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Objective: The noninvasive biomarkers of respiratory impairment were assessed in 15 swine confinement (SC) workers and 9 respiratory healthy, nonsmoking volunteers (HV). Methods: Spirometry, fraction of exhaled nitric oxide (FeNO), and exhaled breath condensate (EBC) pH were assessed in SC workers after one working shift and one working week and in HV after 5-hour exposure in SC. Results: Half of the respiratory symptoms (in 8 of 15 SC workers) were work-related. Basal FeNO values were 7.5 ppb higher in the SC workers compared with HV. In the SC workers, EBC pH increased for 0.17 at the end of a working week (P < 0.001). In HV, 5-hour exposure in SC induced 8% drop in forced expiratory flow at 25% of the pulmonary volume (FEF25 )( P = 0.008), EBC pH drop for 0.10 units (P = 0.003), and FeNO drop by 1.8 ppb (P = 0.047). Conclusions: EBC pH was suggested as a biomarker of acute airway acidification in HV, whereas the SC workers showed signs of the “healthy worker effect.”

Polymorphisms of cytokine genes are an interesting focus for association studies involving atopic diseases due to their role in immune cell communications during inflammation. The aim of this study was to investigate associations of TNFα -308GA, TNFα -238GA, IL-1α -889CT and IL-10 -1082GA polymorphisms with atopic diseases with adjustment for confounding lifestyle and environmental factors.This study was performed on 356 Croatian students. The diagnosis of atopic asthma, atopic rhinitis and atopic dermatitis was based on symptoms reported by the modified International Study of Asthma and Allergies in Childhood questionnaire and a positive skin prick test (SPT) to at least one common inhalatory allergen. Genetic polymorphisms were genotyped using the polymerase chain reaction-based technique. The influence of personal (gender, body mass index, parental history of atopic disease), lifestyle (cigarette smoking, pet ownership) and environmental (urban/rural residency, residency in continental/Mediterranean region) factors reported in the questionnaire was investigated by univariate and multivariate analysis.Compared to the control subjects, univariate analysis showed a significant negative association of the TNFα -308GA polymorphism with atopic asthma, atopic dermatitis, asthma and skin symptoms and positive SPT. These observations were confirmed in a multivariate model only for atopic dermatitis and skin symptoms (atopic dermatitis: OR = 0.27; 95% CI 0.07-1.00; p = 0.050; skin symptoms: OR = 0.29; 95% CI 0.10-0.83; p = 0.021).The results indicate a protective role of TNFα -308GA genetic polymorphisms regarding atopic dermatitis and skin symptoms even after controlling for personal, lifestyle and environmental factors. Further studies are needed to elucidate the molecular patterns of this association in atopic dermatitis and other chronic inflammatory skin disorders.

Thiomersal is used as a preservative in vaccines given to small children. The metabolic product of thiomersal is ethylmercury and its distribution and kinetics are still not known, especially at this early age. The purpose of this study was to compare the body distribution of two forms of mercury: organic (thiomersal) and inorganic (mercury(2+) chloride) in very young, suckling rats. Mercury was applied subcutaneously three times during the suckling period on days 7, 9 and 11 of pups age, imitating the vaccination of infants. A single dose of mercury was equimolar in both exposed groups, i.e. 0.81 micromol Hg kg(-1). At 14 days of age the animals were killed and the total mercury analysed in blood and organs (kidney, liver and brain). The analytical method applied was total decomposition, amalgamation, atomic absorption spectrometry. The results showed that the level of mercury was higher in the liver and kidney of the inorganic mercury group than in the thiomersal exposed group. However, the brain and blood concentrations of mercury were higher in the thiomersal exposed group. These results need to be clarified by additional data on the kinetic pathways of ethylmercury compared with inorganic mercury.

