Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning.

CONTEXT: Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger. OBJECTIVE: To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. METHODS: In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis. RESULTS: The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6-75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14-118.4) and only five (23%) controls (median, < Lower Limit of Quantitation (LLQ); range, < LLQ-43.3 mcg/mL). Significant differences and associations were identified between case status and the following: 1) serum oxalic acid and serum HEAA (both OR = 14.6; 95% C I = 2.8-100.9); 2) serum diglycolic acid and urine diglycolic acid (both OR > 999; exact p < 0.0001); and 3) urinary glycolic acid (OR = 0.057; 95% C I = 0.001-0.55). Two CSF sample results were excluded and two from the same case were averaged, yielding eight samples from eight cases. Diglycolic acid was detected in seven (88%) of case CSF samples (median, 2.03 mcg/mL; range, < LLQ, 7.47). DISCUSSION: Significantly elevated HEAA (serum) and diglycolic acid (serum and urine) concentrations were identified among cases, which is consistent with animal data. Low urinary glycolic acid concentrations in cases may have been due to concurrent AKI. Although serum glycolic concentrations among cases may have initially increased, further metabolism to oxalic acid may have occurred thereby explaining the similar glycolic acid concentrations in cases and controls. The increased serum oxalic acid concentration results in cases versus controls are consistent with this hypothesis. CONCLUSION: Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning. These findings add to animal data suggesting a possible role for traditional antidotal therapies. The detection of HEAA and diglycolic acid in the CSF of cases suggests a possible association with signs and symptoms of DEG-associated neurotoxicity. Further work characterizing the pathophysiology of DEG-associated neurotoxicity and the role of traditional toxic alcohol therapies such as fomepizole and hemodialysis is needed.

Survivors from beta-fluoroethyl acetate poisoning show a selective cerebellar syndrome.

UNLABELLED: AIM/ BACKGROUND: beta-Fluoroethyl acetate (FEA), a derivative of sodium fluoroacetate (Compound 1080, FA), is one of the high-potency toxic chemicals, and it has been used against rats and wild animals. Human casualties from FA or FEA poisoning, accidental or suicidal, have been reported. Survivors of the poisoning are extremely rare. The objective of this study is to present survivors of FEA poisoning. METHOD: Data on the survivors were collected at the Department of Neurology over the past 20 years. Reviews of the medical record and brain imaging were performed. RESULTS: A total of 10 survivors of FEA poisoning were found. All of the cases were suicide attempts. The amount of FEA ingested varied from 600 to 1800 mg with a mean of 1200 mg, which is close to the lethal dose of FEA. Immediately after ingestion, all of the patients had an altered mental status. On awakening, all of the patients had severe cerebellar dysfunction, such as ataxic gait, dysarthria and intention tremor. The cerebellar dysfunction usually improved gradually over the years after the event, but this improvement eventually plateaued, resulting in residual and persistent cerebellar dysfunction. Serial imaging showed swelling in the posterior fossa during the acute phase and progressive cerebellar atrophy on follow-up. CONCLUSION: In summary, FEA poisoning causes a selective cerebellar syndrome in its survivors. The pathomechanism underlying the selective cerebellar toxicity of FEA remains to be elucidated. The selective involvement of the cerebellum might provide a useful model for cerebellar degeneration.

Comparison of the in vitro hemolytic effects produced by alkoxyacetic acids on human and rat erythrocytes.

