Identification of markers of depression and neurotoxicity in pesticide exposed agriculture workers.

Earlier, we reported that chronic exposure to pesticides causes a reduction in the acetylcholinesterase activity and hematological and biochemical alterations in agriculture workers. In continuation with that, the present study aimed to investigate the pesticide-induced neurochemical imbalance and its association with behavior alterations in agricultural workers. A significant increase in depressive symptoms, assessed by the Beck Depression Inventory-II was observed in pesticide exposed workers as compared to the unexposed. A decrease in the level of dopamine in plasma and levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acids, norepinephrine, serotonin, and hydroxyindoleacetic acid in urine was also observed. An increase in the levels of MAO-A and MAO-B has also been observed in these individuals. The decreased levels of neurotransmitters in the blood and urine have been linked with increased levels of MAO and pesticide residues in plasma and urine. Furthermore, these changes were associated with a higher incidence of depression in agricultural workers.

The effects of the exposure to neurotoxic elements on Italian schoolchildren behavior.

Neurodevelopmental disorders are constantly increasing on a global scale. Some elements like heavy metals are known to be neurotoxic. In this cross-sectional study we assessed the neurobehavioral effect of the exposure to trace elements including lead, mercury, cadmium, manganese, arsenic and selenium and their interactions among 299 schoolchildren residing in the heavily polluted Taranto area in Italy. Whole blood, urine and hair were collected for metal analyses, while the Child Behavior Checklist and the Social Responsiveness Scale, administered to the main teacher and the mothers were considered to identify behavioral problems in children. Blood lead mainly influenced social problems, aggressive behavior, externalizing and total problems. Urinary arsenic showed an impact on anxiety and depression, somatic problems, attention problems and rule breaking behavior. A significant interaction between lead and arsenic was observed, with a synergistic effect of the two metals increasing the risk of attention problems, aggressive behavior, externalizing problems and total problems. Overall, we were able to test that higher blood lead, urinary arsenic concentrations and their interaction increase the risk of neurobehavioral problems. This is in line with the U.S. Environmental Protection Agency's priority list of hazardous substances where arsenic and lead are ranked as first and second respectively.

Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity.

The mechanism by which the recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (C(max) and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.

Association between occupational exposure to arsenic and neurological, respiratory and renal effects.

Occupational exposure by inhalation in copper smelter is associated with several subclinical health phenomena. The respiratory tract is usually involved in the process of detoxication of inhaled noxious agents which, as arsenic, can act as inductors of oxidative stress (Lantz, R.C., Hays, A.M., 2006. Role of oxidative stress in arsenic-induced toxicity. Drug Metab. Rev. 38, 791-804). It is also known that irritating fumes affect distal bronchioles of non-ciliated, epithelial Clara cells, which secrete anti-inflammatory and immunosuppressive Clara cell protein (CC16) into the respiratory tract. The study group comprised 39 smelters employed at different workplaces in a copper foundry, matched for age and smoking habits with the control group (n=16). Subjective neurological symptoms (SNS), visual evoked potentials (VEP), electroneurographic (EneG) and electroencephalographic (EEG) results were examined in the workers and the relationships between As concentration in the air (As-Air) and urine (As-U) were assessed. Effects of exposure were expressed in terms of biomarkers: CC16 as early pulmonary biomarker and beta(2)-microglobulin (beta(2)M) in urine and serum and retinol binding protein (RBP) as renal markers, measured by sensitive latex immunoassay. The concentrations of arsenic exceeded about two times the Threshold Limit Values (TLV) (0.01 mg/m(3)). The contents of lead did not exceed the TLV (0.05 mg/m(3)). Low CC16 levels in serum (12.1 microg/l) of workers with SNS and VEP symptoms and highest level As-U (x(a) 39.0 microg/l) were noted earliest in relation to occupational time. Moreover, those effects were associated with increased levels of urinary and serum beta(2)M and urinary RBP. Results of our study suggested the initiative key role of oxidative stress in triggering the processes that eventually lead to the subclinical effects of arsenic on the nervous system.

Excessive apoptosis and disordered autophagy flux contribute to the neurotoxicity induced by high iodine in Sprague-Dawley rat.

