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Ketamine is a dissociative anaesthetic used to induce general anaesthesia in humans and laboratory animals. Due to its hallucinogenic and dissociative effects, it is also used as a recreational drug. Anaesthetic agents can cause toxic effects at the cellular level and affect cell survival, induce DNA damage, and cause oxidant/antioxidant imbalance. The aim of this study was to explore these possible adverse effects of ketamine on hepatocellular HepG2 and neuroblastoma SH-SY5Y cells after 24-hour exposure to a concentration range covering concentrations used in analgesia, drug abuse, and anaesthesia (0.39, 1.56, and 6.25 µmol/L, respectively). At these concentrations ketamine had relatively low toxic outcomes, as it lowered HepG2 and SH-SY5Y cell viability up to 30 %, and low, potentially repairable DNA damage. Interestingly, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) remained unchanged in both cell lines. On the other hand, oxidative stress markers [superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)] pointed to ketamine-induced oxidant/antioxidant imbalance.

Ochratoxin A (OTA) and citrinin (CTN) are nephrotoxic mycotoxins often found together in grain. The aim of this study was to measure their accumulation in the kidney and liver of adult male Wistar rats, see how it would be affected by combined treatment, and to determine if resveratrol (RSV) would decrease their levels in these organs. The rats received 125 or 250 mg/kg bw of OTA by gavage every day for 21 days and/or 20 mg/kg bw of CTN a day for two days. Two groups of rats treated with OTA+CTN were also receiving 20 mg/kg bw of RSV a day for 21 days. In animals receiving OTA alone, its accumulation in both organs was dose-dependent. OTA+CTN treatment resulted in lower OTA but higher CTN accumulation in both organs at both OTA doses. RSV treatment increased OTA levels in the kidney and liver and decreased CTN levels in the kidney. Our findings point to the competition between CTN and OTA for organic anion transporters 1 and 3.

Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially among the adolescents. Very little is known about the general toxicity of these compounds, especially about their possible neurotoxic effects at the cell level. The aim of this study was to address these gaps by assessing the toxic effects of 24-hour exposure to LSD and PCP in the concentration range of 0.39–100 μmol/L in the human neuroblastoma SH-SY5Y cell line. After cell viability was established, cells treated with concentrations that reduced their viability up to 30 % were further subjected to the alkaline comet assay and biochemical assays that enable estimation of oxidative stress-related effects. Treatment with LSD at 6.25 μmol/L and with PCP at 3.13 μmol/L resulted with 88.06±2.05 and 84.17±3.19 % of viable cells, respectively, and led to a significant increase in primary DNA damage compared to negative control. LSD also caused a significant increase in malondialdehyde level, reactive oxygen species (ROS) production, and glutathione (GSH) level, PCP significantly increased ROS but lowered GSH compared to control. Treatment with LSD significantly increased the activities of all antioxidant enzymes, while PCP treatment significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) but decreased catalase (CAT) activity compared to control. Our findings suggest that LSD has a greater DNA damaging potential and stronger oxidative activity than PCP in SH-SY5Y cells.

AbstractDisruption of element homeostasis may contribute to increased susceptibility of men to cancer development. Whether environmental low-level metal exposure could contribute to the pathogenesis of testicular cancer is unknown. Comparison of the level of 18 elements in whole blood, serum and urine and parameters of oxidative stress/antioxidant status between men with testicular germ cell tumors (TGCT) and healthy men showed significant difference between the groups in most parameters. The results of linear discriminant analysis with a discrimination rate of 96% indicated whole blood Ca, Co, Cu, Fe, K, Mg, Na and Zn, serum Ca, Cu, Na and Ni, and urine Cd, Co, Fe and Mn being the strongest predictors of illness. TGCT patients had a significant increase in serum and blood Cu and decrease in serum Fe and blood Zn with cancer progression. Significantly higher concentrations of Al, As, Pb, and Ni in whole blood/serum of men with TGCT confirm the hypothesis that low-level environmental exposure to these elements may contribute to cancer development. Relationship between elements concentrations and treatment outcomes should be carefully monitored during cancer treatment since high concentrations of commonly used platinum-based chemotherapeutics may additionally disturb the homeostasis of elements.

