Selecting an appropriate biomonitoring strategy to evaluate dermal exposure to opioid narcotic analgesics in pharmaceutical production workers.

OBJECTIVES: In a follow-up study of previous research, in which exposure pathways for opioid narcotic analgesics were identified in pharmaceutical workers involved in drug synthesis, the current research focused on the selection of an appropriate biomonitoring strategy. METHODS: Six opioid narcotic production workers were intensively monitored during a (1 week) fentanyl production campaign. A systematic sampling scheme was followed that provided information about hand contamination and biomarker levels at multiple time points. RESULTS: Linear mixed-effects models, incorporating half-shift and end-of-shift hand contamination levels, showed a positive and significant correlation with fentanyl urinary excretion occurring at many of the 4 h time lags investigated (4-28 h). Optimum model characteristics, including both minimal between- and within-worker variability, were obtained at lag times of 24 h and 20 h, respectively, advocating a pre-shift urine sampling strategy on the following day. In addition, for these lag times the portion of the variability explained by the model was maximal. Furthermore, using a distributed lag model, it was demonstrated that urinary fentanyl levels were positively correlated with hand contamination levels measured at the preceding four 8 h time lags (8-32 h), although statistical significance was only shown for a lag time of 24 h. CONCLUSION: Fentanyl levels in pre-shift urine samples reflect dermal exposure to the compound during the previous day. Thus, in the specific working environment investigated, a biological monitoring protocol evaluating pre-shift urinary fentanyl levels could provide an adequate risk estimate in individual workers.

Acquiring symptoms in response to odors: a learning perspective on multiple chemical sensitivity.

In this chapter, a learning account is discussed as a potential explanation for the symptoms in multiple chemical sensitivity. Clinical evidence is scarce and anecdotal. A laboratory model provides more convincing results. After a few breathing trials containing CO2-enriched air as an unconditioned stimulus in a compound with harmless odor substances as conditioned stimuli, subjective symptoms are elicited and respiratory behavior is altered by the odors only. Also, mental images can become conditioned stimuli to trigger subjective symptoms. The learning effects cannot be explained by a response bias or by conditioned arousal, and they appear to involve basic associative processes that do not overlap with aware cognition of the relationship between the odors and the CO2 inhalation. Learned symptoms generalize to new odors and they can be eliminated in a Pavlovian extinction procedure. In accordance with clinical findings, neurotic subjects and psychiatric cases are more vulnerable to learning subjective symptoms in response to odors. Consistent with a learning account, cognitive-behavioral treatment techniques appear to produce beneficial results in clinical cases. Several criticisms and unresolved questions regarding the potential role of learning mechanisms are discussed.

Occupationally related exposures and reduced semen quality: a case-control study.

OBJECTIVE: To determine whether there is an association between abnormal semen parameters and occupational exposures to organic solvents, metals, and pesticides. DESIGN: Case-control study using three case groups based on different cutoff values for semen parameters and one standard reference group. SETTING: University Hospital Utrecht and University Hospital Rotterdam, the Netherlands. PATIENT(S): Male partners of couples having their first consultation at the two infertility clinics (n = 899). INTERVENTION(S): Men provided at least one semen sample. Occupational exposure was assessed with use of job-specific questionnaires, a job exposure matrix, and measurements of metals and metabolites of solvents in urine. MAIN OUTCOME MEASURE(S): Standard clinical semen analyses were used to define case groups and controls. RESULT(S): An association between aromatic solvents and reduced semen quality was demonstrated, irrespective of the exposure assessment method used. The associations were stronger if the case definition was based on stricter cutoff values for semen parameters. Risk estimates were higher if the analysis was restricted to primary infertile men. Exposure to other pollutants at the workplace was not associated with impaired semen quality. CONCLUSION(S): The findings indicated an association between aromatic solvent exposure and impaired semen parameters.

Comparison of styrene-7,8-oxide adducts formed via reaction with cysteine, N-terminal valine and carboxylic acid residues in human, mouse and rat hemoglobin.