The CD14 receptor is expressed on the surfaces of monocytes, macrophages, and, to a lesser extent, of activated granulocytes and B lymphocytes (mCD14). It also exists in soluble form in the serum (sCD14), in which it binds microbial compounds and indoor allergens. The objectives of this study were to see whether serum sCD14 concentrations could be used as a marker of atopic disorders and to estimate the effects of environmental factors (tobacco smoke exposure, childhood residence in urban or rural areas, and having a pet) on sCD14 and IgE values. Mass fraction of sCD14 and total IgE were determined in the sera of atopic (N=53) and non-atopic (N=35) participants using the standard enzyme-linked immunosorbent assay. Exposure to pets and environmental tobacco smoke was estimated based on the International Study of Asthma and Allergies in Childhood questionnaire (ISAAC). Median sCD14 concentration was significantly lower in atopic than in non-atopic girls (3.49 vs. 3.83 μg mL(-1); p0.010). The number of smokers at home positively correlated with the sCD14 level in atopics, and urban atopics had significantly lower sCD14 levels than rural atopics (3.47 vs. 3.92 μg mL(-1), p=0.028). Median total IgE concentration was significantly lower in atopic pet owners than in atopics with no pets (161 vs. 252 kIU L(-1); p=0.021). In conclusion, while sex and environmental factors might be involved in sCD14 expression, particularly in atopics, we found no correlation between sCD14 and total IgE concentrations. The usefulness of sCD14 as a marker of atopic disorders should be investigated further, particularly in relation to the severity of allergic disorders.

The hypothesis that two known chelators 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and desferrioxamine (DFO) might be more efficient as combined treatment than as monotherapies in removing aluminium from the body was tested in a new acute rat model. Five-week old female rats received chelators: L1 (p.o.), DFO (i.p.) or L1+DFO as 100 or 200 mg/kg dose half an hour after a single i.p. administration of 6 mg Al/kg body weight in the form of chloride. Serum aluminium concentration and urinary aluminium and iron excretions were determined by electrothermal or flame atomic absorption spectrometry. Both chelators were effective only at the higher dose level. While DFO was more effective than L1 in enhancing urinary aluminium excretion, L1 was more effective than DFO in enhancing urinary iron excretion. In the combined treatment group L1 did not increase the DFO effect on aluminium and DFO did not increase the effect of L1 on iron elimination. However, in this group a simultaneous increase in both aluminium and iron elimination was observed. Our results support the usefulness of this animal model for preliminary in vivo testing of aluminium chelators. Urinary values were more useful because of the high variability of serum results. Result of combined chelators treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for evaluating the efficiency of chelating agents in aluminium toxicity.

Whole Atlantic mackerel (Scomber scombrus), sardine (Sardina pilchardus) and Mediterranean hake (Merluccius merluccius) from the Croatian Adriatic were stored at 22 degrees C and changes in histamine, putrescine, tyramine and cadaverine levels were monitored in relation to bacterial endotoxin. After 12 h, histamine levels in sardine were above the legal limit of 50 mg kg(-1), set by the US Food and Drug Administration, and an increase in putrescine content preceded the increase in histamine. After 24 h, histamine contents in mackerel and sardine reached 1090 +/- 101 and 577 +/- 275 mg kg(-1), respectively, which exceeded the toxic threshold of 500 mg kg(-1). At the same time, the putrescine content was also high in both fish (353-420 mg kg(-1)). The time-course of endotoxin production was similar in all fish species stored at 22 degrees C. A high correlation was found between endotoxin and histamine, and between endotoxin and putrescine in mackerel and sardine. On the other hand, high endotoxin levels in hake, after 24 h, were associated with the low histamine and putrescine content (40-60 mg kg(-1)).

