An Evaluation of The Toxicity and Teratogenicity of Hexabrominated Naphthalenes in C57B1/6N Mice
- Creator: Miller, Christopher P.
- Collection: Master's Papers
- File Type: pdf
- | Filesize: 2.9 MB
- Date Deposited: 2016-06-20
- Date Created: 1985-08-01
Brominated naphthalenes have been identified as toxic contaminants of the polybrominated biphenyl mixture Firemaster, which was found to be responsible for the 1973 Michigan livestock feed contamination incident. Extensive adult and embryo/fetal toxicity was associated with consumption of the contaminated feed. In order to characterize the embryotoxic and teratogenic properties of hexabrominated naphthalenes (HBNs), the most prevalent of the brominated naphthalenes in Firemaster, pregnant C57B1/6N mice were treated on gestation days 6-15 with 0, 0.5, 1.0, 2.5, 5.0, 7.5 and 10.0 mg HBN/kg body weight/day (p.o.) and sacrificed on gestation day 18. Maternal and fetal toxicity were characterized and a complete teratological evaluation was performed. Dose-related effects on maternal body and thymus weight, and liver to body weight ratios were seen. Dose-related increases were observed for fetal subcutaneous edema, involution of lymphatic organs, delayed cranial ossification and fetal mortality. A steep dose response curve was shown for cleft palate, with 4.8% and 98.6% of the fetuses per litter affected at 1.0 and 2.5 mg/kg, respectively. Kidney lesions, best described as apparent hydronephrosis, were an even more sensitive indicator of fetal toxicity with 100% of the fetuses having bilateral dilated renal pelves at 1.0 mg/kg and 90% having at least a unilateral dilated renal pelvis at 0.5 mg/kg. A pilot teratology study conducted by dosing animals between gestation days 10-13 with 0, 10, 100 or 1000 mg HBN/kg body weight/day revealed that 100% of the fetuses had cleft palate at each of the HBN treatment levels. Results of single and multiple (10 day) dosing toxicity studies with adult, female C5 7B1/6N mice suggest that HBN is much more toxic when administered in multiple smaller doses than as a single large dose. Singly-dosed animals exposed at levels as high as 1000 mg/kg failed to show signs of toxic stress during the course of a 35-day follow-up, while animals that received multiple smaller doses of as low as 5.0 mg/kg/day exhibited overt signs of toxicity (wasting, lethargy and bleeding) at 7 days of dosing. Dose-related hepatic and thymic effects were also seen in multiply-dosed but not singly-dosed animals. Thus, HBN is a potent toxic, teratogenic and fetotoxic agent that produces a spectrum of teratogenic and toxic lesions that is similar to TCDD and other structurally-related halogenated aromatic hydrocarbons.