In recent years, the detrimental effects of high iodine on intelligence are gaining tons of attention, but the relationship between high iodine and neurotoxicity is controversial. This study aimed to explore whether high iodine intake may impair intelligence and the roles of apoptosis and autophagy in high iodine-induced neurotoxicity. The results showed that high iodine exposure reduced brain coefficient and intelligence of rats, and caused histopathological abnormalities in hippocampus. Moreover, high iodine increased hippocampal apoptosis, as confirmed by elevation of apoptotic proteins and TUNEL-positive incidence. Further study showed that high iodine impaired mitochondrial ultrastructure and caused elevation of Bax, cytochrome c and decline of Bcl2, indicating the participation of mitochondrial apoptotic pathway. Simultaneously, high iodine also increased the number of autophagosomes. Intriguingly, the expression of autophagosomes formation protein Atg7, Beclin1 and autophagic substrate p62 were elevated, suggesting that the accumulated autophagosomes is not only due to the enhancement of formation but also the decline of clearance. These, together with the numerous damaged organelles observed in hippocampal ultrastructure, reveal the crucial role of disordered autophagy flux in high iodine-elicited neurotoxicity. Collectively, these findings suggest that excessive apoptosis and disordered autophagy flux contribute to high iodine-elicited neurotoxicity.

A little "dab" will do ya' in: a case report of neuro-and cardiotoxicity following use of cannabis concentrates.

CONTEXT: The use of marijuana and cannabis concentrates is increasing, especially following decriminalization in several states. Psychosis and cardiotoxicity have been reported following cannabis use; however, myocardial injury from "dabbing" has not yet been reported. We report a case of hyperthermia, tachycardia, hypertension, severe agitation, neuro-, and cardiotoxicity following the use of "dabs" where there is concomitant confirmatory biological and sample testing. CASE DETAILS: A 17-year-old athletic man developed agitation requiring sedation and intubation for safety, with peak systolic blood pressures in the 190s and hyperthermia (to 102 °F). He developed elevated serum troponins with persistent tachycardia despite sedation and no clear non-intoxicant etiology. It was discovered that the patient had recently been "dabbing"; an exhaustive search of his home found a sample of the "dabs" which was analyzed along with a comprehensive urine drug screen by tandem liquid mass spectroscopy (t-LCMS) for confirmation. DISCUSSION: Tetrahydrocannabinol (THC) has been increasingly associated with agitation and cardiotoxicity, while cannabidiol (CBD) has been associated with neuroprotective, inhibitory states. We propose that increasing concentrations of THC as well as THC:CBD ratios seen in cannabis concentrates such as "dabs" may cause agitation and end-organ damage through sympathomimetic and serotonergic pathways.

Arsenic groundwater contamination and its health effects in Patna district (capital of Bihar) in the middle Ganga plain, India.

We investigated the extent and severity of groundwater arsenic (As) contamination in five blocks in Patna district, Bihar, India along with As in biological samples and its health effects such as dermatological, neurological and obstetric outcome in some villages. We collected 1365 hand tube-well water samples and analyzed for As by the flow injection hydride generation atomic absorption spectrometer (FI-HG-AAS). We found 61% and 44% of the tube-wells had As above 10 and 50 µg/l, respectively, with maximum concentration of 1466 µg/l. Our medical team examined 712 villagers and registered 69 (9.7%) with arsenical skin lesions. Arsenical skin lesions were also observed in 9 children of 312 screened. We analyzed 176 biological samples (hair, nail and urine). Out of these, 69 people had arsenical skin lesions and rest without skin lesions. We found 100% of the biological samples had As above the normal levels (concentrations of As in hair, nail and urine of unexposed individuals usually ranges from 20 to 200 µg/kg, 20-500 µg/kg and <100 µg/l, respectively), indicating many people are sub-clinically affected. Arsenical neuropathy was observed in 40.5% of 37 arsenicosis patients with 73.3% prevalence for predominant sensory neuropathy and 26.7% for sensor-motor. Among patients, different clinical and electrophysiological neurological features and abnormal quantitative sensory perception thresholds were also noted. The study also found that As exposed women with severe skin lesions had adversely affected their pregnancies. People including children in the affected areas are in danger. To combat As situation in affected areas, villagers urgently need (a) provision of As-safe water for drinking and cooking, (b) awareness about the danger of As toxicity, and (c) nutritious food.

Relationship between Urinary Pesticide Residue Levels and Neurotoxic Symptoms among Women on Farms in the Western Cape, South Africa.

