Biomarkers in patients admitted to the emergency department after exposure to acrylonitrile in a major railway incident involving bulk chemical material.

BACKGROUND: A railway incident with victims of exposure to the cyanogenic substance acrylonitrile (ACN). AIMS: We retrospectively (i)built an inventory of the clinical characteristics of individuals admitted to surrounding emergency departments (ED's) and (ii)studied the correlation between N-2-cyanoethylvaline (CEV), a biomarker used in a population study for evaluating exposure to ACN, with lactate and thiocyanate (SCN), biomarkers determined during emergency care. RESULTS: 438 patients from 11 ED's were included and presented with known symptoms of ACN poisoning but also with concern about the risks. A comparison of CEV with lactate or SCN was possible in 108 and 73 patients respectively. CEV was very high in a critically ill patient with a high lactate. There was no correlation with CEV in the patients with normal or slightly elevated lactate concentrations. A correlation of CEV with SCN was only observed in smokers. LIMITATIONS: First there is a lack of data in some clinical files concerning the time and duration of exposure and the smoking-status. A second limitation is that blood samples for biomarkers were not taken systematically in all patients, which may have induced bias. A third limitation is that blood sampling was possibly done outside the correct time window related to the delayed toxicity of ACN. Finally the number of severely-intoxicated patients was low and ACN exposure may not have taken place e.g. in individuals consulting with psychological symptoms. These aspects may have contributed to the below detection limits' analyses of biomarkers. CONCLUSIONS: CEV was markedly elevated in a severely-intoxicated patient with high lactate, a sensitive marker for CN intoxication. We found no correlation of CEV with normal or slightly elevated lactate concentrations but clinicians should consider the possibility of subsequent rises due to the delay in ACN toxicity. CEV correlated with SCN in smokers, which may be explained by ACN in tobacco smoke and deserves further exploration. Further studies are necessary to evaluate the correlation between biomarkers in acute chemical exposures to ACN and these should be carried out prospectively using a preplanned template.

Acrylonitrile exposure in the general population following a major train accident in Belgium: a human biomonitoring study.

BACKGROUND: On Saturday May 4, 2013, a train transporting chemicals derailed in the village of Wetteren (Belgium) and caused a leak of acrylonitrile (ACN). OBJECTIVES: To assess the human exposure to acrylonitrile in the local population with the highest suspected exposure. METHODS: Between May 18-25, 242 residents participated in the study. N-2-cyanoethylvaline (CEV), a biomarker that is highly specific for ACN exposure, was measured in the blood. To account for potential influence by smoking, cotinine was determined in the urine. Participants also filled in a short questionnaire. RESULTS: In the evacuated zone, 37.3% of the non-smokers and 40.0% of the smokers had CEV concentrations above the reference values of 10 and 200 pmol/g globin, respectively, at the time of the train accident. Spatial mapping of the CEV concentrations depending on the residential address showed a distribution pattern following the sewage system. DISCUSSION AND CONCLUSION: The train derailment resulted in a highly atypical sequence-of-events. In addition to exposure in the direct vicinity of the site of the train derailment, exposure also occurred via the sewage system, into which acrylonitrile had entered shortly after the accident.

Acrylonitrile exposure assessment in the emergency responders of a major train accident in Belgium: a human biomonitoring study.

BACKGROUND: On May 4, 2013, a train transporting chemicals derailed in Wetteren, Belgium. Several tanks loaded with acrylonitrile (ACN) exploded, resulting in a fire and a leakage of ACN. OBJECTIVES: To determine exposure to ACN and to assess discriminating factors for ACN exposure in the emergency responders involved in the on-site management of the train accident. METHODS: The study population consisted of 841 emergency responders. Between May 21 and June 28, they gave blood for the determination of N-2-cyanoethylvaline (CEV) hemoglobin adducts and urine for the measurement of cotinine. They also filled in a short questionnaire. RESULTS: 163 (26%) non-smokers and 55 (27%) smokers showed CEV concentrations above the reference values of 10 and 200 pmol/g globin, respectively. The 95th percentile in the non-smokers was 73 pmol/g globin and the maximum was 452 pmol/g globin. ACN exposure among the non-smokers was predicted by (1) the distance to the accident, (2) the duration of exposure, and (3) the occupational function. DISCUSSION AND CONCLUSION: Emergency responders involved in the on-site management of the train accident were clearly exposed to ACN from the accident. However, the extent of exposure remained relatively moderate with CEV concentrations staying within the ranges described in literature as background for a smoking population. Moreover, the exposure was less pronounced in the emergency responders as compared to that in the local population.

