Pavel Urban

Adverse Health Effects in Humans Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)

The environmental contaminant 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) belongs to the category of highly toxic, persistent organic pollutants that accumulate in animal fat and plant tissues. Today, background TCDD levels in human fat are showing a decreasing trend. The food chain is the main source of exposure in the human population. TCDD regulates the expression of a wide range of drug-metabolizing enzymes and has an impact on a large number of biological systems. The most pronounced effects have occurred in occupational settings following the uncontrolled formation of TCDD after industrial accidents, as well as in rare intentional intoxications. Although the acute effects of TCDD exposure are well described in the literature, the long-term consequences have been underevaluated. The most well-known symptoms of severe acute intoxication are chloracne, porphyria, transient hepatotoxicity, and peripheral and central neurotoxicity. Because of the long-term persistence of TCDD in the human body, atherosclerosis, hypertension, diabetes, vascular ocular changes, and signs of neural system damage, including neuropsychological impairment, can be present several decades after massive exposure. Such chronic effects are nonspecific, multifactorial, and may be causally linked to TCDD only in heavily intoxicated subjects. This opinion is supported by the dose-dependent effect of TCDD found in exposed workers and by experimental animal studies.

Czech mass methanol outbreak 2012: Epidemiology, challenges and clinical features

Abstract Objectives. Methanol poisonings occur frequently globally, but reports of larger outbreaks where complete clinical and laboratory data are reported remain scarce. The objective of the present study was to report the data from the mass methanol poisoning in the Czech Republic in 2012 addressing the general epidemiology, treatment, and outcomes, and to present a protocol for the use of fomepizole ensuring that the antidote was provided to the most severely poisoned patients in the critical phase. Methods. A combined prospective and retrospective case series study of 121 patients with confirmed methanol poisoning. Results. From a total of 121 intoxicated subjects, 20 died outside the hospital and 101 were hospitalized. Among them, 60 survived without, and 20 with visual/CNS sequelae, whereas 21 patients died. The total and hospital mortality rates were 34% and 21%, respectively. Multivariate regression analysis found pH < 7.0 (OR 0.04 (0.01–0.16), p < 0.001), negative serum ethanol (OR 0.08 (0.02–0.37), p < 0.001), and coma on admission (OR 29.4 (10.2–84.6), p < 0.001) to be the only independent parameters predicting death. Continuous hemodialysis was used more often than intermittent hemodialysis, but there was no significant difference in mortality rate between the two [29% (n = 45) vs 17% (n = 30), p = 0.23]. Due to limited stockpiles of fomepizole, ethanol was administered more often; no difference in mortality rate was found between the two [16% (n = 70) vs. 24% (n = 21), p = 0.39]. The effect of folate administration both on the mortality rate and on the probability of visual sequelae was not significant (both p > 0.05). Conclusions. Severity of metabolic acidosis, state of consciousness, and serum ethanol on admission were the only significant parameters associated with mortality. The type of dialysis or antidote did not appear to affect mortality. Recommendations that were issued for hospital triage of fomepizole administration allowed conservation of valuable antidote in this massive poisoning outbreak for those patients most in need.

Trends in incidence of occupational asthma, contact dermatitis, noise-induced hearing loss, carpal tunnel syndrome and upper limb musculoskeletal disorders in European countries from 2000 to 2012

Objectives The European Union (EU) strategy for health and safety at work underlines the need to reduce the incidence of occupational diseases (OD), but European statistics to evaluate this common goal are scarce. We aim to estimate and compare changes in incidence over time for occupational asthma, contact dermatitis, noise-induced hearing loss (NIHL), carpal tunnel syndrome (CTS) and upper limb musculoskeletal disorders across 10 European countries. Methods OD surveillance systems that potentially reflected nationally representative trends in incidence within Belgium, the Czech Republic, Finland, France, Italy, the Netherlands, Norway, Spain, Switzerland and the UK provided data. Case counts were analysed using a negative binomial regression model with year as the main covariate. Many systems collected data from networks of ‘centres’, requiring the use of a multilevel negative binomial model. Some models made allowance for changes in compensation or reporting rules. Results Reports of contact dermatitis and asthma, conditions with shorter time between exposure to causal substances and OD, were consistently declining with only a few exceptions. For OD with physical causal exposures there was more variation between countries. Reported NIHL was increasing in Belgium, Spain, Switzerland and the Netherlands and decreasing elsewhere. Trends in CTS and upper limb musculoskeletal disorders varied widely within and between countries. Conclusions This is the first direct comparison of trends in OD within Europe and is consistent with a positive impact of European initiatives addressing exposures relevant to asthma and contact dermatitis. Taking a more flexible approach allowed comparisons of surveillance data between and within countries without harmonisation of data collection methods.