Purpose. The aim of the study was to evaluate exposure to moulds and house dust mite Dermatophagoides pteronyssinus in poultry farms, and related health effects in poultry workers (PW). Methods. The study involved 41 PW and 45 control office workers. Working environment was evaluated for D. pteronyssinus allergen (Der p 1), moulds and endotoxin. In workers, eye, skin and respiratory symptoms, ventilatory lung function, atopy markers (skin prick test to inhalatory allergens, total IgE) and specific IgG to moulds were assessed. Results. Der p 1 levels ranged

Pyrethrins, natural extracts of Chrysanthemum cinerariaefolium and Chrysanthemum cocineum flowers, and pyrethroids, synthetic analogues and derivatives of pyrethrins, are powerful insecticides. They are widely used in households and insect control in pets or livestock, in textiles such as carpets, wallpapers, furniture and clothes, as well as in agriculture, forestry and public health services. This article brings a list of pyrethrin and pyrethroid insecticides registered for use in plant protection in Croatia. Pyrethrins and pyrethroids can enter the organism by ingestion (accidental or suicidal ingestion or in food), by inhalation and/or by skin contact. Although these pesticides pose a relatively low risk to mammals due to rapid metabolism with no significant accumulation, they can induce adverse health effects, more often in acute poisoning, but also due to chronic exposure. The primary target of pyrethrin and pyrethroid toxicity is the nervous system, since they act directly on the sodium channels of nerve cell axons, leading to hyperexcitation. Another important toxicological mechanism is allergenicity, which is more pronounced with pyrethrins than with synthetic pyrethroids. Because there is no antidote for pyrethrin and pyrethroid poisoning, treatment is symptomatic and supportive. The article discusses the measures for poisoning prevention and alleviation of exposure to pyrethrins and pyrethroids in occupational settings and in general population.

The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-Dpenicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa3DTPA, ZnNa3DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.

The effect of combined treatment with meso-2,3-dimercaptosuccinic acid (DMSA) and calcium supplementation in reducing lead absorption and enhancing lead elimination was evaluated in suckling rats under two experimental conditions: during ongoing oral lead exposure (lead acetate, 2 mg Pb kg−1 day−1, total dose 16 mg Pb kg−1) or after lead exposure (72 h after a 2-day lead exposure, total dose 12 mg Pb kg−1 s.c.). The artificial feeding method was used for calcium supplementation, with 6% Ca (as CaHPO4) suspension in cow's milk to increase the daily calcium intake about three times above control values. Artificial feeding lasted for 7 h a day over eight consecutive days. During this period DMSA was administered on 6 days twice a day (0.5 mmol kg−1 day−1 p.o.). At the end of the experiments, Pb, Ca and Zn in the carcass and Pb, Fe and Cu in the liver, kidneys and brain were analysed by atomic absorption spectrometry. Calcium supplementation during lead exposure reduced tissue lead but had no effect when applied after lead exposure, and DMSA administered either during or after lead exposure lowered the tissue lead. Combined treatment during ongoing lead exposure caused a greater reduction in tissue lead than either DMSA or calcium treatment alone. When administered after lead exposure, it had no advantage over DMSA treatment alone but did not impair its efficacy. Combined treatment had no influence on growth and did not seriously disturb essential element status. It is concluded that calcium supplementation could be applied during DMSA therapy, when indicated. Copyright © 2004 John Wiley & Sons, Ltd.

The influence of chelating agents: meso-2, 3-dimercaptosuccinic acid (DMSA) ; calcium trisodium diethylenetriaminepentaacetate (CaDTPA) and their combination on mobilisation of cadmium (Cd) was compared in female albino rats. After oral Cd administration chelators were applied either orally (DMSA) or intraperitoneally (CaDTPA) at various short time intervals after Cd. Three experiments were carried out with four treatment groups in each: 1) Cd (control) ; 2) Cd+DMSA ; 3) Cd+CaDTPA ; 4) Cd+DMSA+CaDTPA. Time intervals for chelator treatment after Cd administration were: immediate application in the first, half an hour in the second and one hour in the third experiment. At the end of each experiment cadmium was analysed in kidney and liver. Additionally in experiment 3 essential elements (Fe, Cu, Zn) were also determined in the same organs. In experiment 2 the effect of the treatment on urinary elimination of cadmium, copper and zinc were analysed. Results showed that the efficiency of Cd removal from the body (kidneys and liver) is lower when the time between Cd and chelating agents administration is longer. The two chelators differ in efficiency in mobilizing Cd, with DMSA being more efficient than CaDTPA. The combined therapy with the two chelators gave generally better results. It seems that DMSA which is given orally after oral Cd administration removes this element very efficiently from the gastrointestinal tract. CaDTPA, however, which is given parenterally removes absorbed Cd less efficiently, Organs are not significantly depleted in iron and copper after chelation treatment. Only zinc concentration was, however, significantly lower in the liver and higher in kidneys only after CaDTPA and combined DMSA+CaDTPA chelation.

