1,4-Dioxane - Inhalation (Draft, 2011) | Health & Environmental Research Online (HERO)

Health & Environmental Research Online (HERO)

You are here: EPA Home

Research

NCEA

HERO

1,4-Dioxane - Inhalation (Draft, 2011)

EPA has released the Toxicological Review of 1,4-Dioxane (Inhalation) (External Review Draft) for public review and comment. New studies regarding the toxicity of 1,4-dioxane through the inhalation route of exposure are available that were not included in the 1,4-dioxane assessment that was posted on the IRIS database in 2010.

1,4-Dioxane is commonly used as a solvent, cleaning agent, chemical stabilizer, surface coating, adhesive agent, and an ingredient in chemical manufacture. The IRIS Program completed the assessment for oral exposure to 1,4-dioxane on August 11, 2010 and noted that new inhalation studies would be evaluated separately. Additional information regarding 1,4-dioxane toxicity resulting from exposure via inhalation has now been incorporated into the 2010 assessment without changing the oral toxicity conclusions of the previous assessment.

These are the studies used in the Toxicological Review of 1,4-Dioxane (Inhalation).

Although all features of this site will work with javascript and style sheets disabled, you are likely to have a better user experience if you turn them on.

All References (sorted by author)
View as Grid

Export to EndNote

Bibliography Format

Select all 205 references
Select all references on this page

1.

Book/Book
Chapter

Hawley's condensed chemical dictionary

(2001)
This reference book provides precise technical data and descriptive information for chemical substances . . . This reference book provides precise technical data and descriptive information for chemical substances and phenomena. The description of chemicals and processes along with an expanded definition of chemical entities and terminology may include: Name, Synonyms, CAS Registry Number, Formula, Physical Properties, Source or Occurrence, Grade, Hazard, Use, and Derivation.

Tag:

Details
Related Link

2.

Book/Book
Chapter

The Merck index: An encyclopedia of chemicals, drugs, and biologicals

(2001)
Tag:

Details
Related Link

3.

Book/Book
Chapter

1,4-Dioxane

ACGIH (1999)
TLV Recommendation Derivation of the TLV for 1,4-dioxane rests, in part, on interpretation of the rodent . . . TLV Recommendation Derivation of the TLV for 1,4-dioxane rests, in part, on interpretation of the rodent oncogenicity data,(14"19) taken together with data on genotoxicity(24-26) and the pharmacokinetic profile of the compound in animals and humans.(27_32) There are no data to support a suggestion that dioxane-induced tumors arise by any mechanism other than an epigenetic (non-genotoxic) mode of action. In rodents, there is limited ability to metabolize 1,4-dioxane to beta-hydroxyethoxyacetic acid, the major urinary metabolite in both rodents and humans. In addition, doses used in rodent drinking water carcinogenicity bioassays, where increased tumors were seen, were always greater than levels where saturation of metabolic clearance occurred. Inhalation exposure of both rats and humans at 50 ppm dioxane showed no evidence of saturated dioxane clearance/20,32* When dioxane exposures are so high that circulating concentrations accumulate, overt intoxication ensues which precipitates systemic injury and subsequent carcinogenesis. No toxicity has been observed in either animals or humans where exposures were such that 1,4-dioxane could be eliminated by normal first-order processes; the corresponding no-observed-adverse-effect levels (NOAELs) are 111 ppm, 7 hours/day, 5 days/week for 2 years in rats(20) and at least 50 ppm in workplace air for humans.(32) Dioxane pharmacokinetic data show that the disproportionate dose-response found in oral high-dose rodent bioassays cannot be utilized to predict dose-response relationships under Michaelis-Menten conditions. In view of the rodent liver and lung tumors at or near the 10,000-ppm dietary level and the lack of such findings at inhalation exposure concentrations slightly above 100 ppm for 2 years, dioxane has been judged an animal carcinogen of such low potency as to be of no practical significance as an occupational carcinogen. This conclusion is supported by the results of published epidemiologic evaluations of workers exposed to 1,4-dioxane for up to 50 years. NIOSH, however, took an opposite view in its criteria document for dioxane. Its recommendation of a 1 ppm ceiling is based on the"... belief that dioxane can cause tumors in exposed workers and on the belief that information allowing the derivation of a safe exposure limit is not now available."(36) The TLV Committee believes that the TLV should be derived from the data on hepatotoxic and nephrotoxic effects which have occurred in workers and have been shown to result in animals from exposures one-tenth those required to produce a significant carcinogenic response. The revision in the TLV-TWA from 25 ppm to 20 ppm was instituted for the purpose of facilitating harmonization with other international occupational health exposure standards. Therefore, a TLV-TWA of 20 ppm for dioxane is recommended. The drinking water animal carcinogenicity data(14~16) warrant the A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans, designation. Because of reported skin absorption in animals00,11) and its contribution to systemic toxicity in humans,<35) the skin notation is appropriate. At this time, no STEL is recommended until additional toxicological data and industrial hygiene experience become available to provide a better base for quantifying on a toxicological basis what the STEL should be. The reader is encouraged to review the section on Excursion Limits in the "Introduction to the Chemical Substances" of the current TLV/BEI Book for guidance and control of excursions above the TLV-TWA, even when the 8-hour TWA is within the recommended limits.

