Positive association between blood ethylene oxide levels and metabolic syndrome: NHANES 2013-2020.

Purpose: The exposure of Ethylene oxide (EO) is linked to systemic inflammatory response and various cardiovascular risk factors. Hemoglobin's binding to ethylene oxide (HbEO) was used to measure serum EO level. This research aims to explore the association between metabolic syndrome (MetS) and HbEO, and between HbEO and components of metabolic syndrome. Method: This research included 1842 participants from 2013 to 2020 in National Health and Nutrition Examination Survey (NHANES) database. Weighted logistic regression models were used to analyze the relationship between HbEO and metabolic syndrome risk, using odds ratio (OR) and 95% confidence interval (CI). The restricted cubic spline plot explores whether there is a dose-response relationship between HbEO and MetS risk. Subgroup analysis was performed to analyze study heterogeneity. Results: Significant differences were found in gender, educational level, marital status, diabetes status and hypertension among different groups (P < 0.001, P = 0.007, P = 0.003, P < 0.001, P < 0.001, respectively). The serum HbEO level exhibited positive correlation with metabolic syndrome risk in Q2 level (OR=1.64, 1.04~2.48), Q3 level (OR=1.99, 1.29~3.08), and Q4 level (OR=2.89, 1.92~4.34). The dose-response association suggested a possible linear association between serum HbEO and metabolic syndrome risk (P-overall=0.0359, P-non-linear=0.179). L-shaped association was found between HbEO and the risk of MetS in female population, obese population and mid-age and elder population (P-overall<0.001, P-non-linear=0.0024; P-overall=0.0107, P-non-linear=0.0055 P-overall<0.001 P-non-linear=0.0157). Conclusion: This study indicates a linear correlation between MetS and HbEO, with MetS risk escalating as HbEO levels increase. The prevalence of MetS varies depending on BMI, age and gender, and these factors can also influence MetS prevalence when exposed to EO.

Association between blood ethylene oxide levels and the prevalence of periodontitis: evidence from NHANES 2013-2014.

BACKGROUND: The study aimed to establish a link between blood ethylene oxide (EO) levels and periodontitis, given the growing concern about EO's detrimental health effects. MATERIALS AND METHODS: The study included 1006 adults from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) dataset. We assessed periodontitis prevalence across groups, used weighted binary logistic regression and restricted cubic spline fitting for HbEO-periodontitis association, and employed Receiver Operating Characteristic (ROC) curves for prediction. RESULTS: In the periodontitis group, HbEO levels were significantly higher (40.57 vs. 28.87 pmol/g Hb, P < 0.001). The highest HbEO quartile showed increased periodontitis risk (OR = 2.88, 95% CI: 1.31, 6.31, P = 0.01). A "J"-shaped nonlinear HbEO-periodontitis relationship existed (NL-P value = 0.0116), with an inflection point at ln-HbEO = 2.96 (EO = 19.30 pmol/g Hb). Beyond this, ln-HbEO correlated with higher periodontitis risk. A predictive model incorporating sex, age, education, poverty income ratio, alcohol consumption, and HbEO had 69.9% sensitivity and 69.2% specificity. The model achieved an area under the ROC curve of 0.761. CONCLUSIONS: These findings suggest a correlation between HbEO levels and an increased susceptibility to periodontitis.

Levels of Ethylene Oxide Biomarker in an Exposed Residential Community.

The purpose of this study was to examine whether there is a difference in ethylene oxide (EtO) biomarker levels based on residential proximity to facilities emitting EtO, a carcinogen. We recruited residents living near two EtO-emitting facilities and administered a questionnaire on items such as address and length of residency, smoking habits, occupational exposures to EtO, and demographics. We also collected venous blood samples to measure an EtO biomarker, hemoglobin adduct N-2-hydroxyethyl-valine (HbEO), and cotinine, a metabolite of nicotine. Questionnaires and blood samples were collected from 93 participants. The overall geometric HbEO adduct level was 35.0 pmol/gmHb and for nonsmokers it was 29.7 pmol/gmHb. Mean HbEO adduct levels were not significantly associated with sex, age, race, BMI, or education level. HbEO adduct levels for nonsmoking participants who lived in a neighborhood approximately 0.8 km from one of the facilities were significantly higher compared to persons living farther away (p < 0.001). These results suggest that facilities that emit EtO may put nearby communities at risk of cancer and other associated health outcomes.