This study aimed at identifying a calcium compound which could serve as an effective and safe dietary supplement in suckling rats over the period of intense growth and development. The main objective was to assess the effect of additional calcium intake on skeletal calcium in suckling pups. Suckling Wistar rats were fed using a pipettor with one of the following calcium salts from day 6 to 14 after the birth: gluconate, hydrogenphosphate, carbonate (each suspended in cow's milk), or chloride (in demineralized water). Control rats received only cow's milk. Calcium in the carcass (body without organs and skin) was analysed by atomic absorption spectrometry. The only effective dietary supplement that produced no risk for the suckling pups' growth was calcium hydrogenphosphate in cow's milk in the total amount of 340 mg. That dose increased the daily calcium intake 3 to 4 times compared to non-supplemented controls, increasing carcass calcium content by about 16 per cent. Other calcium compounds were either inefficient (carbonate) or had adverse effects on pups' growth (chloride and gluconate).

It was suggested that ascorbic acid as a natural chelating agent can influence lead toxicokinetics and improve chelating properties of dimercaptosuccinic acid (DMSA) in adult rats. In this paper potential benefits of ascorbic acid supplementation, alone or combined with DMSA, in decreasing lead retention in suckling rats were evaluated. Such data in young mammals are not available. L-Ascorbic acid (daily dose 650 mg/kg b.wt.) and/or DMSA (daily dose 91 mg/kg b.wt.) were administered orally to suckling Wistar rats either during ongoing 8-day oral lead exposure (as acetate; daily dose 2 mg lead/kg b.wt.) or after 3-day lead exposure (total dose 12 mg lead/kg b.wt.). Lead concentrations were analysed in the carcass (skeleton), liver, kidneys and brain by atomic absorption spectrometry. By ascorbic acid supplementation lead retention was not reduced under either lead exposure condition. Lead concentration was even increased in the carcass. Treatment with DMSA under both exposure conditions significantly reduced lead in all analysed tissues. Combined treatment with ascorbic acid and DMSA during ongoing lead exposure was substantially less effective than DMSA treatment alone, and did not affect DMSA efficacy when administered after lead exposure. It was concluded that ascorbic acid administered either during or after lead exposure in suckling rats has no beneficial effect on either lead retention or DMSA chelation effectiveness.

In the last fifteen years there were several feed-related outbreaks of morbidity and mortality in the Institute's breeding colony of Wistar rats. The last event took place in April 1999, one month after the use of a new supply of the usual standard rodent feed. Animals did not thrive and manifested generalised oedema, hypoalbuminaemia, elevated liver enzymes, and high mortality. The effect of feed was assessed first by feeding a group of sick females during 14 days with either suspected feed (A-March) or with the earlier supply of feed (A-January) of the same producer. Then a group of healthy male rats Y59 from another breeding colony was fed either suspected feed (A-March) or feed from another producer (feed B). Although neither chemical nor microbiological deviation in feed analysis had been detected, decreased consumption and slower body weight gain in all animals fed with feed A-March suggested an association between this batch of feed and the increased morbidity in those animals. Eventually, the entire rat colony was put down and replaced with a new breed which was given a new brand of feed.

