBLAVT1) were 52.7 km/h, 180 beats/min, and 500.6 W, respectively. Drag coefficient and shape coefficient, measured in a wind tunnel, were 0. 244 and 0.65 m(2), respectively. The cyclist set a world record of 53,040 m, with an estimated average power output of 509.5 W. Based on direct laboratory data of the power vs. oxygen uptake relationship for this cyclist, this is slightly higher than the 497. 25 W corresponding to his oxygen uptake at OBLA (5.65 l/min). In conclusion, 1) the 1-h cycling world record is the result of the interaction between physiological and aerodynamic characteristics; and 2) performance in this event can be predicted using mathematical models that integrate the principal performance-determining variables.

Adult↗
PubMed2000

Detraining: loss of training-induced physiological and performance adaptations. Part I: short term insufficient training stimulus.

Detraining is the partial or complete loss of training-induced adaptations, in response to an insufficient training stimulus. Detraining characteristics may be different depending on the duration of training cessation or insufficient training. Short term detraining (less than 4 weeks of insufficient training stimulus) is analysed in part I of this review, whereas part II will deal with long term detraining (more than 4 weeks of insufficient training stimulus). Short term cardiorespiratory detraining is characterised in highly trained athletes by a rapid decline in maximal oxygen uptake (VO2max) and blood volume. Exercise heart rate increases insufficiently to counterbalance the decreased stroke volume, and maximal cardiac output is thus reduced. Ventilatory efficiency and endurance performance are also impaired. These changes are more moderate in recently trained individuals. From a metabolic viewpoint, short term inactivity implies an increased reliance on carbohydrate metabolism during exercise, as shown by a higher exercise respiratory exchange ratio, and lowered lipase activity, GLUT-4 content, glycogen level and lactate threshold. At the muscle level, capillary density and oxidative enzyme activities are reduced. Training-induced changes in fibre cross-sectional area are reversed, but strength performance declines are limited. Hormonal changes include a reduced insulin sensitivity, a possible increase in testosterone and growth hormone levels in strength athletes, and a reversal of short term training-induced adaptations in fluid-electrolyte regulating hormones.

Blood Volume↗
PubMed2000

Detraining: loss of training-induced physiological and performance adaptations. Part II: Long term insufficient training stimulus.

This part II discusses detraining following an insufficient training stimulus period longer than 4 weeks, as well as several strategies that may be useful to avoid its negative impact. The maximal oxygen uptake (VO2max) of athletes declines markedly but remains above control values during long term detraining, whereas recently acquired VO2max gains are completely lost. This is partly due to reduced blood volume, cardiac dimensions and ventilatory efficiency, resulting in lower stroke volume and cardiac output, despite increased heart rates. Endurance performance is accordingly impaired. Resting muscle glycogen levels return to baseline, carbohydrate utilisation increases and the lactate threshold is lowered, although it remains above untrained values in the highly trained. At the muscle level, capillarisation, arterial-venous oxygen difference and oxidative enzyme activities decline in athletes and are completely reversed in recently trained individuals, contributing significantly to the long term loss in VO2max. Oxidative fibre proportion is decreased in endurance athletes, whereas it increases in strength athletes, whose fibre areas are significantly reduced. Force production declines slowly, and usually remains above control values for very long periods. All these negative effects can be avoided or limited by reduced training strategies, as long as training intensity is maintained and frequency reduced only moderately. On the other hand, training volume can be markedly reduced. Cross-training may also be effective in maintaining training-induced adaptations. Athletes should use similar-mode exercise, but moderately trained individuals could also benefit from dissimilar-mode cross-training. Finally, the existence of a cross-transfer effect between ipsilateral and contralateral limbs should be considered in order to limit detraining during periods of unilateral immobilisation.

Adaptation, Physiological↗
PubMed1999

Gestational exposure to chlorpyrifos: comparative distribution of trichloropyridinol in the fetus and dam.