OBJECTIVES: The alkoxyacetic acids (AAAs) are urinary metabolites of alkoxyethanol solvents. It is well documented that these chemicals can cause acute hemolytic anemia in humans and laboratory animals. There are scarce data on the relative hemolytic activity of these acids. Likewise, information is lacking on the relationship between their hemolytic activity and physicochemical properties. The aim of this study was to compare the hemolytic activity of five AAAs in red blood cells (RBCs) derived from donors' blood and male Wistar rats. Moreover, the possible relationship between lipophilic and hemolytic activity of AAAs was also investigated. MATERIALS AND METHODS: The RBCs washed in TRIS buffer, pH 7.4, were adjusted to a packed cell volume (PCV) of about 20% and incubated in a water bath at 37 degrees C for 0-3 h in the presence of different concentrations of AAAs. The hemolytic effects, in terms of the changes in RBCs, PCV, mean corpuscular volume (MCV) and free hemoglobin (HGBfree) in incubation medium, were evaluated. Based on the dose-response relationship for RBCs, PCV and MCV, the effective concentration values (EC50) and their 95% confidence intervals (95% CI) were calculated. The octanol-water partition coefficient (log P) and distribution coefficient (log D) of AAAs were computed using PALLAS software. The correlation between log P and log D values for AAAs at pH 7.4 and their EC50 was analyzed. RESULTS: Human RBCs were 1.9-3.1 times more resistant to the hemolytic activity of AAAs than rat erythrocytes. Also, the hemolytic activity of individual AAAs did not differ considerably; the maximum differences ranging from 2.0 to 3.3. The EC50 values of AAAs highly correlated with their log P and log D values. CONCLUSIONS: The relatively small differences between the hemolytic effects of AAAs on rat and human erythrocytes may be associated with the strong acidity and relatively similar lipophilicity of these chemicals.

An unusual toxic cause of hemolytic-uremic syndrome.

Hemolytic uremic syndrome (HUS) has been associated with a variety of infective as well as non-infective causes. HUS as a toxic manifestation of exposure to herbicides/pesticides has not been reported so far in literature. We report a subject who presented with clinical features of features of HUS after intentional suicidal ingestion of the herbicidal agent monochloroacetic acid (MCA). A 55-year-old farmer was admitted with a history of consumption of monochloroacetic acid with vomiting, hematochezia and oligo-anuria. Our investigations revealed severe renal failure, metabolic acidosis, anemia, and thrombocytopenia with evidence of intravascular hemolysis. He was treated for HUS with plasma transfusions and haemodialysis in view of renal failure. During the course of hospital admission he developed acute antero-septal myocardial infarction and subsequently succumbed to the disease. MCA is used as an herbicidal agent and also a bleaching agent for silkworm cocoons. The toxicity of MCA has included metabolic acidosis, rhabdomyolysis and renal failure; however HUS has not been described in the literature. Extra -renal manifestations of HUS such as cardiomyopathy have also been infrequently described. This case is presented to highlight an as yet unknown toxicity of MCA.

Fatal workplace accident involving ethyl acetate: a distribution study.

The tissue distribution of ethyl acetate and ethanol in a case of acute intoxication by ethyl acetate is presented. The victim was a 39-year-old man who was found dead lying on his abdomen in the interior of a tank containing ethyl acetate. Confirmation of ethyl acetate was obtained with static headspace gas chromatography with mass spectrometry. In blood, rapid biotransformation of ethyl acetate occurs by plasma esterases resulting in acetic acid and ethanol. Quantitation of ethyl acetate and ethanol in the postmortem samples was performed using static headspace gas chromatography with flame ionization detector. N-butanol was used as internal standard. Separation of the compounds was obtained on a Supelcowaxtrade mark-10 Fused Silica capillary column. The method was linear over the specific ranges investigated and showed a within-run accuracy of 99.8 and 101.0% and a precision of 0.5 and 2.0% for ethanol and ethyl acetate, respectively. The postmortem samples were analyzed in duplicate or triplicate. Coefficients of variation were < or =4.51% for ethyl acetate and < or =0.52% for ethanol. The low ratios of the ethyl acetate concentration to the ethanol concentration found in the postmortem tissue samples confirmed the rapid in vivo biotransformation of ethyl acetate. The highest concentration of ethyl acetate was found in the testis indicating that postmortem percutane absorption may have occurred. To our knowledge, this is the first reported tissue distribution study of ethyl acetate and ethanol in a case of acute intoxication by ethyl acetate.

Impact of aminopolycarboxylates on aquatic organisms and eutrophication: overview of available data.

Aminopolycarboxylic acids, which include ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), diethylenetriaminepentaacetic acid (DTPA), 1,3-propylenediaminetetraacetic acid (1,3-PDTA), beta-alaninediacetic acid (beta-ADA), and methylglycinediacetic acid (MGDA), constitute a class of complexing agents that occur in a wide range of domestic products and that are used intensively as metal sequestrants in several industrial applications. Because they are highly polar and partially nondegradable, aminopolycarboxylates are released into the aquatic environment in significant quantities, mainly via wastewater. The historical and current use of aminopolycarboxylates and their ubiquitous presence in surface waters prompted many studies about their possibly detrimental impact on aquatic organisms. This review summarizes the available data and information on the eutrophication potential and toxicity of aminopolycarboxylates to a multitude of aquatic organisms including vertebrates, invertebrates, algae, bacteria, and protozoa. This article also addresses how the ecotoxic effects of aminopolycarboxylates are dependent on their speciation, that is, on their presence in a free or a metal-complexed form.