The reactive metabolite of styrene, styrene-7,8-oxide (SO), reacts with a variety of nucleophilic sites in hemoglobin (Hb) to form SO-Hb adducts. Following the in vitro incubation of SO with blood from humans, NMRI mice and Sprague-Dawley rats, the second-order reaction rate constants were determined for the reaction of SO with cysteine (through both the alpha- and beta-carbons of SO), N-terminal valine (through the beta-carbon of SO), and carboxylic acid (presumably through both the alpha- and beta-carbons of SO) residues in Hb. The rate constants for cysteine adducts vary dramatically between species [2.04, 10.7, 133 L (mol Hb)-1 h-1 (alpha binding) for humans, mice and rats, respectively] and [0.078, 2.16, 20.4 L (mol Hb)-1 h-1 (beta binding), respectively]. The considerably higher rate of reaction with cysteine in rat Hb probably reflects the presence of an additional cysteine residue at position beta 125. Although the rate constants for valine adducts (1.82, 0.80, 0.29 L (mol Hb)-1 h-1, respectively) and COOH adducts (3.55, 1.94, 2.37 L (mol Hb)-1 h-1, respectively) are much more consistent, the inter-species differences are statistically significant for the reaction of SO with the N-terminal valine of Hb. Following the i.p. administration of styrene to mice and styrene and SO to rats, the levels of adducts at each of these sites were used in conjunction with the calculated rate constants to predict the integrated blood doses of SO. While the SO doses predicted from cysteine and valine adducts were very similar, that based upon COOH-binding was significantly different, presumably due to the instability of SO-COOH adducts. This research affirms the use of both cysteine and valine adducts, but not carboxylic acid adducts, as biomarkers of exposure to styrene and SO.

Comparative urinary excretion of ethoxyacetic acid in man and rat after single low doses of ethylene glycol monoethyl ether.

Male rats were given a single oral dose of ethylene glycol monoethyl ether (EGEE), the dose ranging from plausible human exposures (0.5-1 mg/kg) to doses reported in the literature (100 mg/kg). Urinary excretion of ethoxyacetic acid (EAA) and its glycine conjugate was followed up to 60 h after dosing and compared to data of experimentally exposed human volunteers. In rats, the mean elimination half-life of free as well as conjugated EAA was 7.2 h for all doses. EAA was excreted partly as a glycine conjugate (on average 27%), the extent of conjugation being independent of the dose. The conjugation with glycine showed a clearly diurnal variation, the lowest extent being found during the night. The relative amount of EGEE recovered in urine as EAA was only 13.4% for the lowest dose, but increased as the administered dose of EGEE was higher, indicating that EGEE was metabolised at least in two parallel pathways of which one pathway becomes saturated at relatively low doses. In man, urinary excretion of EAA for equivalent low doses of EGEE differed from that in the rat by a longer elimination half-life (mean 42 h), by the absence of EAA conjugates and by a higher recovery.

Comparison of ethylene, propylene and styrene 7,8-oxide in vitro adduct formation on N-terminal valine in human haemoglobin and on N-7-guanine in human DNA.

Epoxides react at various nucleophilic sites in macromolecules such as haemoglobin and DNA. To study the reaction rate constants of ethylene oxide (EO), propylene oxide (PO) and styrene 7,8-oxide (SO) towards two of these positions, i.e., the N-terminal valine in haemoglobin and N-7-guanine in DNA was the central aim of this investigation. These two reactive sites are the most studied haemoglobin and DNA adducts, respectively. Further attention, therefore, was also paid to the applicability in vivo of the in vitro determined reaction constants. The determination of the second-order rate constants between EO and PO and N-terminal valine in Hb [2.7 l (mol Hb h)-1 and 1.0 l (mol Hb h)-1, respectively] were consistent with the literature values. The constants for the reaction with N-7-guanine [16x10(-3) l (mol DNA nucleotide h)-1 and 7. 7x10(-3) l (mol DNA nucleotide h)-1, respectively] were lower than previously published values, probably due to differences in the methodology used. The use of the in vitro obtained values to model the in vivo situation lead to a consistent picture for EO and PO. In contrast, for SO the in vitro ratio between the adduct formation on N-terminal valine [1.5 l (mol Hb h)-1] and N-7-guanine [0.71x10(-3) l (mol DNA nucleotide h)-1] was about two orders of magnitude greater than for the in vivo situation. This was probably due to a lower than expected reactivity of SO towards N-terminal valine in vivo. Further research is needed to elucidate whether the use of SO in vitro, contrasting with the in vivo experiments in which SO was metabolically formed from styrene, could entail an explanation for this discrepancy. Concerning the methodological part, the use of dipeptide standards to replace the alkylated globins as standard lead to an improvement of the method. Especially the commercial availability of the standards, their stability and accurately known adduct content will make them to the standards of choice in the future.

Cytogenetic analysis of lymphocytes from fiberglass-reinforced plastics workers occupationally exposed to styrene.

