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Absorption

During exposure of rats by inhalation, uptake of ethylene was rapid and steady state concentrations in blood and tissues were attained within 12 hours (Guest et al., 1981; Eide et al., 1995). Approximately 15% of inhaled ethylene is absorbed, a significant proportion of that absorbed is eliminated unchanged in exhaled air; this results in a retained dose at steady state of approximately 3% (Csanady et al., 2000). At atmospheric concentrations below that which saturates metabolism, blood concentrations peak rapidly but then decline to a lower steady state concentration. This effect has also been observed with other alkenes and has been explained by a transient reduction in the activity of the enzymes responsible for metabolism (Fennel et al., 2004).

Distribution

Tissue:air partition coefficients for ethylene have been determined; with the exception of blood, values are similar in rat and human tissue. The human blood:air partition coefficient is approximately half that measured with rat blood; this is attributed to species difference in protein binding (Csanady et al., 2000). Measurements of total radioactivity (Guest et al., 1981), unchanged ethylene (Eide et al., 1995) or adducts (Eide et al., 1999; Rusyn et al., 2005; Walker et al., 2000; Wu et al., 1999) in tissues following exposure of rodents to ethylene by inhalation demonstrated distribution of ethylene or metabolites into all tissues studied.

Metabolism and adduct formation

A fraction of the systemically available ethylene can be metabolised to ethylene oxide, some of which is further metabolised by epoxide hydrolase to form ethane-1,2-diol. Approximately 50% of systemic ethylene oxide is conjugated with glutathione to form S-(2-hydroxyethyl) -glutathione (GSEO); this product has been measured in liver tissue and shown to follow a similar concentration-time profile to that of ethylene oxide (Filser, 2007). Peak blood concentrations of ethylene oxide were achieved within two hours of the start of exposure to ethylene; AUC values for ethylene oxide showed a non-linear dose response (Fennel et al., 2004). 

The rate of metabolism of ethylene is affected by pre-treatment with enzyme inducers or inhibitors of cytochrome P450 (Guest et al., 1981; Filser and Bolt, 1983). Values for Vmaxwere 8.5, 13.7 and 0 µmol/h/kg in untreated rats and those treated with Aroclor 1254 or diethyldithiocarbamate respectively (Filser and Bolt, 1983). In rats and mice, metabolism of ethylene is saturated at exposure concentrations above 1,000 ppm (Filser and Bolt, 1983, Walker et al., 2000). The transient reduction in the activity of metabolising enzymes has been investigated and shown to result predominantly from effects on cytochrome P450 2E1 (Fennel et al., 2004).

A small, dose dependant proportion of the ethylene oxide reacts with haemoglobin or DNA to form adducts; these provide sensitive markers of exposure. Eide et al. (1995) measured the haemoglobin adduct N-(2-hydroxyethyl) valine (HEval) in blood and the DNA adduct 7-ethylguanine in lymphocytes and liver of rats following exposure to 300 ppm ethylene for three consecutive days. A subsequent study showed the presence of low levels of the DNA adduct N7-(2-hydroxyethyl) guanine (7-HEG) in unexposed rats (Eide et al.,1999). Wu et al. (1999) determined the dose-response curves for 7-HEG concentrations in tissues from rats and mice exposed by inhalation to ethylene oxide (0-100 ppm). Background concentrations were 0.2-0.3 pmol/µmol guanine in both species and increased linearly with atmospheric concentrations. Adduct concentrations were higher in rats than mice; values in rats were 5 to 13-fold higher than in control animals while in mice the increase was only 1 to 3-fold. The authors commented that the species difference may be due to either more efficient detoxification or DNA repair in mice. At ethylene exposure concentrations above 1,000 ppm, saturation of metabolism limits the adduct concentrations in rodents, resulting in a non-linear dose-response for both HEVal and 7-HEG. Comparison of 7-HEG concentrations showed that values in rodents exposed to 40 and 3,000 ppm ethylene were similar to rats exposed to 0.7-2.3 and 6.4-23.3 ppm ethylene oxide, respectively, or mice exposed to 3.0-8.8 and 6.7-21.5 ppm ethylene oxide, respectively (Walkeret al.2000). Similar comparisons by Rusyn et al. (2005) found that exposure of rats to 40 ppm ethylene resulted in 38 to 65-fold lower concentrations of 7-HEG than exposure to 100 ppm of the metabolite ethylene oxide. Following exposure of rats to 100 ppm ethylene oxide, HEVal concentrations were greater than 10-fold higher than when rats were exposed to 3,000 ppm ethylene.

Elimination

Rats exposed to [14C]-ethylene by inhalation exhaled small amounts of unchanged ethylene along with some [14C]-CO2. Polar metabolites and conjugates are eliminated predominantly in urine with smaller amounts in faeces (Guest et al., 1981).

Human Information

Exposure of healthy human volunteers by inhalation to initial concentrations of of 5 or 50 ppm ethylene for 2 hours showed that the metabolism of ethylene is not saturated over this concentration range. The alveolar retention of inhaled ethylene was 2±0.8% (Filser et al.,1992).

Tornqvist et al.(1989) demonstrated a statistically significant increase in HEVal concentrations in fruit store workers exposed to ethylene (0.03-3.35 ppm; average 0.3 ppm) when compared to a control population. A similar effect was seen in both smokers and non-smokers, although concentrations of HEVal were higher in both control and exposed smokers than in comparable groups of non-smokers. The authors estimated that approximately 3% of atmospheric ethylene is converted to ethylene oxide by metabolism. Workers exposed occupationally to ethylene in a plastics factory were divided into groups according to their level of exposure. Concentrations of HEVal were 15 pmol/g (range 9-32) in the control group and 110 pmol/g (range 56-200) in the group exposed to approximately 4 mg/m3 (3.5 ppm) ethylene; the fraction of inhaled ethylene converted to ethylene oxide was estimated to be 0.5% (Granath et al.,1996).

Endogenous production of ethylene

Filser and Bolt (1983) identified that control rats excreted low concentrations of ethylene oxide, indicating endogenous production of ethylene. Csanady et al.(2000) determined that the rate of endogenous production of ethylene in rats was 11.5 nmol/h/kg bodyweight resulting in a steady state blood concentration of 0.57nmol/l. The values in humans were 33 nmol/h/70kg bodyweight resulting in a steady state concentration of 0.097nmol/l; this is similar to that resulting from occupational exposure to 0.126 ppm ethylene for 8 h/day, 5 days/week.