Cytogenetic Effects of Ethylene Oxide, with an Emphasis on Population Monitoring

Abstract

Cytogenetic assays are an integral component of the battery of short-term assays that are used for the hazard identification component of a cancer risk assessment. The protocol for the conduct of such assays for maximal sensitivity for detecting clastogenicity has to be attendant to the mechanism of induction of the endpoint being assessed and the fact that several aberration types are cell lethal necessitates that analysis be for cells at their first posttreatment metaphase. Cytogenetic assays for human populating monitoring have been used for predicting potential for carcinogenicity in humans. However, the assays as typically conducted are not appropriate for chronic exposures because nontransmissible alterations are assessed. The use of fluorescent in situ hybridization (FISH) techniques for the assessment of transmissible changes such as reciprocal translocations are required to make population monitoring studies interpretable, and for removing some of the concern over the influence of confounders on outcome. The database for the cytogenetic effects of ethylene oxide in vitro and in vivo, with an emphasis on human population monitoring, has been critically reviewed. Based on the endpoints studied, the size of the study groups, the information on exposure, the nature of any exposure response data, and the possible influence of confounders (i.e., control matching), it is concluded that acute, high exposures to ethylene oxide with sampling shortly (a few days) after exposure can be detected by increases in chromosome aberrations or SCE in peripheral lymphocytes. Such increases are indicators of exposure to a genotoxic chemical and not predictors of subsequent adverse health effects to individuals. The effect of chronic and/or low level (less than about 25 ppm) exposures cannot be reliably evaluated using current methods. The use of FISH, for example, for assessing reciprocal translocation frequencies (as a measure of transmissible events) will greatly improve the ability to detect chronic exposures to clastogenic chemicals.

Reciprocal translocations in somatic and germ cells of mice chronically exposed by inhalation to ethylene oxide: implications for risk assessment

“…Alternatively, and perhaps more likely, the great majority of the EO-induced DNA damage could be repaired prior to meiotic DNA synthesis or that cells containing chromosome damage induced in early spermatogonial cell stages are removed from the cycling population. DNA synthesis is required to convert EO-induced DNA damage into chromosomal aberrations (3). In this regard, it is important to note that the great majority of the chronic exposure will have been to spermatogonial stem cells, given the duration of the exposures (6 weeks and longer) and the duration of spermatogenesis in mice.…”

“…These surrogate biomarkers of cancer included formation of DNA adducts and genotoxicity in EO-exposed humans and rodents. In biomonitoring studies, it has been reported that cohorts of EO-exposed workers showed increased frequencies of several chromosomal aberration endpoints relative to unexposed workers (3). The mortality from lymphatic and haematopoietic cancer was also marginally elevated (2).…”

“…Its mutagenicity in somatic and germ cells has been clearly and repeatedly demonstrated in a variety of test systems, including mouse and rat assays. It has also been reported to have mutagenic effects in humans (2,3,7,12,13). Heritable reciprocal translocations are persistent stable chromosome alterations and are therefore of high importance for generating weight-of-evidence data for describing a potential role for mutagenicity in cancer risk assessments…”

The application of mass spectrometry in molecular dosimetry: Ethylene oxide as an example

“…Sister chromatid exchange (SCE), chromosomal aberration (CA), and micronuclei (MN) have been used as biomarkers for the effects of occupational exposures to EO. In particular, the induction of CA is used as a biomarker for cancer risk, and was used as supportive evidence for the carcinogenicity of EO in humans (IARC, 1994;Preston, 1999). Between 1979 and 1993, more than 20 studies of biological monitoring were conducted at hospital-and factory-sterilization units, and at EO-manufacturing and -processing plants.…”

“…The cytogenetic effects of EO on humans have been reviewed (Preston, 1999). Sister chromatid exchange (SCE), chromosomal aberration (CA), and micronuclei (MN) have been used as biomarkers for the effects of occupational exposures to EO.…”