In this study a group of 52 workers employed in a plant manufacturing fiberglass-reinforced plastic (FRP) pipes and cisterns, and therefore daily exposed to styrene, were monitored. As a control group 24 non-exposed workers from another factory producing and repairing pallets volunteered to participate. The airborne styrene during the monitoring ranged from 2.2 to 110.1 mg/m3. As a metabolic marker for styrene exposure mandelic acid was measured in the urine and ranged from 11 to 649 mg/g creatinine. From 43 exposed and 15 control workers sister-chromatid exchanges (SCE) and high frequency cell (HFC) data and from 49 exposed and 23 control workers micronucleus (MN) data from peripheral lymphocytes are reported. Although the two groups of workers could clearly be distinguished on the basis of the airborne styrene concentrations and urinary mandelic acid concentrations no differences in any of the cytogenetic markers were found. Correlations between the cytogenetic data and the level of airborne styrene concentrations or urinary mandelic acid levels could also not be demonstrated. Otherwise, smoking increased the SCE frequency. Grouping the workers according to smoking habits showed a statistically significant difference in SCE. Moreover, levels of urinary thiocyanate (SCN), which can be used as a metabolic marker for smoking, showed a significant positive correlation with the number of SCE. This indicates that SCE is a sensitive biomarker and might still be useful in biomonitoring. However, only chronic exposures over a long period would probably be detectable. In this study, where exposure was rather low and the number of working years was small (mean of 2.9 years), cytogenetic effects are probably too low or rare to be detectable with any assay.

Experience with a vocabulary test for workers previously and still exposed to styrene.

OBJECTIVES: This study examined the possible influence of styrene exposure on the results of vocabulary tests because verbal ability is assumed to be relatively resistant to the toxic effects of organic solvents and short vocabulary tests are used as "hold tests" in many neurobehavioral epidemiologic studies, METHODS: To evaluate the chronic neurotoxic effects of styrene, a vocabulary test was administered to a group of still-exposed workers (N=27) and an earlier exposed group of workers (N=90). A self-administered questionnaire was filled out on life events, general health, educational level, and amount of education. The still-exposed group had a mean exposure duration of 4700 hours, and that for the formerly exposed group was 3610 hours. RESULTS: The vocabulary score of the still-exposed group was significantly lower [12.5 (SD 2.9, range 6-18)] than that of their former colleagues [14.3 (SD 3.4, range 8-22)], even though they originally belonged to the same group and had done the same tasks. The exposure duration explained a significant part of the vocabulary results, resulting in decreasing vocabulary scores even when the influence of years of education and age was taken into account. Even after correction for the possible influence of having been laid off or staying at work, there remained a negative influence on the vocabulary score for the duration of styrene exposure. CONCLUSIONS: The use of short vocabulary tests as hold tests in cross-sectional studies of solvent-exposed workers may be limited as they seem to lack the essential toxicity-independent property.

Field study of the urinary excretion of ethoxyacetic acid during repeated daily exposure to the ethyl ether of ethylene glycol and the ethyl ether of ethylene glycol acetate.

The urinary excretion of ethoxyacetic acid (EAA) was studied in a group of five women daily exposed to the ethyl ether of ethylene glycol (EGEE) and the ethyl ether of ethylene glycol acetate (EGEE-Ac) during 5 d of normal production and 7 d after a 12-d production stop. The mean combined exposure concentration of EGEE and EGEE-Ac (expressed in equivalent weight of EGEE) was 14.0 mg/m3 with occasional slight excursions above the current Belgian occupational exposure limit. The daily combined exposure profiles for EGEE and EGEE-Ac were rather constant during the first observation period, but they tended to decrease during the last week. The urinary EAA excretion clearly increased during the work week. Over the weekends the elimination was far from complete, and even after a prolonged nonexposure period of 12 d traces of the metabolite were still detectable. Based on the observations from the first period, a good linear correlation (r = 0.92) was found between the average exposure over 5 d (14.4 mg/m3) and the EAA excretion at the end of the week (105.7 mg/g creatinine). An EAA estimate of 150 +/- 35 mg/g was found to correspond with repeated 5-d full-shift exposures to the respective occupational exposure limit of EGEE (19 mg/m3) or EGEE-Ac (27 mg/m3).

Urinary mandelic acid and hemoglobin adducts in fiberglass-reinforced plastics workers exposed to styrene.