Determination of N-(2-hydroxyethyl)valine in globin of ethylene oxide-exposed workers using total acidic hydrolysis and HPLC-ESI-MS2.

Ethylene oxide (EO), an industrial intermediate and gaseous sterilant for medical devices, is carcinogenic to humans, which warrants minimization of exposure in the workplaces. The principal analytical strategy currently used in biomonitoring of exposure to EO consists in the conversion of N-(2-hydroxyethyl) adduct at the N-terminal valine (HEV) in globin to a specific thiohydantoin derivative accessible to GC-MS analysis (modified Edman degradation, MED). Though highly sensitive, the method is laborious and, at least in our hands, not sufficiently robust. Here we developed an alternative strategy of HEV determination based on acidic hydrolysis (AH) of globin followed directly by HPLC-ESI-MS2 analysis. Limit of quantitation is ca. 25 pmol HEV/g globin. Comparative analyses of globin samples from EO-exposed workers by both the AH-based and MED-based methods provided results that correlated well with each other (R2 > 0.95) but those obtained with AH were significantly more accurate (according to external quality control programme G-EQUAS) and repeatible (5% and 6% for intra-day and between-day analyses, respectively). In conclusion, the new AH-based method surpassed MED being similarly sensitive, much less laborious and more reliable, thus applicable as an effective tool for biomonitoring of EO in exposure control and risk assessment.

High-throughput, simultaneous quantitation of hemoglobin adducts of acrylamide, glycidamide, and ethylene oxide using UHPLC-MS/MS.

Ethylene oxide (EO), acrylamide (AA) and glycidamide (GA) exposures are associated with mammary tumors in animals. Currently available information about human exposure to these chemicals is limited creating the need for analytical methods to assess their exposure. We developed a sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to simultaneously quantitate hemoglobin (Hb) N-terminal valine adducts of AA (HbAA), GA (HbGA), and EO (HbEO) using modified Edman reaction. The limits of detection of this method were 3.9, 4.9 and 12.9 in pmol/g Hb for HbAA, HbGA and HbEO, respectively. The among-day and within-day precision for all analytes determined with three levels of quality control pools ranged from 2.2-13.0% in percent coefficient of variation (%CV). The accuracy determined by standard addition was between 94 and 111% among all analytes. The median HbAA, HbGA and HbEO values in 34 self-reported non-smokers were 64.9, 45.3 and 113.6 pmol/g Hb and in 70 self-reported smokers were 127.8, 69.6 and 237.1 pmol/g Hb, respectively. HbAA, HbGA, and HbEO were detectable in all samples suggesting that the described method is suitable for measuring hemoglobin adducts of AA, GA and EO in the general population. This high throughput method can process 148 samples in 8 h. The HbEO/HbGA ratio appears independent of the HbAA levels in non-smokers and decreases with increasing HbAA concentration in smokers. This new method is suitable for measuring human exposure to AA, GA and EO and can provide further insight into the metabolism of these chemicals in humans.

Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans.

The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.

Intracellular delivery mechanism and brain delivery kinetics of biodegradable cationic bovine serum albumin-conjugated polymersomes.