Biochemical, Neuropsychological, and Neurological Abnormalities Following 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Exposure

Abstract Presented herein are the results of follow-up examinations of 13 workers performed in 1996–30 yr following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication in a herbicide production plant. In these workers, the current mean plasma level of 2,3,7,8-TCDD, measured by high-resolution gas chromatography/high-resolution mass spectrometry, was 256 pg/gm lipid (range = 14–760 pg/gm lipid). This mean value corresponded to an estimated concentration of approximately 5,000 pg/gm plasma fat that existed about 30 years ago. Such a mean plasma level indicates that this group was one of the most heavily exposed groups to 2,3,7,8-TCDD described in the literature. Patients with persistent chloracne had significantly higher plasma levels of 2,3,7,8-TCDD than persons without chloracne. A significant, positive correlation was found between plasma levels of 2,3,7,8-TCDD in 1996 and levels of cholesterol and plasma lipids that existed since 1974. During 1996, there was a significant positive correlation between 2,3,7,8-TCDD and levels of beta-lipoproteins, cholesterol, and triglycerides. Also in 1996, significant correlations were found between neuropsychological variables and plasma levels of 2,3,7,8-TCDD. Other significant correlations were observed between neuropsychological variables and (1) the highest levels of triglycerides (i.e., since the year 1989), (2) levels of triglycerides in 1996, (3) levels of cholesterol at the first examination (i.e., 1969–1970), (4) highest level of cholesterol since the year 1969, and (5) cholesterol levels in 1996. Such correlations are biologically plausible, and they provide evidence of impaired cognitive performance (i.e., memory first), with a concurrent increase of plasma lipid levels. Abnormal electromyography, electroencephalography, and visual evoked potentials were observed in 23%, 54%, and 31 %, respectively, of former workers. Abnormal electroencephalography findings occurred more frequently in workers who had 2,3,7,8-TCDD blood levels that exceeded 200 pg/gm plasma fat than in workers with 2,3,7,8-TCDD values lower than 200 pg/gm plasma fat (p < .025). Frequency of polyneuropathic EMG abnormalities decreased from 38% in the 1970s to 23% in 1996. Improvement of conduction velocity in the tibial nerve was statistically significant (p < .05).

Long-term visual damage after acute methanol poisonings: Longitudinal cross-sectional study in 50 patients

