A 90-day drinking water study in mice to characterize early events in the cancer mode of action of 1,4-dioxane.

Studies demonstrate that with sufficient dose and duration, 1,4-dioxane (1,4-DX) induces liver tumors in laboratory rodent models. The available evidence aligns with a threshold-dependent, tumor promotion mode of action (MOA). The MOA and key events (KE) in rats are well developed but less so in the mouse. Therefore, we conducted a 90-day drinking water study in female mice to evaluate early KE at 7, 28, and 90 days. Female B6D2F1/Crl mice consumed drinking water containing 0, 40, 200, 600, 2000 or 6000 ppm 1,4-DX. 1,4-DX was detected in blood at 90-days of exposure to 6000 ppm, but not in the other exposure groups, indicating a metabolic clearance threshold between 2000 and 6000. Early events identified in this study include glycogen-like vacuolization, centrilobular hypertrophy, centrilobular GST-P staining, apoptosis, and pan-lobular increase in cell proliferation observed after 90-days of exposure to 6000 ppm 1,4-DX. There was minimal evidence of hepatotoxicity over the duration of this study. These findings demonstrate a previously unreported direct mitogenic response following exposures exceeding the metabolic clearance threshold of 1,4-DX. Collectively, the information generated in this study supports a threshold MOA for the development of liver tumors in mice after exposure to 1,4-DX.

Effects of octamethylcyclotetrasiloxane (D4) on the luteinizing hormone (LH) surge and levels of various reproductive hormones in female Sprague-Dawley rats.

The objectives of this study were to assess the potential for D(4) to suppress the pre-ovulatory lutenizing hormone (LH) surge, to block or delay ovulation, and to evaluate potential effects on reproductive hormones in rats. Female Sprague-Dawley Crl:CD (SD) IGS BR rats received whole-body vapor inhalation exposure to D(4) (0, 700, or 900ppm) 6h per day for 3 days. Trunk blood obtained on proestrus at 10a.m. was evaluated for levels of follicle stimulating hormone (FSH), estradiol (E2), estrone (E1), and progesterone (P4). Other rats had serial blood samples collected via cannula at 2, 4, 6, 8, and 10p.m. on the day of proestrus and plasma evaluated for LH and prolactin (PRL). Trunk blood was collected at 8a.m. of estrus and plasma evaluated for FSH, E2, E1, and P4. At 10a.m. on proestrus, significant increases in E1 levels in the 700 and 900ppm groups and significant increases in P4 levels in the 900ppm group were noted. At 8a.m. on estrus, significant increases in E1, E2, in the E1/E2 ratio and decreases in FSH were noted in the 700 and 900ppm groups. The major effect on the LH profile was observed most clearly when the rats were grouped by ovulatory status, animals that did or did not ovulate. Regardless of treatment, suppression of the LH surge correlated with blocked ovulation. The percentage of rats that ovulated was (700ppm, 42%; 900ppm, 31%) compared to controls (79%). Overall, the data indicate that high exposures to D(4) attenuated the pre-ovulatory LH surge and significantly decreased the portion of female rats that ovulated.

A silicone-based controlled-release device for accelerated proteolytic debridement of wounds.

A new device for rapid enzymatic debridement of cutaneous wounds has been developed using a controlled-release, silicone-based, dried emulsion. A dehydrated serine protease of the subtilisin family, previously untested for wound debridement, was incorporated into the emulsion. This device exhibited excellent storage stability. Moisture from the wound triggered an even, reproducible, and complete release of the enzyme within the first 8 hours. The device maintains a moist wound environment that allows the enzyme to achieve nearly complete digestion of the hardened eschar of full-thickness burns in a porcine model after an exposure period of 24 hours. Debridement was faster than in untreated wounds or wounds treated with a currently available enzyme ointment. Following rapid enzymatic debridement, healing appeared to progress normally, with no histological evidence of damage to adjacent healthy tissue.

Propylene glycol monomethyl ether (PGME): inhalation toxicity and carcinogenicity in Fischer 344 rats and B6C3F1 mice.

A series of inhalation studies with propylene glycol monomethyl ether (PGME) vapor were undertaken to characterize its subchronic toxicity in mice and chronic toxicity/oncogenicity in rats and mice. Groups of male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 300, 1,000, or 3,000 ppm vapor from 1 week to 2 years. Primary treatment-related effects included: initial sedation of animals exposed to 3,000 ppm and its subsequent resolution correlating with induction of hepatic mixed function oxidase activity and S-phase DNA synthesis; elevated mortality in high-exposure male rats and mice (chronic study); elevated deposition of alpha2u-globulin (alpha2U-G) and associated nephropathy and S-phase DNA synthesis in male rat kidneys; accelerated atrophy of the adrenal gland X-zone in female mice (subchronic study only); and increased occurrence and/or severity of eosinophilic foci of altered hepatocytes in male rats. No toxicologically relevant statistically significant increases in neoplasia occurred in either species. A numerical increase in the incidence of kidney adenomas occurred in intermediate-exposure male rats; however, the association with alpha2U-G nephropathy, a male rat specific effect, indicated a lack of relevance for human risk assessment.