BACKGROUND: A novel brain drug delivery system using cationic bovine serum albumin (CBSA)-conjugated biodegradable polymersomes (CBSA-PO) was prepared, and its intracellular delivery mechanism and brain delivery kinetics were evaluated. METHODS AND RESULTS: Biodegradable poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG-PCL) was used to prepare the polymersomes, and thiolated CBSA was conjugated with the surface of the polymersome. Transmission electron microscopy and dynamic light scattering showed that the CBSA-PO had a round and vesicle-like shape, with a mean diameter of around 100 nm. Coupling of CBSA with polymersomes was confirmed by X-ray photoelectron spectroscopy. Uptake of CBSA-PO by bEnd.3 cells was significantly higher than that of unconjugated polymersomes, but was inhibited by low temperature, free CBSA, and poly-L-lysine, indicating that endocytosis was energy-driven and absorptive-mediated. Cell viability assays confirmed the good safety profile of biodegradable CBSA-PO. Pharmacokinetic results demonstrated that the polymersomes had long circulation times, and CBSA conjugation on the polymersomes significantly increased the blood-brain barrier permeability surface area product by 3.6-fold and the percentage of injected dose per gram brain (% ID/g brain) by 2.1-fold. Capillary depletion experiments showed that CBSA-PO was distributed into the brain parenchyma in a time-dependent manner, with few polymersomes detected, indicating that conjugation of polymersomes with CBSA significantly improved their transcytosis across the brain-blood barrier. CONCLUSION: These results suggest that CBSA-PO is a promising drug brain delivery carrier with low toxicity.

Analysis of hemoglobin adducts from acrylamide, glycidamide, and ethylene oxide in paired mother/cord blood samples from Denmark.

The knowledge about fetal exposure to acrylamide/glycidamide from the maternal exposure through food is limited. Acrylamide, glycidamide, and ethylene oxide are electrophiles and form adducts with hemoglobin (Hb), which could be used for in vivo dose measurement. In this study, a method for analysis of Hb adducts by liquid chromatography-mass spectrometry, the adduct FIRE procedure, was applied to measurements of adducts from these compounds in maternal blood samples (n = 87) and umbilical cord blood samples (n = 219). The adduct levels from the three compounds, acrylamide, glycidamide, and ethylene oxide, were increased in tobacco smokers. Highly significant correlations were found between cord and maternal blood with regard to measured adduct levels of the three compounds. The mean cord/maternal hemoglobin adduct level ratios were 0.48 (range 0.27-0.86) for acrylamide, 0.38 (range 0.20-0.73) for glycidamide, and 0.43 (range 0.17-1.34) for ethylene oxide. In vitro studies with acrylamide and glycidamide showed a lower (0.38-0.48) rate of adduct formation with Hb in cord blood than with Hb in maternal blood, which is compatible with the structural differences in fetal and adult Hb. Together, these results indicate a similar life span of fetal and maternal erythrocytes. The results showed that the in vivo dose in fetal and maternal blood is about the same and that the placenta gives negligible protection of the fetus to exposure from the investigated compounds. A trend of higher levels of the measured adducts in cord blood with gestational age was observed, which may reflect the gestational age-related change of the cord blood Hb composition toward a higher content of adult Hb. The results suggest that the Hb adduct levels measured in cord blood reflect the exposure to the fetus during the third trimester. The evaluation of the new analytical method showed that it is suitable for monitoring of background exposures of the investigated electrophilic compounds in large population studies.

Simultaneous quantification of haemoglobin adducts of ethylene oxide, propylene oxide, acrylonitrile, acrylamide and glycidamide in human blood by isotope-dilution GC/NCI-MS/MS.