Manufacture of lead-containing products has long been associated with various health risks. To get an insight into the related genotoxic risks, we conducted a biomonitoring study in 50 exposed workers and 48 matched controls using a battery of endpoints that sensitively detect the extent of genome instability in peripheral blood lymphocytes. The levels of primary DNA damage were estimated with the alkaline comet assay, while cytogenetic abnormalities were determined with the cytokinesis-block micronucleus (CBMN) cytome assay. Additionally, CBMN slides of 20 exposed and 16 control participants were subjected to fluorescence in situhybridisation (FISH), coupled with pancentromeric probes to establish the incidence of centromere-positive micronuclei, nuclear buds, and nucleoplasmic bridges. Blood lead levels (B-Pb) were measured with atomic absorption spectrometry. To further characterise cumulative effects of occupational exposure, we measured erythrocyte protoporphyrin (EP) concentrations and delta-aminolevulinic acid dehydratase (ALAD) activity in blood. We also assessed the influence of serum folate (S-folate) and vitamin B12(S-B12) on genome stability. Compared to controls, occupationally exposed workers demonstrated significantly higher B-Pb (298.36±162.07 vs 41.58±23.02), MN frequency (18.71±11.06 vs 8.98±7.50), centromere positive MN (C+ MN) (8.15±1.8 vs 3.69±0.47), and centromere negative MN (C- MN) (14.55±1.80 vs 4.56±0.89). Exposed women had significantly higher comet tail intensity (TI) and length (TL) than control women. Furthermore, workers showed a positive correlation between age and nuclear buds and MN, between MN and years of exposure, and between S-B12levels and TI and ALAD activity, while a negative correlation was found between TI and B-Pb. These findings suggest that occupational settings in the manufacture of lead-containing products pose significant genotoxic risks, which calls for developing more effective work safety programmes, including periodical monitoring of B-Pb and genetic endpoints.

In this 28 day-study, we evaluated the effects of herbicide glyphosate administered by gavage to Wistar rats at daily doses equivalent to 0.1 of the acceptable operator exposure level (AOEL), 0.5 of the consumer acceptable daily intake (ADI), 1.75 (corresponding to the chronic population-adjusted dose, cPAD), and 10 mg kg−1body weight (bw) (corresponding to 100 times the AOEL). At the end of each treatment, the body and liver weights were measured and compared with their baseline values. DNA damage in leukocytes and liver tissue was estimated with the alkaline comet assay. Oxidative stress was evaluated using a battery of endpoints to establish lipid peroxidation via thiobarbituric reactive substances (TBARS) level, level of reactive oxygen species (ROS), glutathione (GSH) level, and the activity of glutathione peroxidase (GSH-Px). Total cholinesterase activity and the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were also measured. The exposed animals gained less weight than control. Treatment resulted in significantly higher primary DNA damage in the liver cells and leukocytes. Glyphosate exposure significantly lowered TBARS in the liver of the AOEL, ADI, and cPAD groups, and in plasma in the AOEL and cPAD group. AChE was inhibited with all treatments, but the AOEL and ADI groups significantly differed from control. Total ChE and plasma/liver ROS/GSH levels did not significantly differ from control, except for the 35 % decrease in ChE in the AOEL and ADI groups and a significant drop in liver GSH in the cPAD and 100xAOEL groups. AOEL and ADI blood GSH-Px activity dropped significantly, but in the liver it significantly increased in the ADI, cPAD, and 100xAOEL groups vs.control. All these findings show that even exposure to low glyphosate levels can have serious adverse effects and points to a need to change the approach to risk assessment of low-level chronic/sub-chronic glyphosate exposure, where oxidative stress is not necessarily related to the genetic damage and AChE inhibition.

This review article provides a summary of the studies relying on oxidative stress biomarkers (lipid peroxidation and antioxidant enzymes in particular) to investigate the effects of atrazine and terbuthylazine exposure in experimental animals and humans published since 2010. In general, experimental animals showed that atrazine and terbuthylazine exposure mostly affected their antioxidant defences and, to a lesser extent, lipid peroxidation, but the effects varied by the species, sex, age, herbicide concentration, and duration of exposure. Most of the studies involved aquatic organisms as useful and sensitive bio-indicators of environmental pollution and important part of the food chain. In laboratory mice and rats changes in oxidative stress markers were visible only with exposure to high doses of atrazine. Recently, our group reported that low-dose terbuthylazine could also induce oxidative stress in Wistar rats. It is evident that any experimental assessment of pesticide toxic effects should take into account a combination of several oxidative stress and antioxidant defence biomarkers in various tissues and cell compartments. The identified effects in experimental models should then be complemented and validated by epidemiological studies. This is important if we wish to understand the impact of pesticides on human health and to establish safe limits.

