Melita Kosanovic

Interaction of organophosphorus compounds with carboxylesterases in the rat

Abstract Carboxylesterases (CarbE) are involved in detoxication of organophosphorus compounds (OPC) through two mechanisms: hydrolysis of ester bonds in OPC which contain them and binding of OPC at the active site of CarbE which reduces the amount of OPC available for acetylcholinesterase inhibition. This study of the interaction of rat plasma and liver CarbE with dichlorvos, soman and sarin in vitro and in vivo was undertaken in order to contribute to better understanding of the role of CarbE in detoxication of OPC. The results obtained have shown that inhibitory potency (I50) of dichlorvos, sarin and soman towards rat liver CarbE was 0.2 μM, 0.5 μM and 4.5 μM, respectively, for 20-min incubation at 25°C. Second-order rate constants (ka) for liver CarbE inhibition were 2.3×105 M-1 min-1, 6.9×104 M-1 min-1 and 1.1× 104 M-1 min-1 for dichlorvos, sarin and soman, respectively. The corresponding values for plasma CarbE could not be calculated because of dominant spontaneous reactivation of inhibited CarbE. CarbE inhibited with these OPC in vitro spontaneously reactivate with half-times of 18, 143 and 497 min for sarin, dichlorvos and soman in plasma and 111, 163 and 297 min for sarin, soman and dichlorvos in liver, respectively. These results were also confirmed in experiments in vivo in which rats were subcutaneously treated with 0.5 LD50 of these agents. The half-times of spontaneous reactivation of rat plasma CarbE in vivo were 1.2, 2.0 and 2.7 h for dichlorvos, sarin and soman, respectively. These findings have changed current understanding of the mechanism of interaction of CarbE with OPC and involvement of the enzymes in detoxication of OPC, suggesting an active and important role of the enzymes in metabolic conversions of OPC to their less toxic metabolites.

Neurotoxic effects in patients poisoned with organophosphorus pesticides

In this paper we review neurotoxic disorders appearing in patients poisoned with organophosphorus pesticides. These compounds cause four important neurotoxic effects in humans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP) and chronic organophosphate-induced neuropsychiatric disorder (COPIND). Compared to the cholinergic syndrome, that causes millions of cases of poisoning each year, other disorders involve much smaller numbers of patients. The review is focused on the neurotoxic effects appearing after acute and chronic exposure to organophosphates with emphasis on clinical presentation, pathogenesis, molecular mechanisms, and possibilities for prevention/therapy.

Maternal and fetal cadmium and selenium status in normotensive and hypertensive pregnancy.

Cadmium and selenium concentrations in maternal and umbilical cord blood and amniotic fluid were determined in 37 normotensive and 23 hypertensive women during the last trimester of pregnancy in relation to their smoking status. Thiocyanate concentration in plasma was used as the index of smoking status. Cadmium and selenium were determined with atomic absorption spectrometry (graphite furnace and mercury hydride system). In the group of normotensive and hypertensive women, significantly higher cadmium and lower selenium concentrations in blood in smokers were observed than in nonsmokers. Umbilical cord blood selenium concentrations in both normotensive and hypertensive smokers were significantly lower than in nonsmokers as well. In the group of normotensive women, significant differences in selenium concentrations in amniotic fluid were observed between smokers and nonsmokers. In conclusion, the results of this study show that hypertension in pregnant women smokers is related to significantly higher blood cadmium concentrations, which indicates that cadmium may be considered as an independent factor involved in hypertension.

Organophosphate induced delayed polyneuropathy in man: an overview.

About 80 years have passed since the first cases of organophosphate induced delayed polyneuropathy (OPIDP), as the consequence of human poisoning with certain organophosphorus compounds, were described in the literature. OPIDP is a relatively rare neurodegenerative disorder in humans characterized by loss of function, ataxia and paralysis of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord appearing 2-3 weeks after exposure or later. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). This review discusses OPIDP in man with emphasis on clinical presentation, pathogenesis, molecular mechanisms, and possibilities for prevention/therapy.

Attention Deficit Hyperactivity Disorder and Environmental Toxic Metal Exposure in the United Arab Emirates

No systematic studies have been carried out on the effects of toxic metals on childhood behavior in the Gulf Region including the UAE. The relationship between blood levels of heavy metals and Attention Deficit Hyperactivity disorder (ADHD) were explored in school-aged children of UAE and it was found that increased blood concentrations of lead (Pb), manganese (Mn) and zinc (Zn) were significantly associated with ADHD. The findings suggest that monitoring for exposure to heavy metal levels and education on potential child health hazards related to them are indicated.