Haemoglobin adducts are highly valuable biomarkers of cumulative exposure to carcinogenic substances. We have developed and applied an analytical method for the simultaneous quantification of five haemoglobin adducts of important occupational and environmental carcinogens. The N-terminal adducts were determined with gas chromatography as pentafluorophenylthiohydantoine derivatives according to the modified Edman-procedure and subsequent acetonization of the glycidamide adduct N-(R,S)-2-hydroxy-2-carbamoylethylvaline (GAVal). The use of self-synthesized labelled internal standards in combination with tandem mass spectrometry using negative chemical ionisation guarantees both high accuracy and sensitivity of our determination. The limit of detection for N-2-hydroxyethylvaline (HEVal), N-(R,S)-2-hydroxypropylvaline (HPVal), N-2-carbamoylethylvaline (AAVal) and N-(R,S)-2-hydroxy-2-carbamoylethylvaline (GAVal) was 2 pmol/g globin, for N-2-cyanoethylvaline (CEVal) it was determined as 0.5 pmol/g globin, which was sufficient to determine the background levels of these adducts in the non-smoking general population. The between-day-precision for all analytes using a human blood sample as quality control material ranged from 4.7 to 12.3%. We investigated blood samples of a small group (n=104) of non-smoking persons of the general population for the background levels of these haemoglobin adducts. The median values for HEVal, HPVal, CEVal, AAVal and GAVal in a group of 92 non-smoking persons were 18.1, 4.1, <0.5, 29.9 and 35.2 pmol/g globin, respectively. The adduct levels in 12 persons reporting exposure to passive smoke at home were similar for most adducts with median values of 17.2, 4.1, 1.0, 24.9 and 29.7 pmol/g globin for HEVal, HPVal, CEVal, AAVal and GAVal, respectively. Our results point to an elevated uptake of acrylonitrile caused by passive smoking as indicated by higher levels of the corresponding haemoglobin adduct CEVal.

The effect of ethylene exposure on ethylene oxide in blood and on hepatic cytochrome p450 in Fischer rats.

Ethylene (74-85-1) is an important petrochemical and is produced endogenously. It is metabolized to ethylene oxide (EO) by cytochrome P450. We studied the inhibition of cytochrome P450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood. Male F344 rats were exposed to 1000, 600, and 300 ppm ethylene by nose-only inhalation for up to 6 h. Blood samples were obtained during exposure. On exposure to 600 ppm ethylene, blood EO concentration increased during the first hour of exposure and then decreased to approximately half of the peak blood concentration. A less pronounced decrease was observed at 300 ppm, and at 1000 ppm little change was observed between 10 min and 6 h of exposure. For the analysis of cytochrome P450 and isozyme-specific substrate activities, groups of four male F344 rats were removed for the collection of liver at various times after exposure to 300, 600, or 1000 ppm ethylene. At all concentrations, liver microsomal cytochrome P450 decreased during exposure. Of the various monooxygenase activities measured, 4-nitrophenol hydroxylase was the one most consistently altered, with maximal inhibition (approximately 50%) at 2 h of exposure to 1000 ppm ethylene, 4 h at 600 ppm, and 6 h at 300 ppm. Activity recovered to control levels by 6 h after exposure. Cytochrome P450 2E1 appears to be the major isoform of cytochrome P450 inhibited by exposure to ethylene, and this may explain in part the observed alteration in EO blood kinetics.

Formation of N-(2-hydroxyethyl)valine due to exposure to ethylene oxide via tobacco smoke: A risk factor for onset of cancer.

Human exposure to ethylene oxide (EtO) occurs mainly through inhalation of occupational polluted air and tobacco smoke. EtO is able to react with DNA and proteins producing some molecular adducts. One of these, resulting from reaction between EtO and valine in hemoglobin, is N-(2-hydroxyethyl) valine (HOEtVal). This adduct represents a biological effective dose marker, the level of which correlates linearly with the alkylating activity occurring in DNA. The aim of the present study was to measure HOEtVal in 146 urbanized adult and healthy subjects, nonoccupationally exposed to EtO, and to correlate it with smoke habits. HOEtVal showed a direct positive relationship to tobacco smoke exposure quantified by questionnaire, urinary cotinine (r=0.64509), and the number of cigarettes (r=0. 6308) actively or passively smoked. Results relative to HOEtVal and urinary cotinine in adults distinguish well between active and passive smokers but do not allow distinguishment between passive smokers and nonsmokers. Nevertheless, several authors demonstrated a very good capacity of cotinine to discriminate inside groups of adolescents passive smokers. Therefore, the future objective of the present study is a closer inspection of the two biomarkers with respect to passive exposure to tobacco smoke considering a large group of adolescents. Finally, the correlation between urinary cotinine and HOEtVal increases knowledge about early steps of the carcinogenic process due to active exposure to tobacco smoke.