Reproductive Toxicity of Metals in MenA combination of genetic, environmental and lifestyle factors contributes to adverse effects on the reproductive health in men. Metals are pervasive in food, water, air, tobacco smoke, and alcoholic beverages. Experimental studies suggest that many metals have adverse effects on the male reproductive function. However, information about reproductive effects of human exposure to metals is scarce and/or inconsistent. This review summarises the information from epidemiological studies of the effects of metal exposure on reproductive function in men. Factors capable of affecting these relationships were identified and discussed. A particular attention is given to the studies considering influence of concomitant exposure to various metals.These studies have generally confirmed that even moderate- to low-level exposure to lead affects certain reproductive parameters, and that exposure to cadmium affects the prostate function and serum testosterone levels. Adverse effects of mercury, manganese, chromium and arsenic on semen quality and altered serum hormone are less well documented. There is no clear evidence that boron exposure may impair reproductive health in men. Only a few studies have investigated reproductive effects of concomitant exposure to several metals and controlled for potential confounders. Future studies should consider the contribution of combined exposure to various metals and/or other factors that may influence individual susceptibility to reproductive health impairment in men.

The combined influence of age, smoking, alcohol, blood lead and cadmium concentrations, and serum copper, zinc, and selenium concentrations on prostate-specific antigen (PSA) in serum was investigated in a group of 57 men aged 21 years to 40 years. The subjects had no occupational exposure to metals and no other known reasons suspected of influencing prostate function or metal metabolism. No significant correlation was found between PSA and any of the explanatory variables considered. Nevertheless, when taking into account all of the above-mentioned potentially explanatory variables, the results of stepwise multiple regression showed a significant increase in PSA with respect to an increase in blood lead, and a decrease in PSA with respect to an increase in intensity of alcohol consumption. The median and range values of blood lead concentration in the 57 men were 26.0 μg L-1and (10.1 to 108.0) μg L-1, respectively. These results suggest that even a low-level environmental lead exposure, common for general populations worldwide, may contribute to the risk of prostate cancer in men. The influence of lead as well as cadmium, zinc, and selenium on prostate damage and PSA should be further investigated in relatively young men for the purpose of disease prevention.

In 123 Croatian men with no occupational exposure to metals, the influence of cadmium on reproductive parameters was examined after adjusting for age, smoking, alcohol, and biomarkers of lead, copper, zinc, and selenium. The following variables were measured: blood cadmium (BCd), blood lead (BPb), activity of δ-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin, serum copper (SCu), serum zinc (SZn), serum selenium (SSe), activity of glutathione peroxidase (GPx) in blood, testis size, semen quality (including sperm concentration, motility, viability, and morphology), indicators in seminal fluid (the lactate dehydrogenase isoenzyme LDH-C4, fructose, zinc, acid phosphatase, and citric acid), and hormones in serum (follicle-stimulating hormone – FSH, luteinizing hormone, prolactin, testosterone, and estradiol). The median and range BCd values were 2.94 (0.49-11.93) μg/L in 61 smokers and 0.59 (0.20-3.71) μg/L in 62 nonsmokers (p<0.0001). Smoking habits (cigarettes/day) highly significantly correlated with BCd (p<0.0001). After adjusting for potential confounding variables by multiple regression, BCd was significantly associated with a decrease in testis size (p<0.03) and an increase in serum estradiol (p<0.005), FSH (p<0.03), and testosterone (p<0.04). Smoking was significantly associated with a decrease in serum prolactin (p<0.006) and LDH-C4in seminal fluid (p<0.03). Several reproductive parameters were significantly associated with BPb and ALAD, biomarkers of lead, and/or with SCu, SZn, SSe, and GPx. The necessity of controlling for various metals, and other potential confounders when assessing the influence of a particular metal on reproductive function in men, is emphasized.