BACKGROUND: This cross-sectional study aimed to investigate the relationship between urinary pesticide residue levels and neurotoxic symptoms amongst women working on Western Cape farms in South Africa. METHOD: A total of 211 women were recruited from farms (n=121) and neighbouring towns (n=90). Participant assessment was via a Q16 questionnaire, reporting on pesticide exposures and measurement of urinary OP metabolite concentrations of dialkyl phosphates (DAP) and chlorpyriphos, 3,5,6-trichloropyridinol (TCPY) and of pyrethroid (PYR) metabolite concentrations (3- phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the cis- and trans isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid. RESULTS: Median urinary pesticide metabolites were slightly (6%-49%) elevated in the farm group compared to the town group, with 2 metabolites significantly higher and some lower in the farm group. The prevalence of all Q16 symptoms was higher amongst farm women compared to town women. Three Q16 symptoms (problems with buttoning, reading and notes) were significantly positively associated with three pyrethroid metabolites (cis- and trans-DCCA and DBCA), although associations may due to chance as multiple comparisons were made. The strongest association for a pyrethroid metabolite was between problems with buttoning and DBCA (odds ratio (OR)=8.93, 95% confidence interval (CI):1.71-46.5. There was no association between Q16 symptoms and OP metabolites. CONCLUSIONS: Women farm residents and rural women from neighbouring towns in the Western Cape are exposed to OP and PYR pesticides. The study did not provide strong evidence that pesticides are associated with neurotoxic symptoms but associations found could be explored further.

Neurotoxicity associated with exposure to 1-bromopropane in golf-club cleansing workers.

BACKGROUND: 1-Bromopropane (1-BP) is an alternative to ozone-depleting solvent that is used in degreasing, dry cleaning, spray adhesives, and aerosol solvents. Occupational exposure to 1-BP is associated with adverse peripheral sensory, motor, and central nervous system (CNS) effects. We report our Health Hazard and Medical Evaluation of 6 patients with neurotoxicity associated with occupational exposure to 1-BP. Case series and environmental evaluation. Six workers, 1 male and 5 female, were exposed to high ambient 1-BP concentrations while employed in a golf club cleaning factory. 1-BP was identified in the bulk solvent sample used by the workers and confirmed the workers' daily occupational exposure to 1-BP for 3-10 months. The major presenting symptoms were tingling pain, soreness in lower extremities, and paresthesia. N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys), a 1-BP metabolite, was identified by LC/MS/MS in the urine (0.171-1.74 mg/g-Cr) of these workers 5-26 days following 1-BP exposure. DISCUSSION AND CONCLUSION: An occupational outbreak of 1-BP poisoning occurred as a result of recurrent power outages, condenser, and exhaust fans malfunction, and inadequate personal protection. Occupational exposure to 1-BP may result in peripheral neuropathy as well as adverse CNS effects. Urine AcPrCys may be a specific biomarker for 1-BP exposure.

Altered mental status and end organ damage associated with the use of gacyclidine: a case series.

INTRODUCTION: Over the past decade, there has been a sharp increase in the number of newly identified synthetic drugs. These new drugs are often derivatives of previously abused substances but have unpredictable toxicity. One of these drugs is gacyclidine, a derivative of phencyclidine (PCP). Gacyclidine has been studied as a neuroprotective agent in trauma and as a therapy of soman toxicity. There are no previous reports of its use as a drug of abuse. CASE REPORTS: During a two-month period in the summer of 2013, a series of patients with severe agitation and end-organ injury were identified in an urban academic Emergency Department (ED). A urine drug of abuse screen was performed on all patients, and serum samples were sent for comprehensive toxicology analysis. A total of five patients were identified as having agitation, rhabdomyolysis, and elevated troponin (Table 1). Three of the five patients reported use of methamphetamine, and all five patients had urine drug screens positive for amphetamine. Comprehensive serum analysis identified methamphetamine in three cases, cocaine metabolites in one case, and a potential untargeted match for gacyclidine in all five cases. No other drugs of abuse were identified. DISCUSSION: This is the first series of cases describing possible gacyclidine intoxication. The possible source of the gacyclidine is unknown but it may have been an adulterant in methamphetamine as all patients who were questioned reported methamphetamine use. These cases highlight the importance of screening for new drugs of abuse when patients present with atypical or severe symptoms. Gacyclidine has the potential to become a drug of abuse both by itself and in conjunction with other agents and toxicity from gacyclidine can be severe. It is the role of the medical toxicology field to identify new agents such as gacyclidine early and to attempt to educate the community on the dangers of these new drugs of abuse.

Neurobehavioral effects of exposure to organophosphates and pyrethroid pesticides among Thai children.