The effect of calcium supplementation on absorption and retention of cadmium in the suckling period was evaluated in Wistar rat pups of both sexes. Animals were maintained in the litters with the mother rats and supplemented with 1%, 3% or 6% calcium (as CaHPO4 x 2H2O) in cow's milk by artificial feeding from day of birth 6 through 14. All rats were exposed to cadmium (as CdCl2 x H2O) either orally or parenterally. Oral cadmium dose of 0.5 mg/kg body weight a day was administered through nine-day period of calcium supplementation and parenteral cadmium dose was injected subcutaneously in a single dose of 0.5 mg Cd/kg body weight prior to calcium supplementation. On experimental day 10 (at the age of pups of 15 days) all animals were killed and the liver, kidneys, brain and carcass (body without organs and skin) were removed for element analyses. Cadmium and essential elements calcium, zinc and iron were analysed in the tissues by atomic absorption spectrometry. Results showed that after oral exposure cadmium concentrations in all calcium-supplemented groups were significantly decreased in the organs and carcass and that the effect was dose-related. No such effect of calcium was found after parenteral cadmium exposure. Calcium supplementation per se significantly increased calcium concentration in the carcass and had no effect on iron in organs and zinc in carcass. It was concluded that calcium supplementation during the suckling period could be an efficient way of reducing oral cadmium absorption and retention without affecting tissue essential trace element concentrations.

There is a concern that oral treatment with succimer (meso-2, 3-dimereaptosuceinic acid, DMSA) can promote gastrointestinal lead absorption if not performed in a lead-safe environment. The scope of our investigation was to evaluate the efficacy of oral DMSA treatment during oral lead exposure on tissue lead in suckling rats. Six-day-old Wistar rats of both genders were divided into two groups-untreated (Ph) and treated (Ph + DMSA)-with 10 animals per group. Lead (as acetate) was given orally at a dose of 2 mg kg(-1) body weight day(-1) for eight consecutive days (total dose 16 mg kg(-1), i.e. 0.08 mmol kg(-1)). During this period the treated group received a daily dose of 0.5 mmol DMSA kg(-1) body weight p.o. six times on days 1-3 and 6-8 of the experiment (total dose 3 mmol kg(-1)). Tissue lead was determined by means of atomic absorption spectrometry. The DMSA efficiently reduced the lead concentration in the analysed tissues (carcass, liver, kidneys and brain) by similar to 50% compared with untreated controls. The pups' growth and organ weights were not affected. In conclusion, our results indicate that DMSA is an efficient oral lead chelator in sucklings even if challenged with ongoing lead exposure. Copyright (C) 2001 John Wiley & Sons, Ltd. [References: 10]

The effect of calcium supplementation on tissue lead was evaluated in suckling Wistar rats, Such data are not yet available in the literature. The following artificial feeding regimen was used for calcium supplementation: cow's milk by addition of 1%, 3% or 6% Ca as CaHPO(4)x2H(2)O Suspension to increase the daily calcium intake about 1.4, 2 or 3 times above control values. Artificial feeding was applied during 7 hr each day for nine consecutive days (from day 6 through 15 after birth). The effect of such treatment on lead absorption and elimination was evaluated in two separate experiments: calcium supplementation during oral lead exposure (as acetate, daily dose 2 mg Pb/kg body wt. ; total Ph dose 18 mg/kg body wt.) or after a single intraperitoneal lead administration (5 mg/kg body wt.). At the end of experiments, lead in tissues (liver, kidneys, brain and carcass), and essential elements (Ca, Fe, Zn, Cu) were analysed by atomic absorption spectrometry. Calcium supplementation caused a statistically significant decrease of lead in all tissues of sucklings orally exposed to lead. This decrease was dose-related being about 1.3, 1.5 and 2 times lower in groups supplemented with 1%, 3%, or 6% calcium compared to controls, respectively. Increased calcium intake had no effect on incorporated lead after parenteral lead exposure. Calcium supplementation increased carcass calcium and had no effect on trace elements in tissues, pups' general appearance and body weight gain. It is concluded that higher calcium intake might be a way of efficient reduction of lead absorption during the suckling period. [References: 44]