Background: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are ...increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment. Objectives: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions: For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.
Effects of interleukin-1
β (bath-applied; 500 pM) on rat hippocampal CA3 pyramidal and dentate granule cells were studied using intracellular microelectrode recording in vitro. In both cell types ...membrane input resistance, resting membrane potential and action potential amplitude remained stable throughout. No change was seen in postsynaptic potentials in granule cells. After blocking excitatory synaptic transmission in CA3 pyramids interleukin-1
β was found to consistently decrease synaptic inhibition by about 30%.
S-Methylcysteine (SMC) is formed after exposure to monohalomethanes in rodents as well as in humans. The present study was performed to study whether SMC, directly or indirectly, contributes to the ...well-known neurotoxicity of monohalomethanes. We have investigated the effects of acute exposure to SMC by means of electrophysiolocal measurements in freshly prepared hippocampal slices and dissociated hippocampal neurons in culture. For longer-term exposures (24
h) we have used organotypic cultures (2 weeks in culture), taking electrophysiologic recordings and assessing membrane integrity with propidium iodide (PI) fluorescence. We found that only high concentrations of SMC (10
−2
M; exposure time 30
min) in freshly isolated slices of adult rats reduce synaptically evoked population spikes in the CA1 region. This effect was at least partially reversible. In organotypic cultures, at 5×10
−5
M after 24
h of exposure, SMC compromises membrane integrity as revealed by PI fluorescence, only in the dentate gyrus, spreading to pyramidal cell layers at 5×10
−4
M. At 5×10
−6 and 2×10
−5
M, under the same experimental conditions, no changes were seen with the PI method, but we recorded increased population spike amplitudes, repetitive discharges and frequency potentiation (at a stimulus repetition rate of 0.05
Hz). Using whole-cell patch clamp in hippocampal dissociated neurons we have found that SMC (applied for approximately 1
s) reduces GABA-induced currents (IC
50=4.4×10
−4
M) without having an effect of its own, acting like a competitive antagonist at GABA
A receptors. Our findings are in line with the view that the ability of monohalomethanes to induce the formation of SMC is an important factor for their neurotoxicity, provided that SMC is allowed to act at least for several hours. The effects exerted by SMC seem to be due, at least in part, to its interaction with GABA receptors.
In his letter, Rhomberg raises several issues concerning recommendations in our report of the workshop "Issues and Approaches to Low Dose-Response Extrapolation for Environmental Health Risk ...Assessment" (White et al. 2009). One recommendation of the workshop was to set aside the generally held presumption that dose--response functions should follow a threshold model when extrapolating from higher dose studies of non-carcinogenic responses to lower dose levels typical for environmental exposures to chemicals. Workshop participants generally concluded that the selection of population-level low-dose extrapolation models should be informed by population factors such as interindividual variability in susceptibility and coexposures, as well as by categorization of mechanisms of toxicity. As indicated in the meeting report (White et al. 2009), most workshop participants preferred a linear, no-threshold approach to low-dose extrapolation modeling, combined with modeled estimates of the low range of observed data, for noncancer, as well as cancer, outcomes in the absence of convincing evidence to indicate that an alternative model is more appropriate. We recognize that this recommendation represents a departure from current generally accepted practice.
Effects of the antiepileptic drug sodium valproate (VPA) were studied on neocortical pyramidal cells (layer II/III) of the rat in vitro by intracellular recording. VPA (0.1-1 mM) in a dose-related ...manner suppressed the characteristic transient depolarizations induced by N-methyl-D-aspartate (NMDA) applied iontophoretically Higher concentrations of VPA (5-10 mM) also reduced L-glutamate responses. At these concentrations VPA increased the duration of orthodromically evoked inhibitory postsynaptic potentials and reduced repetitive spike firing induced by depolarizing currents. All effects were fully reversible within about 30 min. These results suggest that an essential mode of action for the anticonvulsant VPA is the attenuation of NMDA receptor-mediated excitation.
Dichlorvos is the active molecule of the pro-drug metrifonate used to revert the cognitive deficits associated with Alzheimer's disease. A few years ago it was reported that dichlorvos inhibits the ...enzyme acylpeptide hydrolase at lower doses than those necessary to inhibit acetylcholinesterase to the same extent. Therefore, the aim of our investigation was to test the hypothesis that dichlorvos can enhance synaptic efficacy through a mechanism that involves acylpeptide hydrolase instead of acetylcholinesterase inhibition. We used long-term potentiation induced in rat hippocampal slices as a model of synaptic plasticity. Our results indicate that short-term exposures (20 min) to 50 kM dichlorvos enhance long-term potentiation in about 200% compared to the control condition. This effect is correlated with approximately 60% inhibition of acylpeptide hydrolase activity, whereas acetylcholinesterase activity remains unaffected. Paired-pulse facilitation and inhibition experiments indicate that dichlorvos does not have any presynaptic effect in the CA3->CA1 pathway nor affect gabaergic interneurons. Interestingly, the application of 100 nM methyllicaconitine, an a sub(7) nicotinic receptor antagonist, blocked the enhancing effect of dichlorvos on long-term potentiation. These results indicate that under the exposure conditions described above, dichlorvos enhances long-term potentiation through a postsynaptic mechanism that involves (a) the inhibition of the enzyme acylpeptide hydrolase and (b) the modulation of a sub(7) nicotinic receptors.
Bisphenol A: developmental toxicity from early prenatal exposurea Golub, Mari S.; Wu, Katherine Lily; Kaufman, Farla L. ...
Birth defects research. Part B. Developmental and reproductive toxicology,
December 2010, 2010-12-00, Letnik:
89, Številka:
6
Journal Article
The body's response to a persistent oxalate challenge is poorly understood. Here we report that calcium (measured by atomic absorbance spectrometry) increases in kidneys in rats exposed to a ...persistent challenge of 360 mumole/d oxalate for 13D. Time dependent increases in renal concentrations of oxalate and calcium occurred for exposures of 12hr to 13D (p'0.02), but these oxalate and calcium concentrations were not intercorrelated (p = 0.8). Since the calcium concentration was always at least five fold the oxalate concentration, it is unlikely that the entire calcium increase was due to its incorporation into calcium oxalate crystals.
Chromium(VI) Ingestion and Cancer Beaumont, James J; Sedman, Richard M; Sandy, Martha S ...
Epidemiology (Cambridge, Mass.),
2009-July, 2009-07-00, Letnik:
20, Številka:
4
Journal Article
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