Dennis E. House

Exposure of Humans to a Volatile Organic Mixture. II. Sensory

Time-course functions for symptoms of the sick building syndrome were derived from 66 healthy males who, during separate sessions, were exposed to clean air and to a volatile organic compound (VOC) mixture. The mixture contained 22 VOCs (25 mg/m3 total concentration) commonly found airborne in new or recently renovated buildings. Subjects rated the intensity of perceived irritation, odor, and other variables before, and twice during, 2.75-h exposure periods. Eye and throat irritation, headache, and drowsiness increased or showed no evidence of adaptation during exposure, whereas odor intensity decreased by 30%. These results indicate that irritation intensity and other symptoms are not related in any simple way to odor intensity, which suggests that the symptoms may not be a psychosomatic response to the detection of an aversive odor. Instead, subthreshold levels of VOCs may interact additively or hyperadditively and stimulate trigeminal nerve receptors. Also, air quality ratings improved by 18% during exposure, which suggests that both odor and irritation intensity may influence assessments of air quality.

Neurobehavioral and sensory irritant effects of controlled exposure to a complex mixture of volatile organic compounds

Subjective reactions of discomfort, impaired air quality, irritation of mucosal membranes, and impaired memory have been reported in chemically sensitive subjects during exposure to volatile organic compounds (VOCs) found in new buildings. Sixty-six normal healthy male subjects aged 18-39 were exposed for 2.75 hr to a complex VOC mixture at 0 and 25 mg/m3. Each subject completed control and exposure sessions at one-week intervals in counterbalanced order. Measurements included comfort ratings of eye, nose and throat irritation, symptom questionnaire and computerized behavioral tests. Subjects found the odor of VOCs unpleasantly strong and reported that VOC exposure degraded air quality, increased headache and produced general discomfort. VOC exposure did not affect performance on any behavioral tests.

Neurobehavioral evaluation system (NES): Comparative performance of 2nd-, 4th-, and 8th-grade Czech children

The Neurobehavioral Evaluation System was designed for field studies of workers, but many NES tests can be performed satisfactorily by children as young as 7 or 8 years old and a few tests, such as simple reaction time, can be performed by preschool children. However, little comparative data from children of different ages or grade levels are available. Studies of school children in the Czech Republic indicate that 2nd-grade children could perform the following NES tests satisfactorily: Finger Tapping, Visual Digit Span. Continuous Performance, Symbol-Digit Substitution, Pattern Comparison, and simpler conditions of Switching Attention. Comparative scores of boys and girls from the 2nd, 4th, and 8th grades and power analyses to estimate appropriate sample size were presented. Performance varied systematically with grade level and gender. Larger samples were needed with younger children to achieve comparable levels of statistical power. Gender comparisons indicated that boys responded faster, but made more errors than girls.

Age-dependent effects of Aroclor 1254R on calcium uptake by subcellular organelles in selected brain regions of rats☆

Earlier reports from our laboratory have indicated that polychlorinated biphenyls (PCBs) affect signal transduction mechanisms in brain, including Ca2+ homeostasis, phosphoinositol hydrolysis, and protein kinase C (PKC) translocation in mature neurons and adult brain homogenate preparations. Present studies were designed to investigate whether there were any brain region-, gender-, or age-dependent effects of PCBs on 45Ca2+-uptake by two subcellular organelles, microsomes and mitochondria. We have studied in vitro effects of a widely studied commercial PCB mixture, Aroclor 1254R, on 45Ca2+-uptake by microsomes and mitochondria in cerebellum, frontal cortex and hippocampus of postnatal day (PND) 7, 21, and 90-120 (adult) male and female Long-Evans (LE)-rats. In general, microsomal and mitochondrial 45Ca2+-uptake in selected brain regions increased with age; PND 7<PND 21< or =adults. Among three brain regions, hippocampus had relatively lower microsomal 45Ca2+-uptake than cerebellum and frontal cortex throughout the development. Mitochondrial 45Ca2+-uptake was comparable in three brain regions of PND 7 and adult animals, but in PND 21 rats, the cerebellum had much higher activity than frontal cortex and hippocampus. No gender-related differences were seen in 45Ca2+-uptake by either microsomes or mitochondria in selected brain regions throughout development. Inhibition of 45Ca2+-uptake by Aroclor 1254 in a concentration-dependent manner was observed throughout the study. However, the degree of inhibition of microsomal 45Ca2+-uptake in these brain regions by Aroclor 1254 increased with age, PND 7<PND 21< or =adults (IC50s=21-34, 8-20 and 10-14 microM, respectively). Brain region-specific differential sensitivity to Aroclor 1254 on the inhibition of microsomal 45Ca2+-uptake was not seen in PND 7 and adult animals but in PND 21 rats, hippocampus was more sensitive than the other selected brain regions. There were no age-, gender- or brain region-specific differential effects of Aroclor 1254 on mitochondrial 45Ca2+-uptake. These results indicate that a commercial PCB mixture, Aroclor 1254, inhibited 45Ca2+-uptake by both microsomes and mitochondria uniformly in selected brain regions of males and females during development. However, the inhibition of microsomal 45Ca2+-uptake by Aroclor 1254 increased with age. The age- and gender-related differential sensitivity to Aroclor 1254 may be attributed to the changes in calcium homeostasis in various brain regions during development.

