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Genetic and environmental risk factors contribute to the pathogenesis of Alzheimer's dementia. Besides known genetic risk factors like the apolipoprotein (APO) Eε4 allele, single nuclear polymorphisms (SNPs) of the estrogen receptors (ESRs) are candidate genetic risk factors, while air pollution represents an environmental risk factor for dementia. Effects of these risk factors and their interaction were investigated in the SALIA cohort of 834 non-demented elderly women. Cognitive function was assessed by the CERAD-plus test battery. Air pollution was estimated by land use regression (LUR) models. Genotyping was carried out for nine ESR1 and ESR2 SNPs and two ApoE SNPs. Carriers of minor ESR2 alleles showed significantly reduced cognitive performance in the CERAD total score with most pronounced deficits in semantic memory (rs1256062, rs10144225, and rs2274705) and executive function (rs1256062). The minor allele effects of ESR2 were stronger in carriers of APOEε4 for the cognitive domain 'executive function' (p value of interaction 0.023 for rs1256062). The investigated ESR1 SNPs were not associated with cognition. Furthermore, we found a significant gene-environment interaction between the ESR2 SNP rs1256062 and air pollution on cognition. Carriers of two major alleles of rs1256062 were more susceptible for an air pollution-induced decrease in performance of 'figure copying' than carriers of minor alleles (p value of interaction, e.g., 0.031 for PM 2.5 ). In conclusion, ESR2 but not ESR1 minor alleles were associated with lower cognitive performance in elderly women with an indication of a gene-gene interaction with APOEε4. We also found indications for gene-environment interactions of ESR2 with traffic-related air pollution exposure on cognitive performance.

Objective: Risk-assessment for environmental odors and the development of an appropriate guideline for protection against undue odor annoyance have long been hampered by the difficulties of assessing odor exposure and community annoyance responses. In recent years, however, dose-response associations between frequency of odor events and odor annoyance level in the affected population were established. However, the influence of hedonic tone (pleasantness-unpleasantness) and perceived odor strength (intensity) on the degree of odor annoyance have long been neglected in such studies and accompanying guidelines. In order to close this gap a pertinent field study was conducted in the vicinity of six odor emitting plants, two with pleasant (sweets production, rusk bakery), with neutral (textile production, seed oil production), and with presumably unpleasant odor emissions (fat refinery, cast iron production)., Methods: A standardized sensory method was developed (described in Part I in the accompanying paper) to quantify intensity and hedonic tone within the assessment of odor exposure by systematic field inspection with trained observers. Additionally, exposure-information, the degree of annoyance, and the frequency of general health complaints and irritation symptoms were collected from the exposed residents through direct interviews. Multiple logistic regression analysis was used to establish dose-response associations between odor frequency, intensity and hedonic tone as independent variables and annoyance or symptom reporting as the dependent variable., Results: It is shown that exposure-annoyance as well as exposure-symptom associations are strongly influenced by odor hedonic. Whereas pleasant odors induced little to no annoyance, both neutral and unpleasant ones did. Additional inclusion of odor intensity did not improve the prediction of odor annoyance. Frequency of reported symptoms was found to be exclusively mediated by annoyance. The results are discussed in terms of environmental stress emphasizing the WHO-definition of health., Conclusions: Based on these findings the existing German guideline against undue odor annoyance was modified.

The uptake of respirable quartz particles by alveolar macrophages (AM) is believed to cause an inflammatory response, which is discussed as a crucial step in quartz pathogenicity. However, little is known about the mechanism and the relevance of particle uptake. Therefore, the aim of this study was to analyze the role of the actin cytoskeleton in quartz particle uptake, reactive oxygen species generation (ROS) and tumour necrosis factor alpha (TNF-alpha) release. Primary rat alveolar and interstitial macrophages (IM) as well as a rat alveolar macrophage cell line (NR8383) were treated with quartz particles at various concentrations and time intervals. Particle uptake was studied using flow cytometry and light/fluorescence microscopy to analyze particle uptake and cytoskeleton recruitment. Intra- as well as extracellular ROS generation was analyzed by flow cytometry and electron spin resonance (ESR). Flow cytometric investigations demonstrated a dose- and time-dependent particle uptake. Primary AM showed a similar uptake indicating that the cell line provides a good model to investigate the mechanisms of particle uptake while primary IM had a lower uptake rate. Inhibition of actin polymerization using cytochalasin-D caused a significant reduction of particle uptake in NR8383 cells. The quartz induced dose-dependent increase of ROS generation and TNF-alpha release was also blocked by inhibition of actin polymerization. Our results demonstrate an active involvement of the cytoskeleton in uptake of quartz particles and suggest a role of the actin framework and/or the particle uptake in DQ12-induced ROS generation and cytokine release.