Chlorpyrifos (O,O'-diethyl O-[3,5,6-trichloro-2-pyridyl] phosphorothionate) is a commonly used anticholinesterase insecticide, and therefore the potential for human exposure is high. The present time course and dose response studies were conducted to delineate the toxicokinetics of chlorpyrifos and its metabolites in the pregnant rat and fetus. Time-pregnant, Long-Evans rats were treated orally with chlorpyrifos during late gestation (Gestational Days 14-18). Following euthanasia the level of chlorpyrifos and its metabolites, chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol (TCP), were measured in both fetal and maternal brain and liver (limits of quantitation: 59.2, 28.8, and 14.0 ng/g tissue, respectively). In addition, cholinesterase inhibition was also measured in the same tissues for comparison. TCP was the only component detected. The highest level of TCP and the lowest level of cholinesterase activity showed the same time of peak effect: 5 h after the last dose. The concentration of TCP in the maternal liver was approximately fivefold higher than the TCP concentration in fetal liver, but, paradoxically, the concentration of TCP in the fetal brain was two- to fourfold higher than the TCP concentration in the maternal brain. The half-life of the TCP was identical in all tissues examined (12-15 h). These toxicokinetic results suggest that the fetal nervous system may be exposed to a higher concentration of chlorpyrifos than the maternal nervous system when the dam is orally exposed to chlorpyrifos during late gestation.

Animals↗
PubMed1999

Gestational exposure to chlorpyrifos: dose response profiles for cholinesterase and carboxylesterase activity.

This study investigates the in vivo dose response profiles of the target enzyme cholinesterase (ChE) and the detoxifying enzymes carboxylesterase (CaE) in the fetal and maternal compartments of pregnant rats dosed with chlorpyrifos [(O,O'-diethyl O-3,5,6-trichloro-2-pyridyl) phosphorothionate], a commonly used organophosphorus insecticide. Pregnant rats were dosed daily (po) with chlorpyrifos in corn oil (0, 3, 5, 7, or 10 mg/kg) on gestational days (GD) 14-18. Animals were sacrificed 5 h after the last chlorpyrifos dose (time of maximum brain cholinesterase inhibition) for analysis of ChE and CaE activity in maternal blood, liver, brain, placenta, and fetal liver and brain. The in vitro sensitivity (i.e., IC50, 30 min, 26 degrees C) of CaE also was determined by assaying the activity remaining after incubation with a range of chlorpyrifos-oxon concentrations. In vivo exposure to 10 mg/kg chlorpyrifos from GD14-18 caused overt maternal toxicity, with dose-related decreases in ChE activity more notable in maternal brain than fetal brain. Dose-related effects were also seen with chlorpyrifos-induced inhibition of fetal liver ChE and maternal brain CaE activities. Gestational exposure caused no inhibition of placental ChE or CaE, fetal brain CaE, or maternal blood CaE. ChE activities in the maternal blood and liver, as well as fetal and maternal liver CaE, however, were maximally inhibited by even the lowest dosage of chlorpyrifos. The in vitro sensitivity profiles of CaE to chlorpyrifos-oxon inhibition were valuable in predicting and verifying the in vivo CaE response profiles. Both the in vivo and in vitro findings indicated that fetal liver CaE inhibition was an extremely sensitive indicator of fetal chlorpyrifos exposure.

Analysis of Variance↗
PubMed1999

Level ground and uphill cycling ability in professional road cycling.

PURPOSE: To evaluate the physiological capacities and performance of professional road cyclists in relation to their morphotype-dependent speciality. METHODS: 24 world-class cyclists, classified as flat terrain (FT, N = 5), time trial (TT, N = 4), all terrain (AT, N = 6). and uphill (UH, N = 9) specialists, completed an incremental laboratory cycling test to assess maximal power output (Wmax), maximal oxygen uptake (VO2max), lactate threshold (LT), and onset of blood lactate accumulation (OBLA). RESULTS: UH had a higher frontal area (FA):body mass (BM) ratio (5.23 +/- 0.09 m2 x kg(-1) x 10(-3)) than FT and TT (P < 0.05). FT showed the highest absolute Wmax (481 +/- 18 W), and UH the highest Wmax relative to BM (6.47 +/- 0.33 W x kg(-1)). WLT and W(OBLA) values were significantly higher in FT (356 +/- 41 and 417 +/- 45 W) and TT (357 +/- 41 and 409 +/- 46 W) than in UH (308 +/- 46 and 356 +/- 41). Scaling of these values relative to FA and BM exponents 0.32 and 0.79 minimized group differences, but considerable differences among mean group values remained. FT and TT had the highest Wmax per FA unit (1300 +/- 62 and 1293 +/- 57 W x m2), whereas TT had the highest absolute W x kg(-0.32) and W x kg(-0.79), as well as W x kg(-0.32), W x kg(-0.79), and W x m2 at the LT and OBLA. CONCLUSIONS: i) Scaling of maximal and submaximal physiological values showed a performance advantage of TT over FT, AT, and UH in all cycling terrains and conditions; and ii) mass exponents of 0.32 and 1 were the most appropriate to evaluate level and uphill cycling ability, respectively, whereas absolute Wmax values are recommended for performance-prediction in short events on level terrain, and W(LT) and W(OBLA) in longer time trials and uphill cycling.