The effect of lead (Pb) and potential confounding variables on blood pressure was examined in healthy male industrial workers 20–43 years of age. In 100 Pb workers and 51 reference subjects, the following variables were measured: blood Pb (BPb), activity of δ-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP), blood cadmium (BCd), serum zinc (SZn), serum copper (SCu), hematocrit (Hct), body mass index (BMI), and blood pressure. The inter-relationship of biomarkers of Pb (BPb, ALAD, EP) and BCd, SZn, SCu, Hct, BMI, age, smoking, and alcohol to systolic and diastolic blood pressure was calculated by forward stepwise multiple regression. There was no significant difference in blood pressure between the two groups, possibly because the reference subjects had relatively high BPb levels and significantly higher BMI (P &lt; 0.05) as compared to the Pb workers. According to the multiple regression results in Pb workers, an increase in systolic blood pressure was significantly associated with increasing EP (P = 0.001) and BMI (P &lt; 0.002), or alternatively with increasing BMI (P &lt; 0.004) and decreasing ALAD (P &lt; 0.04) and BCd (P &lt; 0.05). An increase in diastolic blood pressure was significantly associated with increasing BMI (P &lt; 0.009) and EP (P = 0.05) and decreasing BCd (P &lt; 0.04). With respect to the EP range of 0.73–13.94 µmol/l erythrocytes in 100 Pb workers, an increase of 17 mm Hg in systolic and 6 mm Hg in diastolic blood pressure was found. Long-term cumulative Pb exposure, which is better reflected by EP than by ALAD or current BPb level, can significantly increase blood pressure in moderately Pb-exposed male workers (long-term average BPb &lt;400 µg/l; exposure duration 2–21 years). Am. J. Ind. Med. 45:446–454, 2004. © 2004 Wiley-Liss, Inc.

The interrelationship of blood lead (BPb), activity of δ-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP), blood cadmium (BCd), serum copper (SCu), serum zinc (SZn), serum selenium (SSe), hematocrit (Hct), body mass index (BMI), age, smoking habits, and alcohol consumption to blood pressure was examined in 154 Croatian male subjects 19–53 years of age. None of the subjects had been occupationally exposed to metals, or used any medication that could influence blood pressure or metal metabolism. The median and range values were: BPb, 57 (25–254) μg/L; ALAD, 51.9 (22.8–96.4) European units; EP, 0.68 (0.38–1.68) μmol/L erythrocytes; BCd, 0.83 (0.21–11.93) μg/L; SCu, 1113 (763–1662) μg/L; SZn, 961 (734–1213) μg/L; SSe, 73.6 (44.2–106.9) μg/L; systolic blood pressure, 131 (105–165) mm Hg; and diastolic blood pressure, 94 (71–112) mm Hg. Systolic and diastolic blood pressure significantly correlated with an increase in BMI (P<0.0005 and P<0.0001, respectively), EP (P<0.0002 and P<0.002, respectively), and BPb (P<0.005 and P<0.01, respectively). After adjusting for potential confounding variables by multiple regression, an increase in systolic blood pressure was significantly predictive by BMI (P<0.0005) and log BPb (P<0.02) and inversely by log BPb*SSe interaction term (P<0.007), or alternatively by EP (P<0.0001), BMI (P<0.001), alcohol (P<0.02), and Hct (P<0.05). An increase in diastolic blood pressure was significantly predictive by BMI (P<10−5), log BPb (P<0.04), and alcohol (P=0.05) and inversely by log BPb*SSe interaction term (P<0.0007), or alternatively by BMI (P<0.0001), EP (P<0.002), alcohol (P<0.004), and Hct (P<0.04) and inversely by smoking (P<0.04). With respect to the EP range in the study population, an increase of 27 mm Hg in systolic and 14 mm Hg in diastolic blood pressure was found. The study results indicate a significant Pb-related increase in blood pressure, particularly within the low-level Pb exposure range (BPb of 25–75 μg/L, and/or EP of 0.4–1.0 μmol/L erythrocytes).