The effect of disinfection by-products and mutagenic activity on birth weight and gestational duration.

Epidemiologic studies of disinfection by-products have traditionally focused on total trihalomethane (TTHM) concentration as a surrogate for maternal exposure during pregnancy. We used birth certificate data on 196,000 infants to examine the effect of third-trimester exposures on various indices of fetal development. We examined the effect of town-average concentrations of TTHM and additional exposure metrics in relation to mean birth weight, mean gestational age, small for gestational age (SGA) infancy, and preterm delivery. Trihalomethane data (TTHM, chloroform, and bromodichloromethane) from 1995-1998 were available for 109 towns in Massachusetts. Data from 1997-1998 on haloacetic acid (total haloacetic acids, dichloroacetic acid, and trichloroacetic acid), 3-chloro-4-(dichloromethyl)-5- hydroxy-2(5H)-furanone (MX), and mutagenicity were available for a limited number of towns. We observed reductions in mean birth weight (12-18 g) for maternal trihalomethane exposures > the 90th percentile compared with those < the 50th percentile. Birth weight reductions were detected for chloroform exposures > 20 microg/L and TTHM exposures > 40 microg/L. Elevated trihalomethanes were associated with increases in gestational duration and a reduced risk of preterm delivery. We found evidence of an exposure-response effect of trihalomethanes on risk of SGA, with odds ratios (ORs) ranging from 1.09 to 1.23 for bromodichloromethane exposures > 5 microg/L. Elevated mutagenic activity was associated with SGA [OR = 1.25; 95% confidence interval (CI), 1.04 to 1.51] and mean birth weight (-27 g; 95% CI, -54 to -1). Although smaller in magnitude, our findings are consistent with previous studies reporting associations between trihalomethanes and SGA. These data also suggest a relationship between fetal development indices and mutagenic activity independent of exposure to trihalomethanes, haloacetic acids, and MX.

Exposure assessment in epidemiologic studies of adverse pregnancy outcomes and disinfection byproducts.

A major challenge in studies that examine the association between disinfection byproducts in drinking water and pregnancy outcomes is the accurate representation of a subject's exposure. We used household water samples and questionnaire information on water-use behavior to examine several aspects of exposure assessment: (i) the distribution and correlation of specific disinfection byproducts, (ii) spatial distribution system and temporal variation in byproduct levels, and (iii) the contribution of individual water-use behavior. The level of specific trihalomethanes (THMs) and haloacetic acids (HAAs) was determined for 360 household water samples in Eastern Ontario and Nova Scotia. Subjects were interviewed regarding tap water ingestion and showering and bathing practices. In both provinces, total THMs correlated highly with chloroform (correlation coefficient (r) >0.95) and less so with total HAAs (r = 0.74 in Nova Scotia and r = 0.52 in Ontario). The correlation between total THMs and bromodichloromethane was high in Nova Scotia (r = 0.63), but low in Ontario (r = 0.26). The correlation was between THM level in individual household samples, and the mean THM level during the same time period from several distribution system samples was 0.63, while a higher correlation in THM level was observed for samples taken at the same location 1 year apart (r = 0.87). A correlation of 0.73 was found between household THM level and a total exposure measure incorporating ingestion, showering, and bathing behaviors. These results point to the importance of: measurement of different classes of byproducts; household rather than distribution system sampling; and, incorporation of subject behaviors in exposure assessment in epidemiologic studies of disinfection byproducts and adverse pregnancy outcomes.

An unusual cause of burn injury: skin exposure to monochloroacetic acid.