Adult↗
PubMed1998

Rat brain acetylcholinesterase activity: developmental profile and maturational sensitivity to carbamate and organophosphorus inhibitors.

A growing body of evidence indicates that young animals exhibit an increased susceptibility to the lethal effects of cholinesterase (ChE)-inhibiting insecticides. Our laboratory is engaged in defining factors which may explain this age-related sensitivity. This report includes results from experiments designed to compare the developmental profiles, kinetic parameters and intrinsic (i.e. in vitro) sensitivity of developing male rat brain acetylcholinesterase (AChE) activity to carbamate and organophosphorus anticholinesterases. Total ChE activity in whole brain for each age was composed of about 90% AChE and 10% butyrylcholinesterase (BuChE) activity for the six ages examined. Brain AChE activity showed an age-related increase in Vmax until postnatal day 17 with no change in Km (average of all six ages approximately equal to 72 microM). Optimal substrate (acetylthiocholine) concentration for each age was 1 mM, and there was substrate inhibition (approximately 10%) at 2.5 mM. IC50s (the concentration of compound that inhibits 50% of the AChE activity in 30 min at 26 degrees C) defined concomitantly for postnatal day 4 and adult brain AChE using either aldicarb, carbaryl, chlorpyrifos-oxon or malaoxon were virtually identical at both ages with average IC50 values being: aldicarb = 2.4 microM, carbaryl = 1.7 microM, chlorpyrifos-oxon = 4.9 nM and malaoxon = 140 nM. In summary, AChE in young and adult brain differs mostly in specific activity while the Km(s), substrate profiles, and in vitro sensitivity to selected anticholinesterase insecticides are not different. Therefore, these data support the hypothesis that the greater sensitivity of the young animals to anticholinesterase pesticides is not due to the greater sensitivity of the target molecule AChE to these inhibitors.

Acetylcholinesterase↗
PubMed1998

Ontogenetic differences in the regional and cellular acetylcholinesterase and butyrylcholinesterase activity in the rat brain

Considering the novel functions for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the developing nervous system (reviewed in Layer and Willbold, Prog. Histochem. Cytochem., 1995) a quantitative survey of the spatiotemporal developmental profiles of both AChE and BuChE activity in the neonatal rat brain would be extremely useful. To that end, we collected six brain regions at seven developmental time points, (postnatal day 1, 4, 7, 12, 17, 21, adult; n>/=3) and measured AChE and BuChE activity using both biochemical and histological methods. These results indicated that the developmental pattern of AChE and BuChE activity varied with respect to brain region and age: (1) the ontogeny of either AChE or BuChE specific activity in one region was not necessarily indicative of the developmental pattern of the same cholinesterase in other regions; (2) the AChE developmental profile in a given region did not necessarily predict the BuChE developmental pattern for that same region. The data were also analyzed from a different perspective, i.e., the ratio of BuChE-AChE activity, in order to determine if BuChE activity preceded AChE activity during development as has been proposed for the chick nervous system (Layer, Proc. Natl. Acad. Sci. USA, 1983). Our analysis showed that, in general, the BuChE-AChE ratio decreased as the region matured, data which parallel the pattern of development of these esterases in the chick nervous system.

