title: Marked increase in the teratogenicity of the combined administration of the industrial solvent 2-methoxyethanol and radiofrequency radiation in rats.
abstract: Limited published animal research reports synergistic teratogenic effects following combined hyperthermia (induced by elevated ambient temperature) and administration of chemical teratogens. Radiofrequency (RF) radiation is widely used in occupational environments. Since RF radiation also elevates the body temperature of, and is teratogenic to, exposed animals, concurrent RF radiation and chemical agent administration may enhance teratogenicity. The present exploratory study, consisting of preliminary dose-finding studies and the primary study, was designed to investigate whether concurrent exposure of rats to RF radiation and the industrial solvent 2-methoxyethanol (2ME) can enhance the developmental toxicity of either agent acting alone. Preliminary dose-finding studies using small numbers of rats investigated the ability of various RF radiation conditions and doses of 2ME to produce external malformations (primarily of the paws) when administered on gestation day 13. Based on these preliminary studies, RF radiation exposure [sufficient to elevate rectal temperature to 42.0 degrees C (4 degrees C above normal for rats) for 30 min] and 2ME administration (150 mg/kg) were selected for the primary study. In the primary study, groups of 18 to 27 pregnant rats were administered RF radiation exposure and distilled water gavage, 2ME gavage and sham RF exposure, RF radiation exposure and 2ME gavage concurrently, or sham RF exposure and distilled water gavage. Pregnant rats were sacrificed on gestation day 20, and the offspring were examined for external malformations. Combined exposures enhanced the adverse effects produced by either experimental agent alone (no malformations were detected in the double sham group). Mean fetal malformations/litter increased from 14% after 2ME and sham RF (15/26 litters affected, with an average of 2 fetuses/litter malformed) and 30% after RF radiation and water gavage (10/18 litters affected, with an average of 4 fetuses/litter malformed), to 76% after the combined treatment (18/18 litters affected, with an average of 12 fetuses/litter malformed). In addition to a significant increase in the frequency of malformations, the severity of malformations also was enhanced by the combination treatment (on a relative severity ranking scale, the 2ME severity score was less than 1, the RF score was 3, and the combination score was 6). This study provided evidence of synergism between RF radiation and 2ME administration, but additional research will be required to characterize the extent of synergism between these two agents. Potential interactive effects between chemical and physical agents need to be investigated to determine the extent to which such interactions should impact occupational exposure standards.
authors.affiliation: Division of Biomedical and Behavioral Science, National Institute for Occupational Safety and Health, Cincinnati, Ohio 45226.
authors.forename: B K
authors.initials: BK
authors.lastname: Nelson
authors.forename: D L
authors.initials: DL
authors.lastname: Conover
authors.forename: W S
authors.initials: WS
authors.lastname: Brightwell
authors.forename: P B
authors.initials: PB
authors.lastname: Shaw
authors.forename: D
authors.initials: D
authors.lastname: Werren
authors.forename: R M
authors.initials: RM
authors.lastname: Edwards
authors.forename: J M
authors.initials: JM
authors.lastname: Lary
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005026:Ethylene Glycols / Q000633:toxicity*; D005260:Female; D005313:Fetal Death; D007259:Infrared Rays / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange; D016273:Occupational Exposure; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D005026:Ethylene Glycols; C005219:methyl cellosolve