Chemical burns can be complicated by the absorption of some of the toxic products through the skin and a subsequent systemic toxicity. We report here the case of a 3-year-old child who was accidentally exposed to monochloroacetic acid and sent to our burn unit with second-degree burn wounds. Regardless of the entry route, monochloroacetic is rapidly and very effectively absorbed and induces a severe toxic syndrome. In the case of skin resorption, the severity of the intoxication is directly related to the area of the contaminated skin contaminated with fatalities when the exposure level reaches more than 5% of the body surface. In the case of a chemical burn with a suspicion of systemic toxicity or in case of burn with an unusual product, the correct attitude is to contact a poison information center, to immediately wash the exposed skin, and to start treating the systemic toxicity as soon as possible. The availability of specific antidotes in the case of unusual poisoning can be a problem.

Characterization of gabapentin overdose using a poison center case series.

BACKGROUND: Gabapentin is an anticonvulsant that is being used for an increasing number of off-label indications. The purpose of this study is to document the clinical manifestations and outcomes of gabapentin exposures reported to poison centers. METHODS: A multicenter prospective observational study of all gabapentin exposures reported to three poisoncenters was conducted between 4/1/98 and 4/1/2000. Cases involving gabapentin only were evaluated. RESULTS: There were 20 cases with gabapentin as the sole substance in doses ranging from 50 mg to 35 g. Ten of the 20 cases involved children and adolescents. Clinical effects developed early and resolved within 10 hours in most patients. Seven cases were managed in the home with only observation. Four of these patients remained asymptomatic. Effects reported in the three symptomatic patients were drowsiness (3) and ataxia (1). Thirteen patients were managed in a health care facility. Nine were symptomatic with reported effects of drowsiness (6), dizziness (3), nausea/vomiting (2), tachycardia (2), and hypotension (2). None of the patients were admitted for medical care. CONCLUSION: In this cases series, gabapentin exposures caused no or minimal toxicity.

Massive gabapentin and presumptive quetiapine overdose.

Previous reports of gabapentin overdose have described mild symptoms of somnolence, ataxia and slurred speech. Quetiapine has produced a false positive for cyclic antidepressants on immunoassay drugscreens. Quetiapine overdose is associated with coma, QTc prolongation and hypotension. We report a case of massive gabapentin and presumptive quetiapine overdose with the highest recorded serum gabapentin concentration (104.5 u/ml) associated with coma, respiratory depression requiring mechanical ventilation, and hypotension.

High-dose montelukast exposures in a 3-year-old and a 5-year-old child.

The leukotriene receptor antagonists (LTRAs) is a relatively new class of asthma medication with a lack of toxicity for unintentional poisoningsituations. This makes it difficult to determine which exposures require aggressive decontamination or simple monitoring in the home setting: prompting the question, "What LTRA dose is likely to produce significant toxicity?" We report a case of an unintentional poisoning with 80 mg montelukast in a 3-y-o asthmatic child that was managed in the home with observation alone and a second case of untentional 135 mg montelukast poisoning in a 5-y-o asthmatic child managed in an emergency department. In both cases, symptoms were not observed. These cases and available literature suggest that doses < 4.5 mg/kg in children result in minimal toxicity.

Mixture of N-carbamoyl-L-glutamate plus L-arginine can protect rats with liver cirrhosis from acute ammonia intoxication.

BACKGROUND/AIMS: We earlier reported that N-carbamoyl-L-glutamate (CG) plus L-arginine (Arg) protected normal and 70% hepatectomized rats from intoxication by a lethal or sub-lethal dose of ammonium acetate, respectively. In the present study, the protective effect of these compounds on cirrhotic rats was assessed. METHODS: CG plus Arg were administered prior to the injection of a sub-lethal dose of ammonium acetate into dimethylnitrosamine-induced cirrhotic rats. Control rats were given phosphate-buffered saline (PBS) instead of the mixture. The behavior of the rats was monitored until the time of sacrifice. Blood ammonia level, blood urea nitrogen (BUN) and liver carbamoylphosphate synthetase I (CPS I) activity were determined. RESULTS: Pretreatment of rats with the mixture of CG plus Arg could significantly lower the blood ammonia level (P<0.05), increase the activity of CPS I (P<0.05), improve abnormal behavior associated with ammonia intoxication (P<0.05), and increase BUN (P<0.05), as compared with the PBS-injected control group. There were significantly close correlations between (1) the increase of CPS I activity; (2) the improvement of abnormal behavior; (3) the increase of BUN; and (4) the decrease of the blood ammonia level. CONCLUSIONS: A mixture of CG plus Arg could protect rats with liver cirrhosis from acute ammonia intoxication.