Journal Article↗
PubMed1998

Ontogenetic differences in the regional and cellular acetylcholinesterase and butyrylcholinesterase activity in the rat brain.

Considering the novel functions for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the developing nervous system (reviewed in Layer and Willbold, Prog. Histochem. Cytochem., 1995) a quantitative survey of the spatiotemporal developmental profiles of both AChE and BuChE activity in the neonatal rat brain would be extremely useful. To that end, we collected six brain regions at seven developmental time points, (postnatal day 1, 4, 7, 12, 17, 21, adult; n > or = 3) and measured AChE and BuChE activity using both biochemical and histological methods. These results indicated that the developmental pattern of AChE and BuChE activity varied with respect to brain region and age: (1) the ontogeny of either AChE or BuChE specific activity in one region was not necessarily indicative of the developmental pattern of the same cholinesterase in other regions; (2) the AChE developmental profile in a given region did not necessarily predict the BuChE developmental pattern for that same region. The data were also analyzed from a different perspective, i.e., the ratio of BuChE-AChE activity, in order to determine if BuChE activity preceded AChE activity during development as has been proposed for the chick nervous system (Layer, Proc. Natl. Acad. Sci. USA, 1983). Our analysis showed that, in general, the BuChE-AChE ratio decreased as the region matured, data which parallel the pattern of development of these esterases in the chick nervous system.

Acetylcholinesterase↗
PubMed1998

Comparison of the in vitro sensitivity of rat acetylcholinesterase to chlorpyrifos-oxon: what do tissue IC50 values represent?

The toxicological literature is replete with studies which have attempted to correlate differences in in vivo sensitivity to anticholinesterases with a common in vitro measure: acetylcholinesterase (AChE) IC50 values. Generally, it is assumed that these IC50 values reflect the intrinsic sensitivity of the AChE molecule to the inhibitor. Our goal was to ascertain whether differences in AChe sensitivity to an organophosphate (i.e., IC50 values) are due to varying properties of the enzyme molecule (i.e., present assumption) or to extrinsic factors. Tissue samples were obtained from immature and adult Long-Evans rats. AChE IC50 values were determined by incubating tissue homogenates with chlorpyrifos-oxon (active metabolite of chlorpyrifos, a common organophosphate insecticide) for 30 min at 26 degrees C, and then measuring residual AChE activity. The following IC50 values were noted for postnatal day 4 and adult animals, respectively: brain, 10 nM for both ages; liver, 96 and 527 nM; plasma, 18 and 326 nm. Thus, the "apparent" sensitivity of AChe was prone to vary dramatically with age and tissue type. In contrast, when AChE was isolated from the same tissues by immunoprecipitation, there were no age- or tissue- related differences (IC50 approximately equal to 3 nM in every case). These data show clearly that IC50 values from a crude homogenate do not measure the true sensitivity of AChE to the inhibitor. Presumably, for chlorpyrifos-oxon, at least, the tissue IC50 values depend greatly on a tissue's propensity to sequester or hydrolyze chlorpyrifos-oxon.

Acetylcholinesterase↗
PubMed1998

Age- and gender-related differences in the time course of behavioral and biochemical effects produced by oral chlorpyrifos in rats.