Context. Visual disturbances due to the toxic effect of formic acid in acute methanol poisonings are generally transient. The subjective symptoms of visual toxicity may resolve within few weeks and fundoscopic signs of acute optic neuropathy subside within 1–2 months; therefore, the prevalence of long-term visual sequelae in the population of survivors of poisonings may be underestimated. Objective. To study the prevalence and character of long-term visual sequelae of acute methanol poisonings based on the data from the Czech mass methanol outbreak in 2012. Patients and methods. A total of 50 patients with confirmed methanol poisoning were included in this longitudinal cross-sectional study, median age: 48 (range, 23–73) years. The following tests were performed: optical coherence tomography or OCT with evaluation of the retinal nerve fibers layer (RNFL), visual evoked potentials (VEP), magnetic resonance imaging (MRI) of brain, complete ocular examination (visual acuity/field, color vision, contrast sensitivity, and fundus), neurological examinations, and biochemical tests. Results. Of 50 patients, 7/50 (14%) were discharged with diagnosed visual sequelae and 6/50 (12%) were discharged with both visual and central nervous system sequelae of poisoning. On the follow-up examination, 20/50 (40%) of the patients had long-term visual sequelae, with 8% of blindness. A total of 38% of the patients had abnormal (28% borderline) findings on RNFL, and 40% had abnormal (18% borderline) VEP. Among the patients discharged without detected visual sequelae, 8/37 (22%) had abnormal RNFL and VEP. Patients with visual sequelae had brain lesions more often (70% vs. 27%, p < 0.01). MRI identified optic nerve lesions in 2/20 cases with abnormal VEP only. The groups with and without visual sequelae differed in serum methanol, ethanol, HCO3-, formate, pH, anion gap, and base deficit (all p < 0.01). Visual disturbances on admission and coma were more prevalent in the patients with visual sequelae (p < 0.05). Patients with positive serum ethanol on admission were 93% less likely to have optical axonal damage (OR: 0.07 (95% CI: 0.01–0.8); p < 0.05). No association was found between visual sequelae and type of antidote administered, mode of hemodialysis, or folate substitution. Pre-hospital administration of ethanol seemed beneficial: these patients were 90% less likely to have abnormal RNFL findings (OR: 0.10 (95% CI: 0.02–0.52); p < 0.01). Conclusions. The long-term visual sequelae were clearly underestimated on discharge, suggesting a significantly higher amount of patients with long-term sequelae than earlier reported. Thorough examinations before discharge and during follow-up will likely uncover a higher morbidity also after methanol poisonings in general.

Two-year follow-up of two patients after severe thallium intoxication

Information on the prognosis and electrophysiological follow-up of severe thallium poisoning is limited. We report two patients (mother and daughter) who were repeatedly exposed to thallium poisoning experienced hair loss, polyneuropathy, and visual impairment. Nerve conduction studies (NCSs), visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP) changes, and optical neuropathy developed within a few months latency after the first subjective signs. Normal findings of these electrophysiological methods in the first 2 weeks therefore led in one of our patients to exclusion of thallium as the cause of symptoms. Thallium poisoning was, however, later confirmed by toxicological analysis of blood and/or urine and feces in both the patients and in the microscopic hair analysis of the daughter. Both patients were treated with Prussian blue that increased the elimination of thallium in urine and feces. The hair loss was fully reversible. During a 2-year follow-up after the poisoning, polyneuropathy in the lower extremities improved substantially, but residual impairment in both motor and sensory function, NCSs, VEP, and BAEP remained. Additionally, severe asymmetrical vision impairment persists in both women, with central scotomata and impaired color discrimination in both eyes. Substantial improvement of their visual function is unlikely.

2,3,7,8-TCDD exposure, endothelial dysfunction and impaired microvascular reactivity

Vascular function was examined in subjects with long-term high level of serum 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) during their follow-up visits. Their earlier mean peak TCDD level at the time of exposure in 1965—1968 was estimated in the range of 3300—74 000 pg/g lipids. Ten former pesticide production workers heavily exposed to TCDD (age 57 ± 2 years, TCDD about 170 pg/g lipids) were examined in 2001. Extended group of 15 TCDD-exposed men (age 59 ± 3 years, TCDD about 130 pg/g lipids) underwent the same examination in 2004. Findings were compared with a control group of 14 healthy men (age 54 ± 2 years). Skin microvascular reactivity (MVR) was measured by laser Doppler perfusion monitoring in the forearm during post-occlusive reactive hyperemia (PORH) and thermal hyperemia (TH). Several parameters of MVR in men exposed to TCDD were significantly impaired, compared with the control group and further progression of the impairment of MVR has been observed between years 2001 and 2004. Serum concentration of E-selectin and inhibitor of tissue plasminogen activator 1 (PAI-1) was significantly higher in exposed subjects (56.0 ± 18.4 ng/mL versus 40.0 ± 12.0 ng/mL, P = 0.022 and 90.9 ± 33.3 ng/mL versus 45.0 ± 18.0, P = 0.002, respectively). In addition, PORH in the forearm was significantly negatively associated with SOD activity (r = —0.77, P = 0.009) as well as the velocity of perfusion increase during TH (r = —0.68, P = 0.03) and TH% (r = —0.78, P = 0.008). Our data document the presence of endothelial dysfunction in TCDD-exposed men. Human & Experimental Toxicology (2007) 26, 705—713

Somatosensory evoked potentials in workers exposed to toluene and styrene.