Follow-up biomonitoring after accidental exposure to acrylonitrile:- implications for protein adducts as a dose monitor for short-term exposures.

The analysis of protein adducts is a valuable tool for the biomonitoring of humans exposed to alkylating compounds. In case of single or intermittent exposures, however, the significance and validity of adduct analysis is limited due to the typically small increase in adduct levels and a nonlinear adduct elimination kinetic. This issue was addressed in a follow-up observation of four workers accidentally exposed to acrylonitrile (ACN) in a train depot. N-2-Cyanoethylvaline (CEV) in hemoglobin was analyzed in blood samples of the workers and of seven rescue team and hospital members, approximately, 25 days after the accident. Of the 11 potentially exposed persons, only the cleaning workers revealed adduct levels significantly above the general background. Further blood samples of the workers were analyzed after 85, 115 and 175 days, respectively. In these cases, the adduct concentrations declined to background levels associated with individual smoking habits. A linear regression analysis of the data points to a total elimination interval of 148 days, 2 weeks longer than the standard lifespan of erythrocytes and possibly due to a period of acrylonitrile circulation in the blood stream or release from unstable intermediates. The data allow a rough estimate of the initial protein adduct concentration and an evaluation of the internal dose on the basis of biological exposure equivalents. In conclusion, adduct analyses offer valuable information even in the case of short-term exposures.

The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals: consequences for occupational and environmental medicine.

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/ RsaI (mutant allele: CYP2E1*5B) located in the 5'-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

Polymorphism of glutathione S-transferases and susceptibility to acrylonitrile and dimethylsulfate in cases of intoxication.

In this paper, the difficulties of genetic screening of occupationally exposed subjects for the evaluation of retrospective, and prospective, health risk assessments is illustrated with reference to glutathione S-transferase (GST) function. Individual differences in the magnitude and half-life of adduct levels, derived from background and occupational exposure, are observed largely independently of genetically determined conjugator status. During detoxification, GSTs play a critical role in providing protection against electrophiles and products of oxidative stress. GSTs are a superfamily of enzymes that may have broad and overlapping substrate specificities. Deficiencies of GST isoenzymes may be compensated by the presence of other isoforms and by the use of alternative metabolic pathways. This may be one reason for the abundance of controversial data on GST polymorphisms and adverse health effects.

[Effect of the cholinesterase reactivator dipyroxime in various models of delayed hypersensitivity during acute intoxication by acrylonitrile]. / Vliianie reaktivatora kholinésterazy dipiroksima na formirovanie giperchuvstvitel'nosti zamedlennogo tipa.

Delayed type hypersensitivity (DTH) response with respect to sheep erythrocytes was studied on various models in CBA mice against the background of acute intoxication with nitrile acrylic acid (NAA). The effect of dipiroxime on the DTH response under these conditions was determined and the relationship of these reactions with the activity of alpha-naphthylbutyratesterase in splenic cells and popliteal lymph nodes was assessed. Dipiroxime partly recovered DTH in various experimental series (except for the reaction of suppressor cell transfer) by restoring the alpha-naphthylbutyratesterase activity in cells of the lymphoid organs studied.

Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human accidental poisonings.

The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized in humans and experimental animals via two competing pathways; the glutathione-dependent pathway is considered to represent an avenue of detoxication whilst the oxidative pathway leads to a genotoxic epoxide, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acrylonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalation and/or by skin contact. The combined observations lead to the conclusion of a much higher impact of the oxidative metabolism of acrylonitrile in humans than in rodents. This is confirmed by differences in the clinical picture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine with sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences. Furthermore, differential adduct monitoring, assessing protein adducts with different rates of decay, enables the development of more elaborated biological monitoring strategies for the surveillance of workers with potential acrylonitrile contact.

[The effect of sodium thiosulfate on nonspecific body resistance and on the immune reactions in acute acrylonitrile poisoning]. / Vliianie tiosul'fata natriia na nespetsificheskuiu rezistentnost' organizma i immunnye reaktsii pri ostrom otravlenii akrilonitrilom.

Experiments on noninbred Wistar mice and rats showed that acute acrylonitrile (0.5 LD50) intoxication leads to decrease of nonspecific resistance of the organism and humoral and cellular immunity responses. The antidote sodium thiosulfate increases suppression of the responses under study.

N-alkylvaline levels in globin as a new type of biomarker in risk assessment of alkylating agents.