Details
Related Link

4.
The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer
Reviewed
Journal
Article

The development of the human blood-CSF-brain barrier

Adinolfi, M (1985)

Details
Related Link

5.
The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer
Reviewed
Journal
Article

Phytoestrogens: Epidemiology and a possible role in cancer protection

Adlercreutz, H (1995) Environmental Health Perspectives 103:103-112.
Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that . . . Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism, or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds.

Tag:

Details
Related Link

6.
The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer
Reviewed
Journal
Article

Differential expression of gender-dependent hepatic isoforms of cytochrome P-450 by pulse signals in the circulating masculine episodic growth hormone profile of the rat

Agrawal, AK; Shapiro, BH (2000) Journal of Pharmacology and Experimental Therapeutics 292:228-237.
The masculine profile of growth hormone (GH) secretion characterized by episodic bursts ( approximately . . . The masculine profile of growth hormone (GH) secretion characterized by episodic bursts ( approximately 200-300 ng/ml plasma) every 3.5 to 4 h, separated by interpulse periods devoid of detectable hormone, was restored at various peak heights to hypophysectomized, thyroxine-supplemented male rats to determine the minimum signaling amplitudes of the hormone pulse required to maintain male-like expression levels of gender-dependent hepatic cytochrome P-450s (CYP P-450s). Restoration of the pulse to as little as 2.5% of normal elevated CYP2C11 (the predominant isoform in male liver) protein and dependent catalytic activities to approximately 50% of normal, whereas transcript concentrations increased to 150% of physiologic. Renaturalizing the masculine plasma GH profile to 5% of normal was sufficient to increase CYP2C11 protein and catalytic activity to intact levels while further elevating mRNA to approximately 200% of normal (subsequently declining to intact concentrations with physiologic pulses). In dramatic contrast, CYP2C7 (mRNA and protein) declined to barely detectable levels following hypophysectomy and remained completely unresponsive to GH until replaced with the physiologic masculine profile. The repressive effects of the episodic GH profile on CYP2A2 and CYP3A2 expression similarly required replacement of near physiologic pulse amplitudes. Exhibiting an intermediate response to the masculine profile, restoration of 25% of the normal pulse amplitude was sufficient to significantly elevate CYP2A1 and CYP2C6 expression levels in hypophysectomized rats. These findings illustrate the importance of the pulse amplitudes (in addition to the interpulse periods) in the circulating masculine GH profile as differential signals regulating the expression and/or repression of each sex-dependent hepatic P-450 isoform in the rat.

Tag:

Details
Related Link

7.
The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer
Reviewed
Journal
Article

Physiologically based pharmacokinetics and the risk assessment process for methylene chloride

Andersen, ME; Clewell, HJ III; Gargas, ML; Smith, FA; Reitz, RH (1987) Toxicology and Applied Pharmacology 87:185-205.
Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation . . . Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.

Tag:

Details
Related Link

8.

Book/Book
Chapter

Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models

Andersen, ME; Krishnan, K (1995)

Details
Related Link

9.
The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer
Reviewed
Journal
Article

Studies on the carcinogenic activity of protein-denaturing agents: Hepatocarcinogenicity of dioxane

Argus, MF; Arcos, JC; Hoch-Ligeti, C (1965) Journal of the National Cancer Institute 35:949-958.
The carcinogenic activity of diethylformamide, diethylacetamide, N,N'-dimethyl-N,N'-dinitrosophthalamide, . . . The carcinogenic activity of diethylformamide, diethylacetamide, N,N'-dimethyl-N,N'-dinitrosophthalamide, heptylamine, and dioxane, compounds selected both because of their potency to denature proteins and their structural resemblance to nitrosamine derivatives, was investigated. Dioxane, when administered orally, was found to be a hepatic carcinogen, producing hepatomas in 6 of 26 rats. Diethylacetamide ingestion produced a transitional cell carcinoma of the kidney in 1 of 30 rats. Dioxane, diethylacetamide, and N,N'-dimethyl-N,N'-dinitrosophthalamide caused severe kidney damage. The possible relationship between the carcinogenic activity of dioxane and its capacity to alter cellular metabolic control sites by virtue of its protein-denaturing ability is discussed.

Tag:

Details
Related Link

10.
The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer
Reviewed
Journal
Article

Dose-response and ultrastructural alterations in dioxane carcinogenesis. Influence of methylcholanthrene on acute toxicity

Argus, MF; Sohal, RS; Bryant, GM; Hoch-Ligeti, C; Arcos, JC (1973) European Journal of Cancer 9:237-243.
A dose-response study with dioxane revealed the hepatocarcinogenicity of this compound in male rats . . . A dose-response study with dioxane revealed the hepatocarcinogenicity of this compound in male rats to be a function of the total oral dose administered. The progressive development of these tumors was studied histopathologically, and detailed electronmicroscopy was carried out on precancerous liver tissue and on hepatocellular carcinoma produced by dioxane. The LD50 dose of dioxane in male rats (5•60 g/kg body weight) is significantly decreased (5•18 g/kg) in animals pretreated with 3-methylcholanthrene. This suggests that a metabolite is involved in the toxicity and possibly carcinogenicity of dioxane, and that both may be potentiated by enzyme inducers. Because certain hydroperoxides are known to be carcinogenic, it was shown by micro-iodimetric titrations that the dioxane used does not contain a dioxane hydroperoxide and that no peroxide is formed under the conditions of administration.

Tag:

Details
Related Link

Please wait while we submit your request.
This may take several minutes...

1,4-Dioxane - Inhalation (Draft, 2011)

HERO Navigation