It is well known that young animals are generally more sensitive to lethal effects of cholinesterase-inhibiting pesticides, but there are sparse data comparing less-than-lethal effects. We compared the behavioral and biochemical toxicity of chlorpyrifos in young (postnatal Day 17; PND17) and adult (about 70 days old) rats. First, we established that the magnitude of the age-related differences decreased as the rat matures. Next, we evaluated the time course of a single oral dose of chlorpyrifos in adult and PND17 male and female rats. Behavioral changes were assessed using a functional observational battery (with age-appropriate modifications for pre-weanling rats) and an evaluation of motor activity. Cholinesterase (ChE) activity was measured in brain and peripheral tissues and muscarinic receptor binding assays were conducted on selected tissues. Rats received either vehicle (corn oil) or chlorpyrifos (adult dose: 80 mg/kg; PND17 dose: 15 mg/kg); these doses were equally effective in inhibiting ChE. The rats were tested, and tissues were then taken at 1, 2, 3.5, 6.5, 24, 72, 168, or 336 h after dosing. In adult rats, peak behavioral changes and ChE inhibition occurred in males at 3.5 h after dosing, while in females the onset of functional changes was sooner, the time course was more protracted and recovery was slower. In PND17 rats, maximal behavioral effects and ChE inhibition occurred at 6.5 h after dosing, and there were no gender-related differences. Behavioral changes showed partial to full recovery at 24 to 72 h, whereas ChE inhibition recovered markedly slower. Blood and brain ChE activity in young rats had nearly recovered by 1 week after dosing, whereas brain ChE in adults had not recovered at 2 weeks. Muscarinic-receptor binding assays revealed apparent down-regulation in some brain areas, mostly at 24 and 72 h. PND17 rats generally showed more receptor down-regulation than adults, whereas only adult female rats showed receptor changes in striatal tissue that persisted for 2 weeks. Thus, compared to adults (1) PND17 rats show similar behavioral changes and ChE inhibition although at a five-fold lower dose; (2) the onset of maximal effects is somewhat delayed in the young rats; (3) ChE activity tended to recover more quickly in the young rats; (4) young rats appear to have more extensive muscarinic receptor down-regulation, and (5) young rats show no gender-related differences.

Age Factors↗
PubMed1998

Gestational exposure to chlorpyrifos: apparent protection of the fetus?

Previous studies have shown that, in general, young, postnatal animals are more sensitive than adults to the toxic effects of anticholinesterase (antiChE) pesticides. Paradoxically, often fetal brain cholinesterase (ChE) is less inhibited than maternal brain after gestational exposure to an antiChE, presumably due to placental and fetal detoxification of the antiChE. The present investigation was designed to study selected toxicokinetic and toxicodynamic factors surrounding the toxicity of chlorpyrifos (CPF; [O,O'-diethyl O-3,5,6-trichloro-2-pyridyl] phosphorothionate) in pregnant rats dosed repeatedly or singly during late gestation. Dams were dosed daily (po) with CPF in corn oil (0 or 7 mg/kg) on gestational days (GD) 14 to 18. Animals were euthanized at 2 to 120 h after the last dose and tissues were collected for enzyme analysis. Using this dosing regimen, we found that (1) the time of maximal ChE inhibition was the same (i.e., 5-10 h after dosing) for both maternal and fetal brain, (2) the degree of fetal brain ChE inhibition was 4.7 times less than maternal brain inhibition, and (3) the detoxification potential (i.e., carboxylesterase and chlorpyrifos-oxonase) of the fetal tissues was very low compared to the maternal tissues. A separate group of experiments showed that if pregnant dams received only one oral dose of 7 or 10 mg/kg CPF on GD18, the degree of ChE inhibition in the fetal brain was comparable to the maternal brain ChE inhibition. Taking into consideration the net increase (more than fourfold) in fetal brain ChE activity from GD14 to 18 in control animals, and the fact that maternal brain ChE was inhibited more than fetal brain ChE only in a repeated-dosing regimen, we conclude that the fetus is not genuinely protected from the toxic effects of a given dose of CPF. We propose that fetal brain ChE is simply able to recover more fully between each dose as compared to maternal brain ChE, giving the illusion that the fetal compartment is less affected than the maternal compartment.

Animals↗
PubMed1998

Common mechanism of toxicity: a case study of organophosphorus pesticides.

The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity ... in establishing, modifying, leaving in effect, or revoking a tolerance for a pesticide chemical residue." This directive raises a number of scientific questions to be answered before the FQPA can be implemented. Among these questions is: What constitutes a common mechanism of toxicity? The ILSI Risk Science Institute (RSI) convened a group of experts to examine this and other scientific questions using the organophosphorus (OP) pesticides as the case study. OP pesticides share some characteristics attributed to compounds that act by a common mechanism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothesis, anticholinesterase OP pesticides act by a common mechanism of toxicity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgrouping OP compounds. Some of the alternative hypotheses were rejected outright and the rest were not supported by adequate data. The Working Group concluded that OP pesticides act by a common mechanism of toxicity if they inhibit acetylcholinesterase by phosphorylation and elicit any spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms.

Animals↗