Ethylene oxide dosimetry in the mouse.

Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Understanding the exposure-dose relationship for EO in rodents is critical for developing human EO exposure-dose models. The study reported here examined the dosimetry of EO in male B6C3F1 mice by direct determination of blood EO concentrations. Steady-state blood EO concentrations were measured during a single 4-h nose-only inhalation exposure (0, 50, 100, 200, 300, or 400 ppm EO). In addition, glutathione (GSH) concentrations were measured in liver, lung, kidney, and testis to assess the role of the GSH depletion in the saturable metabolism previously observed in mice (Brown et al., Toxicol. Appl. Pharmacol. 136, 8-19, 1996). Blood EO concentrations were found to increase linearly with exposure concentration up to 200 ppm. Markedly sublinear blood dosimetry was observed at exposure concentrations exceeding 200 ppm. An EO exposure concentration-dependent reduction in tissue GSH levels was observed, with both liver and lung GSH levels significantly depressed at EO exposure concentrations of 100 ppm or greater. Our results also indicate that depletion of GSH is likely responsible for nonlinear dosimetry of EO in mice and that GSH depletion corresponds with reports of dose-rate effects in mice exposed to EO.

Hemoglobin adducts of acrylamide and acrylonitrile in laboratory workers, smokers and nonsmokers.

Acrylamide is a chemical which is extensively used in research laboratories for the preparation of polyacrylamide gels for electrophoresis (PAGE). Blood samples were collected from laboratory personnel who were working with PAGE, from smokers, and from nonsmokers. Hemoglobin adducts of acrylamide, acrylonitrile, and ethylene oxide were determined using the modified Edman degradation procedure. Acrylamide adducts were detected in all persons. The PAGE workers (mean 54 pmol/g) had a significantly increased adduct level compared to nonsmoking controls (mean 31 pmol/g). The acrylamide adducts in smokers (mean 116 pmol/g) correlated with the number of cigarettes smoked per day. This confirms the presence of acrylamide in tobacco smoke and shows that it is an important source of acrylamide exposure. The increased level of acrylamide adducts in the PAGE workers corresponds to an uptake of acrylamide from about 3 cigarettes per day. It is not possible from this study to draw any conclusion as to which step in the working procedure is most critical for exposure. The PAGE workers are probably not at risk for neurotoxic damage to the peripheral nervous system. However, it needs to be investigated whether the exposure to acrylamide in PAGE workers represents a risk for genotoxic and reproductive effects. The high background of acrylamide adducts in nonsmoking controls was unexpected. The origin of this background is not known. Acrylonitrile adducts were below the detection limit (< 2 pmol/g) in nonsmoking controls. In the smokers (mean 106 pmol/g) this adduct correlated with cigarettes/day and with ethylene oxide adducts. Acrylonitrile adducts could be a better indicator of tobacco smoking than ethylene oxide adducts since the latter are showing a background of endogenous origin.

[Extemporaneous production of gas standard for the determination of carbon monoxide, hydrogen cyanide and ethylene oxide]. / Production extemporanée d'étalons gazeux pour le dosage chromatographique du monoxyde de carbone, de l'acide cyanhydrique et de l'oxyde d'éthylène.

This paper describes a new calibration method for headspace chromatographic assay of carbon monoxide, hydrogen cyanide and ethylene oxide. The calibration method is based on the in situ formation of gas in a closed system in order to avoid, the dangerous handling of pure gas or harmful substances. In the first method, the standardization is based on the in situ formation of carbon monoxide by the reaction of hot concentrated sulfuric acid with formic acid. In the second method, the standardisation is based upon the in situ reduction of ethyl thiocyano by dithiothreitol to produce HCN. In the third method, the standardisation is based upon the in situ chemical transformation of 2-chloro-ethanol into ethylene oxide with a recovery of about 60%.