The use of pesticides for crop production has grown rapidly in Thailand during the last decade, resulting in significantly greater potential for exposure among children living on farms. Although some previous studies assessed exposures to pesticides in this population, no studies have been conducted to evaluate corresponding health effects. Twenty-four children from a rice farming community (exposed) and 29 from an aquaculture (shrimp) community (control) completed the study. Participants completed a neurobehavioral test battery three times at 6 month intervals: Session I: preliminary orientation; Session II: high pesticide use season; Session III: low pesticide-use season. Only sessions II and III were used in the analyses. High and low pesticide use seasons were determined by pesticide use on rice farms. Urinary metabolites of organophosphates (OPs) and pyrethroids (PYR) were analyzed from first morning void samples collected the day of neurobehavioral testing. Rice farm participants had significantly higher concentrations of dialkylphosphates (DAPs) (common metabolites of OPs) and TCPy (a specific metabolite of chlorpyrifos) than aquaculture farm children during both seasons. But, TCPy was significantly higher during the low rather than the high pesticide use season for both participant groups. Rice farm children had significantly higher DCCA, a metabolite of PYR, than aquaculture participants only during the high exposure season. Otherwise, no significant differences in PYR metabolites were noted between the participant groups or seasons. No significant adverse neurobehavioral effects were observed between participant groups during either the high or low pesticide use season. After controlling for differences in age and the Home Observation for Measurement of the Environment (HOME) scores, DAPs, TCPy, and PYR were not significant predictors of adverse neurobehavioral performance during either season. Increasing DAP and PYR metabolites predicted some relatively small improvement in latency of response. However, due to the small sample size and inability to characterize chronic exposure, any significant differences observed should be regarded with caution. Moreover although not statistically significant, confidence intervals suggest that small to moderate adverse effects of pesticide exposure cannot be ruled out for some indicators of neurobehavioral performance.

Neuropsychological effects of low mercury vapor exposure in chloralkali workers.

Neuropsychological effects were examined in 47 mercury vapor exposed male chloralkali workers with current low concentrations of urinary mercury (mean U-Hg 5.9 nmol/mmol creatinine (Cr)). Their average duration of exposure was 13.3 years, and the calculated mean concentration of U-Hg was 9.0 nmol Hg/mmol Cr per year (exposure intensity) during their time of exposure. They were compared with 47 age-matched male referents in a cross-sectional study. The two groups were not statistically significantly different with respect to neuropsychological test performance or number of self-reported subjective symptoms. The test results of the Static Steadiness Test, which assesses tremor, were not associated with exposure to mercury vapor. However current smokers had more hand tremor than non-smokers. Statistically significant associations were found between indices of current exposure (the concentration of inorganic mercury in whole blood) and the results of the WAIS Digit Symbol Test and the Benton Visual Retention Test (number of correct responses). This could indicate a small effect of current exposure on visuomotor/psychomotor speed and attention, and immediate visual memory. Whether the association found between the historical exposure intensity and the Digit Symbol Test results may represent long-term consequences of exposure cannot be determined in this study.

2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe): clinical case with unique confirmatory testing.

INTRODUCTION: 2C designer drugs have been in use since the 1970s, but new drugs continue to develop from substitutions to the base phenethylamine structure. This creates new clinical profiles and difficulty with laboratory confirmation. 2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe) is a relatively new 2C drug that is more potent than structural 2C analogs; exposure reports are rare. Testing for 2C drugs is developing; specific testing for new analogs such as 25I-NBOMe is a challenge. These drugs do not reliably trigger a positive result on rapid drug immunoassays. Additionally, most facilities with confirmatory testing capabilities will not identify 25I-NBOMe; methods for detecting 25I-NBOMe in biological samples have not been clearly described nor have optimal metabolic targets for detecting 25I-NBOMe ingestion. CASE REPORT: An 18-year-old female presented following use of 25I-NBOMe. She had an isolated brief seizure, tachycardia, hypertension, agitation, and confusion. She improved with intravenously administered fluids and benzodiazepines and was discharged 7 h postingestion. Urine was analyzed using quantitative LC-MS/MS methodology for 25I-NBOMe, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)-methyl]ethanamine (25C-NBOMe), and 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe). 25I-NBOMe was found at a concentration of 7.5 ng/mL, and 25H-NBOMe was detected as well. Additional testing was pursued to characterize the metabolism of 25I-NBOMe; the sample was reanalyzed with UPLC-time-of-flight mass spectrometry to identify excreted metabolites. The sample was additionally analyzed for the presence of 2,5-dimethoxy-4-iodophenethylamine (2C-I), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), and 1-(2,5-dimethoxy-4-ethylphenyl)-2-aminoethane (2C-E). DISCUSSION: This is a report of a patient presenting following exposure to 25I-NBOMe, a dangerous member of the evolving 2C drug class. The exposure was confirmed in a unique manner that could prove helpful in guiding further patient analysis and laboratory studies.