The interrelationship of dietary calcium (Ca) intake, alcohol consumption, blood lead (BPb), blood cadmium (BCd), age, and body mass index (BMI) to blood pressure was examined in 267 peasant women 40–85 years of age. They were residents of two rural areas in Croatia and differed with regard to dietary Ca intake: 100 women with low Ca intake (approximately 450 mg/day) and 167 women with relatively high Ca intake (approximately 940 mg/day). All of the women were nonsmokers and consumed very little or no alcohol. Median and range BPb values were 74 (29–251) μg/L in women with low Ca intake and 59 (21–263) μg/L in women with high Ca intake (p < 0.0002), whereas corresponding BCd values were 0.6 (0.2–3.6) μg/L and 0.6 (0.3–4.5) μg/L (p > 0.10). Results of multiple regression showed a significant (p < 0.05) increase in systolic blood pressure with age, BMI, and BCd, and marginally with alcohol consumption (multiple r = 0.48, p < 10−6). An increase in diastolic blood pressure was significantly (p < 0.05) associated with BMI, age, and residence area (i.e., it was higher in women with low Ca intake), and marginally with BCd, and alcohol consumption (multiple r = 0.38, p < 10−6). When the two groups of women with different Ca intake were subdivided into consumers and nonconsumers of alcohol, BPb was related positively to alcohol consumption and inversely to Ca intake. The highest BPb was found in the subgroup of alcohol consumers with low Ca intake, and the lowest BPb in the subgroup of nonconsumers with high Ca intake: 78 (42–251) μg/L and 51 (22–192) μg/L, respectively (p < 10−8). Diastolic blood pressure was significantly higher in the former subgroup as compared to the latter: 95 (72–130) mm Hg and 90 (60–120) mm Hg, respectively (p < 0.05). This cannot be explained by age, BMI, or BCd, which were comparable in the two subgroups. The results indicate that alcohol consumption and low Ca intake can increase BPb, which may significantly contribute to an increase in diastolic blood pressure in female nonsmokers even at relatively low-level Pb exposure.

Abstract: Blood cadmium (B-Cd) and seminal fluid cadmium (Sf-Cd) were measured in 120 adult male subjects not occupationally exposed to cadmium (Cd), comprising 42 nonsmokers (including nine former smokers) and 78 smokers. The respective median and range values were: 0.46 (0.19–1.49) μg/l of B-Cd and 0.54 (0.17–1.67) μg/l of Sf-Cd in nonsmokers, and 4.33 (0.49–13.33) μg/l of B-Cd and 0.85 (0.29–3.56) μg/l of Sf-Cd in smokers. Both indicators showed a highly significant difference in Cd exposure between the groups (P<0.0001), although the increase in B-Cd was considerably more pronounced than that of Sf-Cd in smokers compared with nonsmokers. The results suggest a nonlinear relationship (log Sf-Cd/log B-Cd: r=0.501, P<0.0001), rather than linear relationship (Sf-Cd/B-Cd: r=0.430, P<0.0001), between the indicators. Significant correlations were found between smoking habits, i.e., the number of cigarettes per day, and an increase in B-Cd in smokers (r=0.296, P<0.01) and in all 120 subjects (r=0.685, P<0.0001), as well as between smoking habits and an increase in Sf-Cd in smokers (r=0.378, P<0.001) and in all 120 subjects (r=0.488, P<0.0001). Both indicators are necessary for evaluation of individual internal Cd dose, since they appear to differ in reflecting recent and long-term cumulative Cd exposure and/or the amount of Cd at the site(s) of its effect(s) in the body.

Objective: The aim of this study was to confirm the connection between lead poisoning and the use of traditional Ayurvedic metal mineral tonics. Methods: The study group comprised 29 subjects (26 adults and three children) who had previously taken Ayurvedic metal mineral tonics. All subjects were tested for lead absorption by blood lead, erythrocyte δ-aminolevulinic acid dehydratase activity and erythrocyte protoporphyrin. Results: Eighteen samples of Ayurvedic preparations were obtained from 15 subjects and analyzed for lead content. Five adult subjects with established lead poisoning received chelation therapy. In Ayurvedic preparations a wide range of lead content was found (0.9-72,990 μg Pb/g; 0.35-29,900 μg Pb/capsule or tablet). The blood lead, erythrocyte δ-aminolevulinic acid dehydratase and erythrocyte protoporphyrin of the subjects, grouped according to the remedies used, correlated with the lead content in the preparations (p < 0.001). Chelation therapy was successful in normalization of laboratory findings and clinical recovery. Conclusion: Ayurvedic metal-mineral tonics are again identified as a potential source of high lead. The import of such tonics should be strictly controlled.