Ethylene oxide review: characterization of total exposure via endogenous and exogenous pathways and their implications to risk assessment and risk management

Ethylene Oxide Exposure in U.S. Populations Residing Near Sterilization and Other Industrial Facilities: Context Based on Endogenous and Total Equivalent Concentration Exposures

“…In 2016, the U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment of ethylene oxide (EO) estimated risk-specific concentrations (RSCs) of 0.0001 to 0.01 parts per billion by volume (ppb), associated with a 10 −6 to 10 −4 increase in inhalation cancer risk, respectively [1]. As everyone is exposed to single-digit, parts per billion (ppb) equivalent levels of endogenous, metabolically-produced EO and fractions of ppb levels from inhalation of ambient air, regardless of their occupation or location of residence [2][3][4][5], these exceedingly low RSCs relative to endogenous levels and variability raise questions as to their practical utility in risk management of public exogenous EO exposure, as well as their scientific merit. In contrast, the Texas Commission on Environmental Quality (TCEQ) using the same cohort data as EPA IRIS, but a different doseresponse model, estimated 10 −6 to 10 −4 RSCs of 0.24 to 24 ppb, respectively [6].…”

“…The EPA assessment short comings left a gap in our ability to interpret the health significance of general population exogenous EO background exposures from non-industrial and natural EO sources, and, perhaps more importantly, local general population exposures from point source industrial emissions. Kirman and Hays [2] and Kirman et al [3] proposed an endogenous exposure metric, endogenous equivalent concentration, to provide context to exogenous exposures for decision-making by risk managers. This study proposes and evaluates the utility of a total exposure metric (total equivalent concentration) incorporating both background endogenous and exogenous EO exposures to help inform the health significance of excess ambient air exposures to EO.…”

“…These RSCs are also more than two orders of magnitude below the EO ambient air concentrations, which are not associated with industrial emission sources (mean of 0.13 ppb based on recent EPA monitoring [5]). More importantly, these RSCs are more than three orders of magnitude below airborne concentrations equivalent to endogenously produced EO, in the general nonsmoking population (mean concentrations of~1.9 and 2.9 ppb) based on data evaluated by Kirman and Hays [2], based on data from published unexposed control subjects [8][9][10][11][12][13][14][15][16][17] and Kirman et al [3], and based on data from nonsmoking U.S. individuals [4], respectively. For additional perspective, as described by Bogen et al [7], these RSCs are up to seven orders of magnitude below the levels of EO to which 1930s-1970s sterilization operators and other highly exposed sterilization workers in the National Institute for Occupational Safety and Health (NIOSH) cohort used by EPA in its risk assessment were exposed (50,000 to >100,000 ppb).…”

“…Total EO exposures in humans were characterized using hemoglobin adducts, specifically 2-hydroxyethylvaline (HEV), which serves as a useful biomarker of exposure, regardless of the exposure pathway. A summary of HEV levels in non-smokers and smoker populations and the relatively high variability in adduct levels in these population is provided in Kirman and Hays [2] and Kirman et al [3]. The distribution of HEV levels for the non-smoking general population, therefore, describes the expected range of adducts from background exposure from endogenous and exogenous sources to which everyone is exposed in their daily lives.…”

“…The distribution of HEV levels for the non-smoking general population, therefore, describes the expected range of adducts from background exposure from endogenous and exogenous sources to which everyone is exposed in their daily lives. Kirman et al [3] describe the three primary pathways of EO exposure to the non-occupational general population in the U.S.-(1) EO is produced endogenously in the body via multiple pathways, including ethylene from bacterial pathways in the gastrointestinal lumen and systemic enzymatic production from methionine and 2-keto-4-methylthiobutyric acid, (2) exogenous ethylene inhaled from ambient air and converted metabolically to EO, and (3) exogenous EO inhaled from ambient air from sources other than industrial emissions. To compare the contribution of these sources to total background EO exposure, HEV levels were converted to endogenous equivalent air concentrations (i.e., the amounts of exogenous EO exposures necessary to result in the measured endogenous HEV adduct concentrations, regardless of the three potential sources).…”