Role of formate in methanol‐induced exencephaly in CD‐1 mice

Dorman, David C.; Bolon, Brad; Struve, Melanie F.; LaPerle, Krista M. D.; Wong, Brian A.; Elswick, Barbara A.; Welsch, Frank

doi:10.1002/tera.1420520105

Cited by 34 publications

(7 citation statements)

References 41 publications

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“…This modified nose-only system has also been used in a developmental toxicity study in which methanol-induced exencephaly in CD-1 mice was examined (Dorman et al, 1995). In this study, use of the modified nose-only system for sham HEPA-air exposures was associated with a low incidence of neural-tube defects in CD-1 mice (1.8 f 0.9%).…”

Section: Discussion An D Conclusionmentioning

confidence: 91%

Development of a Mouse Whole-Body Exposure System from a Directed-Flow, Rat Nose-Only System

Dorman

Wong

Struve

et al. 1996

Inhalation Toxicology

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In many inhalation exposure experiments, such as pharmacokinetic studies in unrestrained pregnant animals, i t is desirable to expose unrestrained animals and to remove animals from the exposure system at intermediate time points. A two-tiered, 32-port, directed-flow, noseonly exposure system was modified with extended 0.635-mm stainless steel inlet tubes to create a whole-body, modified nose-only (WB-MNO) exposure system. lndividual pregnant CD-1 mice held within a rat nose-only tube were exposed to a well-mixed methanol (MeOH) atmosphere. The volume of an individual mouse (-30 ml) constituted approximately 1 5 % of the 600-ml tube volume. Maternal M e O H pharmacokinetics were obtained on gestational day 8 following 6-11 WB-MNO MeOH exposures at either 10,000 or 15,000 ppm. Results from these WB-MNO exposures were compared with a 6-h, 15,000 ppm M e O H exposure using a Hinners-type 1-m' whole-body inhalation chamber (WB-HI. The WB-MNO exposure atmosphere was produced using a wick generator heated to 29-35°C and a fluid-metering pump. The vapor was mixed with the total air supply (12-15 Llmin). Atmospheric M e O H concentrations (mean + SEM) achieved were 10,224 ? 35 and 15,210 2 39 ppm for the WB-MNO and 14,980 2 70 ppm for the WB-H exposures. End-of-exposure maternal plasma MeOH concentrations were 65 + 25 (10,000 ppm, WB-MNO), 223 2 23 (15,000 ppm, WB-MNO), and 194 f 13 m M (15,000 ppm, WB-H). These findings suggest that the WB-MNO system results in maternal M e O H pharmacokinetics that are similar to those observed using more conventional WB-H exposure systems. The WB-MNO should lend itself to numerous additional applications for pharmacokinetic and toxicity studies. ~In many inhalation experiments, it is desirable to expose unrestrained animals and to remove certain animals from the exposure system at intermediate time points. Whole-body exposure systems are ideal for the unrestrained exposure of animals, but most do not lend themselves t o the easy removal of animals during the exposure. O n e application in which an unre-

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Section: Discussion An D Conclusionmentioning

confidence: 91%

Development of a Mouse Whole-Body Exposure System from a Directed-Flow, Rat Nose-Only System

Dorman

Wong

Struve

et al. 1996

Inhalation Toxicology

Self Cite

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“…Interestingly, sodium formate and formic acid were 4-10-fold more potent at inducing embryo toxicity than MeOH (Andrews et al, 1995(Andrews et al, , 1998Dorman et al, 1995), which might suggest that formate is the proximate toxicant. However, the concentrations of formate required to affect development in WEC (Z40 mM) greatly exceeded the blood levels in mice associated with teratogenic exposures to MeOH.…”

Section: Identification Of Proximate Toxicant: Role Of Metabolites Inmentioning

confidence: 95%

Whole embryo culture: a “New” technique that enabled decades of mechanistic discoveries

Ellis-Hutchings

Carney

2010

Birth Defects Research Pt B

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Denis New's development of the rodent whole embryo culture (WEC) method in the early 1960s was a groundbreaking achievement that gave embryologists and teratologists an unprecedented degree of access to the developing postimplantation rodent embryo. In the five decades since its development, WEC has enabled detailed investigations into the regulation of normal embryo development as well as a plethora of research on mechanisms of teratogenesis as induced by a wide range of agents. In addition, WEC is one of the few techniques that has been validated for use in teratogenicity screening of drugs and chemicals. In this review, we retrace the steps leading to New's development of WEC, and highlight many examples in which WEC played a crucial role leading to important discoveries in teratological research. The impact of WEC on the field of teratology has been enormous, and it is anticipated that WEC will remain a preferred tool for teratologists and embryologists seeking to interrogate embryo development for many years to come.

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“…Many 10.5-day-old embryos had edema of the cranial mesenchyme, and at least 21% of the GD 9.5 and 10.5 embryos had occult dysraphism associated with narrowing and angularity of the mesencephalon. Dorman et al (1995) determined that Methyl Alcoholinduced exencephaly in offspring of treated female CD-1 mice was the direct result of the effects of the parent compound (administered via inhalation at 10,000 to 15,000 ppm or by gavage at 1.5 g/kg) rather than the accumulation of formate.…”

Section: Micementioning

confidence: 99%

Final Report on the Safety Assessment of Methyl Alcohol

Lanigan¹

2001

International Journal of Toxicology

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Methyl Alcohol is an aliphatic alcohol with use in a few cosmetic formulations as a solvent and denaturant. Concentrations up to 5% are typically used to denature ethyl alcohol in cosmetic products. Methyl Alcohol is readily absorbed through the skin and from the gastrointestinal and respiratory tracts, is distributed throughout all organs and tissues (in direct relation to the body's water distribution), and is eliminated primarily via the lungs. Undiluted Methyl Alcohol is an ocular and skin irritant. Inhalation studies showed a no-effect level for maternal damage of 10,000 ppm and for teratogenic effects of 5000 ppm. Overall, Methyl Alcohol is not considered mutagenic. Carcinogenicity data were unavailable. The toxicity of Methyl Alcohol in humans results from the metabolism of the alcohol to formate and formic acid through a formaldehyde intermediate. Formate accumulation causes metabolic acidosis and inhibits cellular respiration. Methyl Alcohol toxicity is time and concentration dependent, and its toxic effect is competitively inhibited with ethyl alcohol. Because of the moderating effect of ethyl alcohol, it was concluded that Methyl Alcohol is safe as used to denature ethyl alcohol used in cosmetic products. No conclusion was reached regarding any other use of Methyl Alcohol.Methyl Alcohol is readily absorbed through the skin and from the gastrointestinal and respiratory tracts, and distribution

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Role of formate in methanol‐induced exencephaly in CD‐1 mice

Cited by 34 publications

References 41 publications

Development of a Mouse Whole-Body Exposure System from a Directed-Flow, Rat Nose-Only System

Development of a Mouse Whole-Body Exposure System from a Directed-Flow, Rat Nose-Only System

Whole embryo culture: a “New” technique that enabled decades of mechanistic discoveries

Final Report on the Safety Assessment of Methyl Alcohol

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