Association of aryl hydrocarbon receptor gene polymorphism with the neurobehavioral function and autonomic nervous system function changes induced by benzo[a]pyrene exposure in coke oven workers.

OBJECTIVE: To analyze the association of aryl hydrocarbon receptor (AhR) gene polymorphism and the neurotoxicity induced by benzo[a]pyrene (B[a]P) in coke oven workers. METHODS: Subjects, 214 coke oven workers and 81 controls, were detected for neurobehavioral function and autonomic nervous system (ANS) function. Airborne B[a]P concentration, urinary 1-hydroxypyrene level, and AhR gene polymorphisms were determined and analyzed for their association with B[a]P neurotoxicity. RESULTS: Neurobehavioral function and ANS function were significantly decreased and dependent on B[a]P dose. The AhR GG, GA, and AA genotypes in G1661A fitted the Hardy-Weinberg equation, whereas C1549T and G1708A gene mutants were not detected. Indices indicating neurotoxicity showed no significant difference among individuals with AA, GG, or GA genotype except for the confusion-bewilderment (P > 0.05). CONCLUSION: The AhR gene polymorphism is not thought to correlate with B[a]P neurotoxicity among coke oven workers.

Nephrotoxicity, neurotoxicity, and mercury exposure among children with and without dental amalgam fillings.

PURPOSE: A scientific review panel for the US Food and Drug Administration (FDA) recently identified the need for more data on the health risk of mercury exposure from dental amalgam among susceptible populations. We evaluated impacts of low-level mercury exposure on renal function and neurobehavioral and neuropsychological performance among children. METHODS: Dental histories for 403 children aged 7-11 years in five schools from Xuhui, Shanghai were checked by dentists. Of them, 198 with confirmed amalgam fillings were recruited (exposure group). Reference children (N=205) were those who never had dental amalgam treatment. In May 2004, each child provided a urine sample for measurements of total mercury, N-acetyl-beta-D-glucosaminidase activity, microalbumin, and creatinine (Cr). The Child Behavior Checklist, Eysenck Personality Questionnaire, and an intelligence screening test were administered. RESULTS: The geometric mean urinary mercury concentration was 1.6 microg/g Cr for children with and 1.4 microg/g Cr for children without amalgam fillings. No differences were found between children with and without fillings for either renal function biomarker, or on neurobehavioral, neuropsychological, or intelligence tests. CONCLUSIONS: Although urinary mercury concentration was slightly elevated among children with amalgam fillings, we found no evidence of adverse effects on the outcomes evaluated. These results agree with those from recent trials in developed countries.

Monitoring for adverse effects of antiepileptic drugs.

Best practices for monitoring the adverse effects of antiepileptic drugs (AEDs) have not been carefully studied. Routine blood and urine studies do not appear to be of value in asymptomatic patients to avoid severe acute reactions. Subtle chronic AED side effects exist but algorithms for their detection and treatment are not well developed. Randomized clinical trials do not support the value of routine AED serum levels to improve compliance, seizure control, or avoid side effects. Simple screening procedures for neurotoxicity have not been developed. Some personal suggestions are offered.

[Increased urinary excretion of the neurotoxic side-chain metabolites of ifosphamide in children with polymorphism of the glutathione S-transferases genes]. / Zwiekszone dobowe wydalanie neurotoksycznych metabolitów ifosfamidu u dzieci z dziedziczonym polimorfizmem genów kodujacych transferazy S-glutationu.