Melatonin enhances junctional transfer in normal C3H/10T1/2 cells☆

Gap junctional intercellular communication is known to be involved in controlling cell proliferation and differentiation, and seems to play a crucial role in suppression of tumor promotion. The pineal gland and its hormone, melatonin, are believed to intervene in the control of neoplastic processes. Several possible mechanisms have been suggested to be potentially responsible for melatonins oncostatic action; however, the actual mechanisms involved in melatonins effects at the cellular level remain unidentified. In the present study low-density cultures of C3H/10T1/2 mouse embryo fibroblasts were incubated until relatively quiescent monolayers were established (17-18 days). Gap junctional intercellular communication in control samples and in cells treated with 10(-12) to 10(-8) M melatonin was determined by the scrape-loading assay using the fluorescent dye Lucifer yellow. The results showed that concentrations of melatonin considered physiological (10(-11) and 10(-10) M) induced a significant increase in the transfer of the dye to adjacent cells through gap junctions; both higher and lower concentrations were ineffective. These results suggest that melatonin could exert its putative oncostatic action, in part, by modulating the levels of gap junctional intercellular communication.

Methanol potentiation of carbon tetrachloride hepatotoxicity: The central role of cytochrome P450

Evidence to explain the enhanced hepatotoxicity of carbon tetrachloride (CCl4) following methanol exposure by inhalation is presented. Hepatic microsomes prepared from male F344 rats exposed to methanol at concentrations up to 10,000 ppm showed increased p-nitrophenol hydroxylase activity but no increase in pentoxyresorufin-O-dealkylase or ethoxyresorufin-O-deethylase activities. Hepatic antioxidant levels, glutathione levels and glutathione-S-transferase activity in methanol-treated animals were not different from controls. In vitro metabolism of CCl4 was also increased in microsomes from methanol-treated animals. Pretreatment with allyl sulfone, a specific chemical inhibitor of cytochrome P450 2E1, abolished the difference in microsomal metabolism between exposed and control animals. This study shows that methanol exposure induces cytochrome P450 2E1, which appears to be the principal toxicokinetic mechanism responsible for the increased metabolism and thus the increased hepatotoxicity of CCl4.

The influence of vision on computerized neurobehavioral test scores: A proposal for improving test protocols☆

Computerized tests of neurobehavioral function are frequently administered in neurotoxicological studies with little attention given to the optical properties of test stimuli or to the vision of subjects. Yet many test stimuli are small or briefly presented, and test endpoints often involve short reaction times. Stimulus detection and reaction time are known to be strongly dependent upon stimulus luminance, contrast, and size, as well as on the subjects visual abilities. The current study assessed the influence of visual contrast sensitivity on Neurobehavioral Evaluation System 2 (NES2) test results in three data sets. Analyses indicated that vision was associated with up to 24% of the variance (Hand Eye Coordination test) in NES2 scores, even when visual acuity was normal, and that vision often influenced the significance of group differences. It is suggested that researchers measure the luminance, contrast, and size of test stimuli, the distance from the subjects eyes to the monitor, and the subjects visual contrast sensitivity. The measurement and control of stimulus parameters and the inclusion of visual function scores in analysis models could reduce the variability among computerized test scores both within and between studies. Models that assess the influence of vision on computerized test results may help to identify the CNS domains and specialized functions adversely affected by neurotoxicant exposures.