A note on the physiological background of the ethylene oxide adduct 7-(2-hydroxyethyl)guanine in DNA from human blood.

A newly developed high-performance liquid chromatography (HPLC) method involves derivatization with phenylglyoxal and fluorescence detection, using 7-methylguanine as internal standard. The physiological background of the adduct 7-(2-hydroxyethyl)guanine in DNA isolated from human blood was determined by this method. In five persons the range of the adduct was between 2.1 and 5.8 pmol/mg DNA (mean 3.2). This finding is consistent with previous data obtained by others, using different analytical methods, and points to an intrinsic carcinogenic risk due to endogenous ethylene oxide.

Refinement and verification of the physiologically based dosimetry description for acrylonitrile in rats.

The physiologically based dosimetry description for acrylonitrile (ACN) and its mutagenic epoxide metabolite 2-cyanoethylene oxide (CEO) in F-344 rats (M. L. Gargas, M. E. Anderson, S.K.O. Teo, R. Batra, T. R. Fennell, and G. L. Kedderis, 1995, Toxicol. Appl. Pharmacol. 134, 185-194) has been refined to include a physiological stomach compartment and the reactions of ACN with tissue glutathione (GSH). The second-order rate constant for reaction of ACN and GSH at pH 7.3 was measured and included in the dosimetry description. Metabolic parameters for ACN and CEO were estimated from oral bolus pharmacokinetic studies and previously obtained iv bolus data (3.4, 47, 55, or 84 mg ACN/kg). Rats were given bolus oral doses of 3, 10, or 30 mg ACN/kg in water, and blood samples were collected at selected time points. ACN and CEO blood concentrations were determined by gas chromatography. The brain and liver concentrations of ACN and CEO were also measured after 10 mg ACN/kg po. ACN elimination from blood was described by saturable P450 epoxidation (Vmax of 5.0 mg/hr/kg and K(M) of 1.5 mg/liter) and first-order GSH conjugation (73 hr(-1)/kg). CEO elimination was described by first-order GSH conjugation (500 hr(-1)/kg). The pharmacokinetic data were well simulated, although CEO blood concentrations after bolus oral dosing were somewhat overestimated. Sensitivity analysis of the dosimetry description indicated that the inhalation exposure route was much more sensitive to changes in metabolic and physiological parameters than either the iv or oral bolus routes. Therefore, inhalation pharmacokinetic data were obtained and compared to simulations of the dosimetry description. Rats were exposed to 186, 254, or 291 ppm ACN for 3 hr. ACN and CEO concentrations were measured in blood, brain, and liver at selected postexposure time points. The dosimetry description accurately simulated the ACN inhalation pharmacokinetic data, providing verification of the parameter estimates. The verified rat dosimetry description for ACN and CEO will be used as the basis for development of a dosimetry description for ACN in people.

In vivo dosimetry of ethylene oxide and propylene oxide in the cynomolgus monkey.

In mammals, including the cynomolgus monkey, a striking difference between the potencies of ethylene oxide (EO)* and propylene oxide (PO) with respect to induction of certain clastogenic effects has previously been observed. In order to clarify to what extent such differences can be ascribed to a difference in detoxification rate, cynomolgus monkeys were administered an equimolar mixture of the two epoxides at two dose levels, and the blood doses were determined by measurement of the degree of alkylation of N-terminal valines in hemoglobin (Hb). For the highest exposure a saturation in the detoxification of PO was evident from a marked increase in adduct level. At the lower exposure, the dose in blood resulting from exposure to PO was about one fourth of that from EO. Although playing a great role, differences in detoxification rate, therefore, cannot fully account for the much lower clastogenic potency of PO, which has been found in earlier studies. Furthermore, the determination of doses in blood gives data on relationship between in vivo dose and exposure dose (accounting for detoxification), with relevance for risk estimation.