OBJECTIVES: A field study was undertaken to investigate the effects of occupational styrene exposure on mandelic acid excretion and the formation of styrene-7,8-oxide hemoglobin adducts. Especially the sensitivity of a gas chromatography-mass spectrometry method for determining hemoglobin adducts was evaluated. METHODS: Over a four-week period, each individual of a group of 52 fiberglass-reinforced plastics workers was monitored once a week by the simultaneous measurement of styrene in the air and urinary postshift mandelic acid. In addition mandelic acid and hemoglobin adducts were monitored in a group of 24 unexposed referents. At the end of the monitoring period styrene-7,8-oxide adduct formation on N-terminal valine in hemoglobin was examined by gas chromatography-mass spectrometry according to the modified Edman degradation technique. RESULTS: Personal air samples showed an average styrene exposure of 31 mg.m-3. The average postshift mandelic acid was 98 mg.g creatinine-1. For workers not wearing respirators and not showing breath ethanol, the correlation coefficient between styrene and mandelic acid was 0.78. The blood samples were analyzed for styrene-7,8-oxide adducts on hemoglobin. With a detection limit of 10 pmol.g-1, no styrene-7,8-oxide adducts were found under these exposure conditions. CONCLUSION: Adduct formation in humans is less effective than in mice. In comparison with ethylene, styrene is at least 70 times less effective in forming hemoglobin adducts. Investigating adduct formation in humans at or below the exposure levels reported in this study would require a detection limit of about one order of magnitude better.

Exposure to metalworking fluids and respiratory and dermatological complaints in a secondary aluminium plant.

OBJECTIVE: Metal working fluids (MWF) are used during the machining or treatment of metal components as aluminium. The study of adverse health effects of exposure to MWF is very important because the potentially exposed population is large. In this study, we evaluated 31 workers of three departments (Extrusion, Hot and Cold Rolling Mill) in a secondary aluminium plant. METHODS: We combined exposure assessment to MWF and their biodegradation products (aldehydes, etc.) with biomonitoring 1-OH-pyrene in the urine and an evaluation of respiratory and dermatological complaints by using the Saint-George's respiratory questionnaire (SGRQ) and Dalgard's skin questionnaire. RESULTS: We only detected MWF vapour levels of 4.1 and 5.5 mg/m3 at the Cold Rolling Mills. Only very small traces of solvents, organic acids and carbon-gasses were identified in all work environments. Several aldehydes were measured in low concentrations, e.g. formaldehyde at 0.03 mg/m3. 1-OH-pyrene levels were all around the detection limit of 0.2 microg/l. The scores of the Extrusion department were all within normal values as defined in the manual of the SGRQ. In contrast, the Hot and Cold Rolling Mill were scoring significantly above the score of a population without respiratory health problems. Moreover, the participants of the Hot and Cold Rolling Mill displayed a Dalgard's Skin score = 1.3 indicating that these individuals have an increased risk of developing skin diseases CONCLUSION: We recommend measuring oil vapour, additives and contaminants in addition to oil mist only for assessing exposure to MWF. We also found indications that exposure to MWF vapours and emulsified MWF might lead to respiratory and skin problems, but a bigger epidemiological study in exposed workers will be necessary to make more definitive conclusions.

Comparison of genotoxic potency of styrene 7,8-oxide with gamma radiation and human cancer risk estimation of styrene using the rad-equivalence approach.

Styrene is suspected to cause lympho-hematopoietic malignancies through the formation of styrene 7,8-oxide. However, we are still unable to calculate the cancer risk for workers exposed to styrene using epidemiological data. The aims of this study were to determine the blood dose after styrene exposure and to compare the genotoxic potency of styrene 7,8-oxide and gamma radiation in order to calculate the cancer risk by means of the rad-equivalence approach. Leucocytes of 20 individuals were exposed to 0, 0.1, 0.2 or 0.3 mM styrene 7,8-oxide (1 h) or 1, 2 or 3 gray (=100, 200, 300 rad) gamma radiation. Genotoxicity was evaluated with the cytokinesis-block micronucleus assay. Comparison of the two slopes of the regression lines between micronuclei and dose revealed a genotoxic potency for styrene 7,8-oxide of 37 rad/mMh, corresponding with a median value derived from mutagenicity studies (1, 37, 208 rad/mMh). At exposure levels of 1 ppm styrene, a blood styrene 7,8-oxide concentration between 0.03 x 10(-)(6) and 0.42 x 10(-)(6) mM is to be expected using data of toxicokinetic models and human exposure studies. With the cancer risk per unit dose of gamma radiation as benchmark, we calculated a lifetime risk of acquiring a fatal lympho-hematopoietic cancer of 0.17 in 10(3) workers (between 0.037 x 10(-)(3) and 5.0 x 10(-)(3)) exposed to 20 ppm styrene during 40 years.

