Concentration‐response curves for ethylene‐oxide‐induced heritable translocations and dominant lethal mutations

Generoso, W.M.; Cain, K.T.; Cornett, C.V.; Cacheiro, N.L.A.; Hughes, L.A.

doi:10.1002/em.2850160209

Cited by 50 publications

(29 citation statements)

References 21 publications

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“…First, evidence can be found in the dose‐response curve for EO and heritable translocations in mice (Fig. 1, Generoso et al , 1990), also in which a notable increase in the slope of the response curve is evident with increasing exposure level. Although these data represent chromosomal aberrations in germ cells rather than hematopoietic/lymphatic stem cells, there is no information available to suggest that the molecular interaction between EO and DNA would differ for these two tissue types.…”

Section: Resultsmentioning

confidence: 99%

Addressing Nonlinearity in the Exposure‐Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide

Kirman¹,

Sweeney²,

Teta³

et al. 2004

Risk Analysis

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Ethylene oxide (EO) has been identified as a carcinogen in laboratory animals. Although the precise mechanism of action is not known, tumors in animals exposed to EO are presumed to result from its genotoxicity. The overall weight of evidence for carcinogenicity from a large body of epidemiological data in the published literature remains limited. There is some evidence for an association between EO exposure and lympho/hematopoietic cancer mortality. Of these cancers, the evidence provided by two large cohorts with the longest follow-up is most consistent for leukemia. Together with what is known about human leukemia and EO at the molecular level, there is a body of evidence that supports a plausible mode of action for EO as a potential leukemogen. Based on a consideration of the mode of action, the events leading from EO exposure to the development of leukemia (and therefore risk) are expected to be proportional to the square of the dose. In support of this hypothesis, a quadratic dose-response model provided the best overall fit to the epidemiology data in the range of observation. Cancer dose-response assessments based on human and animal data are presented using three different assumptions for extrapolating to low doses: (1) risk is linearly proportionate to dose; (2) there is no appreciable risk at low doses (margin-of-exposure or reference dose approach); and (3) risk below the point of departure continues to be proportionate to the square of the dose. The weight of evidence for EO supports the use of a nonlinear assessment. Therefore, exposures to concentrations below 37 microg/m3 are not likely to pose an appreciable risk of leukemia in human populations. However, if quantitative estimates of risk at low doses are desired and the mode of action for EO is considered, these risks are best quantified using the quadratic estimates of cancer potency, which are approximately 3.2- to 32-fold lower, using alternative points of departure, than the linear estimates of cancer potency for EO. An approach is described for linking the selection of an appropriate point of departure to the confidence in the proposed mode of action. Despite high confidence in the proposed mode of action, a small linear component for the dose-response relationship at low concentrations cannot be ruled out conclusively. Accordingly, a unit risk value of 4.5 x 10(-8) (microg/m3)(-1) was derived for EO, with a range of unit risk values of 1.4 x 10(-8) to 1.4 x 10(-7) (microg/m3)(-1) reflecting the uncertainty associated with a theoretical linear term at low concentrations.

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Section: Resultsmentioning

confidence: 99%

Addressing Nonlinearity in the Exposure‐Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide

Kirman¹,

Sweeney²,

Teta³

et al. 2004

Risk Analysis

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Section: Ethylene Oxidementioning

confidence: 99%

“…The data of Generoso et al (19) for the induction of heritable translocation in the mouse were used. Translocations increased with a higher power of the dose than simple dose-squared (17,19). Here I assume that at low doses, the two breaks required for the formation of a translocation are formed by one event, and thus use linear extrapolation from the lowest dose point.…”

Section: Ethylene Oxidementioning

confidence: 99%

Approaches to assessing genetic risks from exposure to chemicals.

Sobels

1993

Environ Health Perspect

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An effort to assess and quantify genetic risks from human exposure to mutagenic chemicals is urgently needed; otherwise genetic toxicology may well lose its credibility. Genetic biomonitoring provides us with an indication of mutagenic effectiveness in human somatic cells. The populations and chemicals selected for such studies form a useful database for genetic risk-assessment studies. Extrapolation to what can be expected in germ cells of exposed individuals should be possible by using good dosimetry (adducts) and a parallelogram approach. The principle is that genetic damage in the inaccessible human germ cells can be estimated by determining the effects on lymphocytes (or other somatic cells) from humans and mice and in germ cells of mice. Worldwide, opportunities for the costly mouse germ cell studies are limited. Knowledge of type of DNA adducts, their persistence and/or removal and dominant lethal studies, will be helpful in predicting stage sensitivity. Extrapolation from a lowest effective dose level is proposed. The available data for ethylene oxide and benzene are reviewed. The risk of heritable translocations in progeny of populations exposed to ethylene oxide is so high that more precise estimates seem desirable. In discussing the expression of the induced mutations, the importance of dominant mutations and of heterozygous effects of deletions and other recessives is pointed out. The molecular changes underlying dominant mutations in man are more limited than is the case for recessive mutations. This raises the question whether mutagenic agents can produce the specific changes leading to recoverable, dominant mutations. Extrapolation from increased mutation rates to predictable increases of human disease, whether by doubling dose or direct methods, have been criticized.

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“…Of the chemicals evaluated to date, all appear to have their predominant or strongest effect on post-stemcell stages (i.e., spermatocytes, spermatids, spermatozoa) in producing transmitted germ-line translocations (30,32,34 (36).…”

Section: Chromosomal Rearrangementsmentioning

confidence: 99%

Genetic Anomalies in Mammalian Germ Cells and Their Significance for Human Reproductive and Developmental Risk

Dellarco¹

1993

Environmental Health Perspectives

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Concentration‐response curves for ethylene‐oxide‐induced heritable translocations and dominant lethal mutations

Cited by 50 publications

References 21 publications

Addressing Nonlinearity in the Exposure‐Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide

Addressing Nonlinearity in the Exposure‐Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide

Approaches to assessing genetic risks from exposure to chemicals.

Genetic Anomalies in Mammalian Germ Cells and Their Significance for Human Reproductive and Developmental Risk

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