UNLABELLED: From 5% to 30% of children treated with ifosphamide (IF) develop symptoms of neurotoxicity due to toxic metabolites of the drug: 2- and 3- dechloroifosphamide (2- and 3-DCIF) and chloracetaldehyde (CAA), which cause glutathione depletion in cells. The aim of the study is to establish the influence of polymorphism of genes encoding for glutathione S-transferases classes pi (GSTP1), mi (GSTM1) and theta (GSTT1) on frequency of neurotoxicity of IF and amounts of toxic metabolites of the drug excreted in urine. MATERIAL AND METHODS: Neurotoxicity of IF was assessed in 76 children (38 girls and 38 boys), aged 9 to 210 months with diffrent kinds of neoplasms. They were treated with IF in 3-hours infusion in doses from 1.5 g/m2 to 3 g/m2 for 3 to 5 days. Before chemotherapy, deletions of GSTT1, GSTM1 genes and transition at +313 A-G in GSTP1 gene were identified with PCR and PCR-FRLP method, respectively. Daily urine excretion of 2-DCIF, 3-DCIF and unmetabolised IF was assessed with nuclear magnetic resonance (31P NMR). RESULTS: Symptoms of neurotoxicity were observed in 14 (18%) of 76 examined children treated with IF Comparing to children without neurological symptoms, in children with encephalopathy urinary excretion of unchanged ifosphamide was lower (p=0.055) and 2DCIF and 3DCIF was increased. Concomitantly, in children with transition at 313 A-->G GSTP1 gene concentrations of 2DCIF and 3DCIF were increased. Excretion of unmetabolised IF was statistically significantly higher in children with deletion of GSTT1 gene (p=0.02). Moreover, no correlation was found between the GSTM1 genotype and the excretion of ifosphamide and its metabolites. CONCLUSION: The results suggest that ifosphamide can be the substrate for glutathione S-transferases. Polymorphism of genes coding for glutathione S-transferases can influence individual reactions to iphosphamide.

Role of GSTM1, GSTP1, and GSTT1 gene polymorphism in ifosfamide metabolism affecting neurotoxicity and nephrotoxicity in children.

The aim of this study was to evaluate the impact of GSTM1, GSTT1, and GSTP1 gene polymorphism on urinary excretion of unchanged ifosfamide, 2-dechloroethylifosfamide (2DCIF), and 3-dechloroethylifosfamide (3DCIF) with regard to the incidence of ifosfamide-related nephrotoxicity and neurotoxicity in children. The study comprised 76 children (38 girls, 38 boys) ages 9.84 to 210 months who were being treated for various malignant diseases with ifosfamide. The children were enrolled after identification of genotype coding for three classes of glutathione S-transferases (GSTM1, GSTT1, and GSTP1) at the initial stage of diagnosis. (P) nuclear magnetic resonance spectroscopy was used to analyze the urinary excretion of unchanged ifosfamide, 2DCIF, and 3DCIF metabolites on consecutive days after the end of the 3-hour infusion of ifosfamide. In children with polymorphic locus of the GSTP1 gene compared with children with homozygous wild alleles, increased urinary excretion of 3DCIF (P=0.029) and decreased creatinine clearance was found (Mann-Whitney P=0.03; median 81.1 mL/min/1.73 m vs. 105.0 mL/min/1.73 m, respectively). The authors' multidimensional analysis model revealed that besides the total ifosfamide dose and co-administration of other toxic drugs, polymorphic locus of GSTP1 gene may be one of the factors determining a higher toxicity of the cytostatic agent. The model was construed at P=0.029. Moreover, no correlation was found between the GSTM1 or GSTT1 genotype and ifosfamide toxicity and the urinary excretion of its metabolites. The results of this analysis indicate that individual reactions to ifosfamide can depend on inherited genetic polymorphisms, especially associated with the GSTP1 gene coding detoxifying enzyme.

Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish.

This study documents the effects of puffer-fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus-responses, strength-duration time constant (tau(SD)), threshold electrotonus, and current-threshold relations were recorded. The urine of each patient tested positive for tetrodotoxin. Compared with controls, axons were of higher threshold, compound muscle action potentials and compound sensory nerve action potentials were reduced in amplitude, latency was prolonged, and tau(SD) was reduced. In recovery cycles, refractoriness, superexcitability, and late subexcitability were decreased. Threshold electrotonus of motor axons exhibited distinctive abnormalities with less threshold decline than normal on depolarization and greater threshold increase on hyperpolarization (p < 0.0005 for each patient). The changes in excitability were reproduced in a mathematical model by reducing sodium (Na(+)) permeabilities by a factor of two. This study confirms that the neurotoxic effects of puffer-fish poisoning can be explained by tetrodotoxin blockade of Na(+) channels. It demonstrates the ability of noninvasive nerve excitability studies to detect Na(+) channel blockade in vivo and also the utility of mathematical modeling to aid interpretation of altered excitability properties in disease.