Trace element composition of plasma and breast milk of well-nourished women

A wide variation in the composition of breast milk has been reported from various countries. This study was undertaken to determine the trace element content of breast milk and plasma in lactating women. Mothers of children 4 weeks to 80 weeks in age, were studied. Blood and breast milk from the mothers were analysed for trace element content. Prepared samples were analysed using ICP-MS. 209 women agreed to take part in the study, 68 of whom were from the UAE and 124 were other nationalities (17 did not fill the this part of the questionnaire). Ninety-seven infants were male. The concentration of different trace elements in blood and breast milk were little different between women from the UAE and those from outside the UAE. Molybenum, chromium and arsenic significantly increased with increasing age of the infant, while manganese, copper and zinc significantly decreased with increasing age of the infant. The trace element concentrations of breast milk and maternal blood were comparable to published values. Normal values for plasma and breast milk trace metal concentrations have been obtained for UAE women.

Quantitative analysis of toxic and essential elements in human hair. Clinical validity of results

Over the last three decades, there has been an increasing awareness of environmental and occupational exposures to toxic or potentially toxic trace elements. The evolution of biological monitoring includes knowledge of kinetics of toxic and/or essential elements and adverse health effects related to their exposure. The debate whether a hair is a valid sample for biomonitoring or not is still attracting the attention of analysts, health care professionals, and environmentalists. Although researchers have found many correlations of essential elements to diseases, metabolic disorders, environmental exposures, and nutritional status, opponents of the concept of hair analysis object that hair samples are unreliable due to the influence of external factors. This review discusses validity of hair as a sample for biomonitoring of essentiall and toxic elements, with emphasis on pre-analytical, analytical, and post-analytical factors influencing results.

Simultaneous Determination of Cadmium, Mercury, Lead, Arsenic, Copper, and Zinc in Human Breast Milk by ICP‐MS/Microwave Digestion

Abstract An analytical method using microwave digestion and inductively coupled argon plasma-mass spectrometry (ICP‐MS) analysis was developed for the measurement of Cd, Hg, Pb, As, Cu, and Zn in human breast milk. We applied external calibration, internal calibration, and standard addition for reference material and pooled milk analysis. Method performances were defined in terms of detection limits, accuracy, and precision. Accuracy varied between 93% and 105% and precision between 3% and 8%. External calibration and background interferences were checked through a calibrator addition procedure. Our method has shown high accuracy, precision, and sensitivity, as well as linearity within a wide range of values. Our methodology, developed by treatment of reference material and pooled milk samples, was applied for determination of Cu, Zn, As, Cd, Hg, and Pb in 120 human breast milk samples.

The association of exposure to cadmium through cigarette smoke with pregnancy-induced hypertension in a selenium deficient population

Oxidative stress has been postulated as major contributor to endothelial dysfunction and pregnancy-induced hypertension. We have examined the association of exposure to cadmium through cigarette smoke with hypertension disorders during pregnancy in the selenium deficient population. Markers of lipid peroxidation and antioxidative defense were measured and correlated with cadmium blood concentration in normotensive and hypertensive pregnant smokers and nonsmokers. We have observed significantly higher blood Cd in hypertensive smokers and significant differences in all other parameters. Se concentrations were lower in smokers, both in normotensive and hypertensive group as well as values of nonenzymatic (Zn, Cu, and glutathione) and enzymatic (superoxide dismutase, glutathione peroxidase, and glutathione reductase) parameters of antioxidative defense. Results of the study indicate that exposure to cadmium through cigarette smoke in pregnant women, living in Se deficient areas is associated with significantly higher cadmium concentrations and lower levels of enzymatic and nonenzymatic antioxidants and that it can be considered as a risk factor for pregnancy-induced hypertension. Selenium supplementation should be considered for recommendation in such condition.

Learning disorder and blood concentration of heavy metals in the United Arab Emirates

Children are frequently exposed to toxic metals in the environment, and their developing central nervous system is particularly vulnerable to their effects. This study examined the blood level of heavy metals in children with learning disorder (LD) as compared to children without LD in the United Arab Emirates (UAE). Significantly high blood concentrations of seven heavy metals were found in children with LD. Further analysis using forward stepwise logistic regression showed that molybdenum levels and family history of developmental problems were the best predictors of LD. Our findings suggest the need for monitoring for toxic metals in the environment.