Adducts with the N-terminal valine of erythrocyte globin can serve as individual biomarkers of systemic and cellular exposure to endogenous and exogenous alkylating agents. In contrast to "detoxification markers" of this kind of mecapturic acids derived from alkylation of glutathione, individual N-alkylations of valine in globin reflect the formally "toxifying" part of the stress due to alkylating agents transformed into the ultimate toxicant. Thus, in contrast to the traditional methods of biological monitoring this approach enables a better evaluation of systemic exposure to reactive agents, adapted more sensibly to the exposure situation over the whole life span of erythrocytes, and it can serve as a specific biomarker of exposure for the purpose of health surveillance in occupational medicine. An individual evaluation of exposures in comparison with the range of corresponding background levels is discussed from the point of view of supplementary risk assessment in medical surveillance of occupationally exposed persons.

[Glutathione and the redox index in different types of cellular oxidative stress. I. Acrylonitrile (ACN) poisoning]. / Glutationul si indexul redox in diferite tipuri de stres oxidativ celular. I. Intoxicatia cu acrilonitril (ACN).

The professional poisoning with acrylonitrile of some subjects induced a significant decrease of reduced glutathione (81.30%), redox ratio reduced glutathione/oxidized glutathione (90.74%) and "Benzi-redox index" (55.84%) but an increase of oxidized glutathione level (112.6%) as compared to normal controls (100%). This proves the occurrence, in time, of the cellular oxidative stress and/or were obtained.

Acute acrylonitrile toxicity: studies on the mechanism of the antidotal effect of D- and L-cysteine and their N-acetyl derivatives in the rat.

Thiol-containing antidotes for acute acrylonitrile (AN) toxicity may exert their action by chemically reacting with AN, by replacing critical sulfhydryl groups cyanoethylated by AN, and by detoxifying cyanide produced from AN metabolism. We have evaluated the ability of the optical isomers of cysteine and N-acetylcysteine to act as antidotes against AN toxicity in order to assess the relative importance of each of these three antidotal mechanisms. The toxicity of AN was determined in male Sprague-Dawley rats and compared to the toxicity determined after treatment with 2 mmol/kg of thiol antidote by computing a protective index (median lethal dose with antidote/median lethal dose without antidote). The protective indices of L-cysteine, D-cysteine, N-acetyl-L-cysteine, and N-acetyl-D-cysteine were 2.03, 1.97, 1.76, and 1.25, respectively. Measurements of urinary mercapturates, derived from the non-oxidative pathway of AN metabolism, indicated that none of the antidotes was able to significantly increase the excretion of these metabolites. Blood cyanide generated from the oxidative metabolism of AN and butyronitrile was also determined. All of the antidotes, except N-acetyl-D-cysteine, lowered blood cyanide levels. A comparison of these results with the predicted relative abilities of the enantiomers to participate in each of the three antidotal mechanisms leads to the conclusion that, under these experimental conditions, the best correlation exists with the cyanide detoxification mechanism.

[Study of the activity of membrane-bound leukocyte enzymes in chronic acrylonitrile poisoning in experimental studies and occupational environment]. / Issledovanie aktivnosti membranno-sviazannykh fermentov leikotsitov pri khronicheskoi intoksikatsii akrilonitrilom v éksperimente i v usloviiakh proizvodstva.

It was established that acrylonitrile (AN) toxic action resulted in changes in the morphofunctional characteristics of white blood cells. Deviations were found in the activity of the marker enzymes of alkaline phosphatase neutrophil secretory granules and myeloperoxidase. Other changes were established in the markers of acid phosphatase lysosomes, the enzyme of plasma membrane--5 nucleotidase, in the endoplasm network of glucose-6-phosphatase, in succinate dehydrogenase mitochondria, and in alpha-glycerolphosphate dehydrogenase. Along with a considerably lowered succinate dehydrogenase activity, lymphocyte cell deformation against the activity of this enzyme was detected. The data obtained specified newly revealed changes in the blood at AN intoxication and indicated to innovated means of its prophylaxis.

[Use of antioxidants for preventing the hepatotoxic effect of acrylonitrile]. / Ispol'zovanie antioksidantov dlia preduprezhdeniia gepatotoksicheskogo éffekta akrilonitrila.

The authors examined the possibility of using antiooxidants in the chemoprophylaxis of poisonings with alkylating chemical compounds. It was demonstrated that vitamin E, ionol and low-molecular thiols (cystein, glutatione and unithiol) prevent the increased permeability of plasma membranes and impairment of the protein-synthesizing function of the endoplasmic reticulum of hepatoytes in acute and chronic acrylonitrile poisoning.