Fasting for less than 24 h induces cytochrome P450 2E1 and 2B1/2 activities in rats.

Cytochrome P450 (CYP) 2E1 activity is induced after 24 h of fasting but no information is available for shorter fasting periods. We investigate the induction of CYP 2E1, 2B1/2 and 1A1 in young adult male F344 rats after 8, 16 and 24 h of fasting compared to control. Liver microsomes were analyzed for the following enzyme activities: p-nitrophenol hydroxylase (PNP) for CYP 2E1, pentoxyresorufin-O-dealkylase (PROD) for CYP 2B1/2 and ethoxyresorufin-O-deethylase (EROD) for CYP 1A1. After each fasting interval, the activities per mg microsomal protein for PNP and PROD increased but the activity of EROD remained unchanged. Western blots for CYP 2E1 and CYP 2B1 showed increases comparable to the PNP and PROD activities, respectively. On a whole organ basis, increases were found for PNP and PROD activities, while decreases were found for EROD activity and total microsomal protein. The results are consistent with an induction of CYP 2E1 and CYP 2B1/2 activities after as little as 8 h of fasting.

Defining the neurotoxin derived illness chronic ciguatera using markers of chronic systemic inflammatory disturbances: A case/control study☆

BACKGROUNDnCiguatoxins are extremely potent neurotoxins, produced by tropical marine dinoflagellates, that persistently enter into our food web. Over 100,000 people annually experience acute ciguatera poisoning from consuming toxic fish. Roughly 5% of these victims will develop chronic ciguatera (CC), a widespread, multisymptom, multisystem, chronic illness that can last tens of years. CC is marked by disproportionate disability and non-specific refractory symptoms such as fatigue, cognitive deficits and pain, and is suggestive of other illnesses. Its unknown pathophysiology makes both diagnosis and treatment difficult.nnnOBJECTIVESnWe wanted to compare objective parameters of visual contrast sensitivity testing, measures of innate immune response and genetic markers in cases to controls to assess the potential for the presence of persistent inflammatory parameters that are demonstrated in other biotoxin associated illnesses at a single specialty clinic.nnnMETHODSnUsing 59 CC cases and 59 controls we present in retrospective review, in all cases, abnormalities in immune responses paralleling the chronic systemic inflammatory response syndrome seen in several other chronic diseases.nnnRESULTSnThis study defines a preliminary case definition using medical history, total symptoms, visual contrast sensitivity, HLA DR genotype analysis, reduction of regulatory neuropeptides VIP and MSH, and multiple measures of inflammatory immune response, especially C4a and TGFβ1, thereby providing a basis for identification and targeted therapy.nnnCONCLUSIONSnCC provides a model for chronic human illness associated with initiation of inflammatory responses by biologically produced neurotoxins.

Lead absorption and psychological function in Zagreb (Croatia) school children

A cross-sectional study was performed on 275 pupils from the third and fourth grade of three elementary schools (three urban areas with different traffic conditions) in Zagreb. Lead exposure was environmental, mostly through leaded gasoline. The difference in traffic density around the schools was consistent with biological indicators of lead absorption. The aim of the study was to clarify the relationship between characteristic biological indicators of lead absorption including indicators of hematological status with some psychological functions. Lead absorption in pupils was relatively low (mean blood lead: 70.8 +/- 17.88 microgram/L). Pupils socio-economic status was evaluated by parents education. The results obtained indicate that gender and school were associated with both biological and psychological variables. After adjusting for age, parental education, and gender, lead appears to have no association with cognitive or psycho-motor measures. The nonstandardized regression coefficients for blood lead-as a measure of the size of lead effect on VIQ, NIQ, and IQ-were -0.016, -0.031, and -0.025, respectively, all nonsignificant.