Somatosensory evoked potentials (SEPs) were used to evaluate possible subclinical impairment of the nervous system due to occupational exposure to toluene and styrene. A group of 36 rotogravure printers with severe exposure to toluene, 20 workers with severe exposure to styrene in a glass laminate manufacturing plant, and a comparison group of healthy subjects were studied. The severity of exposure was documented by measurements of toluene and styrene concentrations in breathing zone air, by hippuric acid concentration in urine in the group exposed to toluene, and by urinary mandelic acid concentration in the group exposed to styrene. Somatosensory evoked potentials were measured by stimulation of the median nerve at the wrist and the tibial nerve at the ankle. Peripheral conduction velocities (CVs) in both extremities and central conduction time (CCT) after tibial nerve stimulation were significantly decreased in both exposed groups. Significantly prolonged latencies of peripheral and cortical SEPs to median nerve stimulation as well as cortical SEPs to tibial nerve stimulation were found in workers exposed to styrene. Some abnormalities in SEPs at peripheral or spinal and cortical levels were found in eight workers exposed to toluene and six workers exposed to styrene. Of these, in three workers exposed to toluene and two to styrene increased CCT and delayed latencies of cortical responses at normal conduction values in the periphery were found. A trend for increased frequency of abnormal SEPs with duration of exposure to toluene and styrene and alcohol abuse was found. Abnormalities in SEPs in the exposed groups are most probably of multifactorial origin. Central SEP abnormalities in both exposed groups could indicate early signs of subclinical dysfunction at spinal and cortical levels and could be due to toluene or styrene exposure probably potentiated by alcohol consumption in the group exposed to toluene.

Rare Alleles within the CYP2E1 (MEOS System) Could be Associated with Better Short‐Term Health Outcome after Acute Methanol Poisoning

Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short‐term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI – rs2031920; PstI – rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (p = 0.34 for the RsaI variant; p = 0.59 for the PstI variant and p = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short‐term outcome after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/central nervous system (CNS) outcome.

Visual evoked potentials in patients after methanol poisoning.

OBJECTIVES We report the results of the visual evoked potentials (VEP) examination in patients after severe poisoning by methanol. MATERIAL AND METHODS The group of 47 patients (38 males and 9 females) was assembled out of persons who survived an outbreak of poisoning by the methanol adulterated alcohol beverages, which happened in the Czech Republic in 2012-2013. The visual evoked potentials examination was performed using monocular checkerboard pattern-reversal stimulation. Two criteria of abnormality were chosen: missing evoked response, and wave P1 latency > 117 ms. Non-parametric statistical methods (median, range, and the median test) were used to analyze factors influencing the VEP abnormality. RESULTS The visual evoked potential was abnormal in 20 patients (43%), 5 of them had normal visual acuity on the Snellen chart. The VEP abnormality did not correlate significantly with initial serum concentrations of methanol, formic acid or lactate; however, it showed statistically significant inverse relation to the initial serum pH: the subgroup with the abnormal VEP had significantly lower median pH in comparison with the subgroup with the normal VEP (7.16 vs. 7.34, p = 0.04). The abnormality was not related to chronic alcohol abuse. CONCLUSIONS The visual evoked potentials examination appeared sensitive enough to detected even subclinical impairment of the optic system. Metabolic acidosis is likely to be the key factor related to the development of visual damage induced by methanol. The examination performed with a delay of 1-9 months after the poisoning documented the situation relatively early after the event. It is considered as a baseline for the planned long-term follow-up of the patients, which will make it possible to assess the dynamics of the observed changes, their reversibility, and the occurrence of potential late sequelae.