Identification of exposure pathways for opioid narcotic analgesics in pharmaceutical production workers.

The protection of workers from the potential harmful effects of active pharmaceutical ingredients (APIs) poses a significant challenge for the drug manufacturing industry. The actual pathways through which pharmaceutical production workers are exposed to potent drugs and the processes resulting in actual uptake are up till now virtually unknown. In this study, a detailed exposure assessment survey was conducted in a pharmaceutical 'primary manufacturing' production facility during which environmental and biological exposure monitoring for potent opioid narcotic drugs was performed. On the occasion of multiple consecutive production days, personal half-shift air samples were collected and hand wipes were taken at the end of each half-shift and analysed for fentanyl. All environmental samples showed detectable amounts of fentanyl (>0.1 ng per sample), indicating a potential for both inhalation and dermal exposure. Spatial distribution of fentanyl dermal contamination was further investigated by means of patch samplers placed on five anatomical regions of the body. Body locations showing the highest level of fentanyl contamination were identified as the hands, the neck and lower arms. The effective uptake of fentanyl was demonstrated by the detection of this opioid in urine samples of the workers involved. Individual and group-level analysis of combined external and internal fentanyl exposure measures revealed a positive and significant correlation between fentanyl hand exposure and urinary excretion, while it seemed that the effect of inhalation exposure was largely due to its correlation with dermal exposure. The results of the established individual linear and mixed effects models strongly suggest that in most workers the dermal pathway is actually the primary route of fentanyl exposure.

Exposure and inhalation risk assessment in an aluminium cast-house.

To date the exposure, absorption and respiratory health effects of cast-house workers have not been described since most studies performed in the aluminium industry are focused on exposure and health effects of potroom personnel. In the present study, we assessed the external exposure and the absorbed dose of metals in personnel from the aluminium cast house. This was combined with an evaluation of respiratory complaints and the lung function of the personnel. 30 workers from an aluminium casting plant participated and 17 individuals of the packaging and distribution departments were selected as controls. The exposure was assessed by the quantification of total inhalable fume with metal fraction and by the determination of urinary aluminium, chromium, beryllium, manganese and lead concentration. Carbon monoxide (CO), carbon dioxide (CO2), aldehydes and polyaromatic hydrocarbons and man-made mineral fibres concentration were assessed as well. In order to evaluate their respiratory status each participant filled out a questionnaire and their lung function was tested by forced spirometry. Total inhalable fume exposure was maximum 4.37 mg m(-3). Exposure to the combustion gases, man-made mineral fibres and metal fume was well below the exposure limits. Beryllium could not be detected in the urine. The values of aluminium, manganese and lead in the urine were all under the respective reference value. One individual had a urinary chromium excretion above the ACGIH defined biological exposure index (BEI) of 30 microg g(-1) creatinine. There was no significant difference in any of the categories of the respiratory questionnaire and in the results of the spirometry between cast house personnel and referents (Chi-square, all p > 0.05). Exposure in cast houses seem to be acceptable under these conditions. However, peak exposure to fumes cannot be excluded and the potential risk of chromium and beryllium exposure due to the recycling of aluminium requires further attention.

Urinary excretion of ethoxyacetic acid after experimental human exposure to ethylene glycol monoethyl ether.

Ten healthy male subjects were exposed to ethylene glycol monoethyl ether (EGEE) under various conditions of exposure concentration and physical workload and their urinary excretion of ethoxyacetic acid was followed up for 42 hours. Maximal excretion of ethoxyacetic acid was reached three to four hours after the end of the four hour exposure period. Afterwards, ethoxyacetic acid excretion declined slowly with a biological half life of 21-24 hours. Ethoxyacetic acid excretion increased as the uptake of EGEE increased as a consequence of higher exposure concentration or pulmonary ventilation rate during physical exercise. On average, 23.1 +/- 6.3% of EGEE was recovered as ethoxyacetic acid within 42 hours and the recovery did not change as the uptake of EGEE increased. Quantitative relations between ethoxyacetic acid excretion and EGEE uptake were obtained and the relevance of ethoxyacetic acid excretion as a measure for exposure to EGEE is discussed.

Respiratory uptake and elimination of ethylene glycol monoethyl ether after experimental human exposure.