The research background for risk assessment of ethylene oxide: aspects of dose.

Data for relationships between in vivo doses inferred from levels of hemoglobin (Hb) or DNA adducts and administered (by inhalation or injection) doses of ethylene oxide (EO) in mice, rats and humans are reviewed. At low absorbed doses or dose rates these relationships appear to be linear, whereas at higher dose rates deviations from linearity due to saturation kinetics of detoxification and of DNA repair as well as certain toxic effects have to be allowed for. If these factors are taken into consideration, a rather consistent picture is obtained for animal studies, with a variation by less than a factor 2 between estimates of adduct level increments or in vivo dose increments per unit of administered dose. Although the value for in vivo dose per unit of exposure dose (ppm-hour) in humans is uncertain because of unreliable data for the time-weighted average exposure level, the most likely value for this relationship, supported by data for ethene, agrees with data for the rodents. In the animal species testis doses are approximately one-half of the blood doses inferred from Hb adducts.

Uptake and metabolism of ethene studied in a smoke-stop experiment.

Knowledge of the relationships between exposure levels and levels of hemoglobin adducts are essential when the latter are to be used for exposure monitoring or risk estimation, the hygienic control being based on measurements of exposure. These ratios are mostly very uncertain, mainly due to difficulties of determining the time-weighted average exposure concentration. A solution to this problem has been suggested involving adduct measurement before and after two consecutive periods of about 1 week, the first with absence from exposure, the second with careful measurement of exposure. This model was tested in two smokers who abstained from smoking for one week. Analysis of inhaled ethene and of adducts from ethylene oxide (EO) to N-terminal valine of hemoglobin are compatible with metabolism of 2% of inhaled ethene to EO and a detoxification rate of 1 h-1 of EO.

Determination of tissue partition coefficients for volatile tissue-reactive chemicals: acrylonitrile and its metabolite 2-cyanoethylene oxide.

Partition coefficients (PCs) are chemical-specific parameters used in physiologically based pharmacokinetic models to describe chemical solubility in tissues. Tissue:air PCs for volatile chemicals can be estimated using vial equilibration techniques in which the chemical concentration in the vial headspace is measured by gas chromatography after equilibrium is reached between the chemical in tissue and air. However, equilibrium would not be expected with tissue-reactive chemicals such as acrylonitrile (ACN) or its epoxide metabolite 2-cyanoethylene oxide (CEO). Active uptake of ACN was observed in rat blood due to reaction with blood sulfhydryl groups, while CEO reacted with all tissues examined (rat blood, muscle, fat, liver, and brain). The active uptake processes were first order as evidenced by a linear decrease in the log of the vial headspace concentrations over time. Linear extrapolation of the log of the apparent PC to zero time, where the contribution of the active uptake process is zero, yielded an estimated PC of 487 for ACN in blood. Equilibrium was achieved with ACN after treatment of blood with diethyl maleate to modify blood sulfhydryl groups, with a PC of 512 +/- 29 (mean +/- SE, n = 14). These PC estimates were verified by direct measurement of ACN concentrations in both the air and the blood (stabilized by acidification). The directly measured ACN blood:air PC was 437 +/- 8 (n = 8), which compared well with the estimated values. Treatment of tissues with diethyl maleate or 2,4-dinitrofluorobenzene did not abolish the active uptake of CEO. However, pretreatment of tissues with CEO itself abolished subsequent CEO uptake. The CEO blood:air PC estimates obtained from zero time extrapolation of four CEO concentrations (1672 +/- 139) and from CEO pretreatment (1658 +/- 137, n = 8) were in good agreement. These data indicate that tissue:air PCs for volatile reactive chemicals can be estimated by extrapolation of a first-order uptake process to zero time or at equilibrium following chemical modification of reactive groups in tissues.