When comparing neurobehavioural observations from occupational lead-exposure of adults on the one hand, and environmental lead exposure of children on the other, it appears that the developing relative to the mature brain is more at risk. Neurobehavioural toxicity in occupational lead-exposure has typically not been observed at blood lead-concentrations (PbBs) below 400 micrograms/l, whereas ih environmentally exposed children such deficit has been reported to occur down to PbB of 100-150 micrograms/l and, perhaps, even below this range. Both cross-sectional and prospective studies have arrived at similar conclusions in this respect. The preferred endpoint in most such studies has been the IQ-measure, which has good psychometric qualities, is sufficiently well standardized to be comparable across studies, and exhibits attractive simplicity for the regulator in a public health context. At the same time, however, this IQ-focus has also interfered with systematic efforts to identify more specific lead-induced functional deficits by means of more detailed neurobehavioural analyses (Bellinger 1995). Metanalyses on both cross sectional and prospective studies in lead-exposed children have concluded that a typical doubling of PbB from 100 to 200 micrograms/l is associated with an average IQ-loss of 1-3 points (Pocock et al. 1994; WHO 1995), and no threshold has as yet been identified. Since, however, cause-effect contingencies necessarily remain doubtful in epidemiological studies if the observed effects are as subtle as these, experimental studies in animals have become helpful in supporting the causative role of lead to produce neurobehavioural deficit at steady-state PbB down to about 150 to 200 micrograms/l. Such deficit has been demonstrated by means of a variety of learning/memory models with positive and negative reinforcement contingencies in the rat--and in primates as well. It has also been shown in such studies that neurobehavioural deficit subsequent to early developmental exposure extends long into adulthood after cessation of exposure at weaning. It, therefore, appears that the neurobehavioural teratology of lead has more convincingly been demonstrated in animal models than in human exposure conditions, so far. A coherent theory to explain the particular vulnerability to lead of the developing brain is still lacking. Recent data do suggest, however, that Pb-induced disruption of calcium homeostasis in the immature brain might interfere with normal brain development.

In the isolated phrenic nerve-hemidiaphragm preparation from the rat, thallium acetate induced a dose-dependent irreversible paralysis. There was a major time lag between the onset of the exposure and the decline in the indirectly elicited muscle twitches. The slope of the decline was in proportion to the applied concentration, which ranged from 1 X 10(-3) to 5 X 10(-6) mol/l. The paralysis was definitively manifest after approximately 40 min of incubation. In the phase of paralysis, both electrical stimulation of the muscle and chemical stimulation by addition of K+ were fully effective. However, addition of 4-aminopyridine and/or guanidine restored the indirect muscle twitches, indicating a previous reduction of synaptic activity by thallium. Lowering the Ca2+-concentration resulted in a reduced paralysis time. From these results it is suggested that thallium interferes with synaptic transmission by presynaptically antagonizing Ca2+-dependent processes.

Frequencies and amplitudes of miniature endplate potentials (MEPP's) were recorded from neuromuscular junctions of the rat phrenic nerve-diaphragm preparation in vitro. Superfusion of the preparations with Ringer solution containing thallium acetate (Tlac) gradually increased the frequency of MEPP's by a factor of 10 within 30 min (1 X 10(-3) mol/l Tlac) and 180 min (5 X 10(-4) mol/l Tlac), whereas the amplitude of MEPP's remained unchanged. Frequency of MEPP's fitted a Poisson-distribution which persisted during superfusion with Tl+-Ringer. Sub-MEPP amplitudes remained unaffected by the action of thallium. It is concluded that thallium interferes presynaptically with spontaneous transmitter release.