Ten male volunteers were exposed to ethylene glycol monoethyl ether (EGEE) under various conditions of exposure concentration and physical workload. Steady state levels of retention, atmospheric clearance, and rate of uptake were reached immediately after the start of the exposure period for all experimental conditions. Retention was high (64% in resting condition) and increased as physical exercise was performed during exposure. Atmospheric clearance increased as the pulmonary ventilation rate increased. The rate of uptake was higher as exposure concentration or pulmonary ventilation rate, or both, increased. Individual uptake appeared to be governed mainly by transport mechanisms (pulmonary ventilation or cardiac output or both) and not by anthropometric factors. Respiratory elimination of unchanged EGEE accounted for less than or equal to 0.4% of the total body uptake. Postexposure breath concentrations declined rapidly during the first minutes after cessation of exposure, after which a much slower decrease was observed. This slow decrease could be described by a regression equation containing two exponential terms indicating that at least two pharmacological compartments are concerned.

Exposure to ethylene glycol ethers and spermatogenic disorders in man: a case-control study.

A case-control study was conducted among first time patients at a clinic for reproductive disorders. The study group consisted of 1019 cases, defined as patients diagnosed infertile or subfertile on the basis of a spermiogram and 475 controls who were diagnosed as normally fertile by the same procedure. Possible exposure to ethylene glycol ethers was assessed by the presence of the urinary metabolites methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) respectively for 2-methoxyethanol and 2-ethoxyethanol or their acetates. In total, EAA was detected in 39 cases and six controls, with a highly significant odds ratio of 3.11 (p = 0.004). On the other hand, MAA was only found in one case and two controls. The presence of EAA in urine proved to be strongly associated with exposure to preparations containing solvents, especially paint products, and with some groups of occupations, the most important of which were also directly or possibly connected with paint products. The absence of a significant correlation between the concentration of urinary EAA and the various measures of sperm quality could be explained by the expected latent period between exposure and observed effects. Other temporal aspects of the relation between exposure as judged from the presence of urinary EAA and diagnosis are also discussed.

Gas chromatographic determination of methoxyacetic and ethoxyacetic acid in urine.

Methoxyacetic acid (MAA) and ethoxyacetic acid (EAA), the major metabolites of, respectively, ethylene glycol monomethyl ether and ethylene glycol monoethyl ether and their acetates, are determined by gas chromatography after extraction from urine and methylation using 2-furoic acid (2-FA) as an internal standard. The mean recoveries (n = 30) from urine of MAA, EAA, and 2-FA are 31.4 +/- 7.0%, 62.5 +/- 13.4%, and 58.4 +/- 8.7%, respectively. The recoveries decreased (p less than 0.001), however, as the total amount of acids increased. Standard curves for MAA and EAA in urine are presented. The detection limits of MAA and EAA are 0.15 and 0.07 mg/l. Intra-assay variation for MAA and EAA was 6.0 +/- 2.5% and 6.4 +/- 2.8% and inter-assay variation was 6.2 +/- 2.2% and 8.9 +/- 2.4%. When volunteers were exposed to air containing ethylene glycol monoethyl ether (20 mg/m3), urinary concentration of EAA rose significantly one hour after the exposure period (2.39 +/- 1.03 v less than or equal to 0.07 mg/l, t = 5.2, p less than 0.005).

Pulmonary absorption and elimination of ethylene glycol monoethyl ether acetate in man.

Ten male volunteers were exposed to ethylene glycol monoethyl ether acetate (EGEE-Ac) under various conditions of exposure and physical workload. As exposure proceeded, retention, atmospheric clearance, and uptake rate declined slowly to reach steady state levels after three to four hours. Retention increased as a consequence of higher exposure concentrations and of physical workload performed during exposure. Uptake rate was higher as exposure concentration or pulmonary ventilation rate, or both, increased. Subject related factors such as pulmonary ventilation, cardiac output, height, and body fat content also determined individual uptake. During exposure, partial respiratory elimination of EGEE was observed. This finding confirms the hypothesis that EGEE-Ac is first converted to EGEE by (plasma) esterases. The amount of EGEE eliminated at steady state levels correlated more with uptake rate of EGEE-Ac than with exposure concentration. Respiratory elimination of unmetabolised EGEE-Ac accounted for less than or equal to 0.5% of total body uptake. The elimination curves were biexponential indicating that at least two pharmacological compartments are involved. Postexposure breath concentrations were higher as total body uptake increased. Several observations may indicate that the hydrolysis of the ester moiety of EGEE-Ac is hindered by the presence of the natural esterase substrates. With increasing plasma concentrations, however, EGEE-Ac competed more favourably for the available esterase.