Teratogenic laboratory animals

Chronic toxicity in laboratory animals by two-year or lifetime feedings in two species of laboratory animals, multiple-generation teratogenicity, and, not always required, one-year feeding of dogs. 

Grossly elevated concentrations of dissolved copper produce teratogenicity in fish embryos. A significant number of malformed fish larvae came from eggs treated with 500 pg Cu/L (Birge and Black 1979). In studies with laboratory animals and elevated concentrations of copper salts, copper penetrates the placental barrier into the fetus intramuscular injection of 4 mg Cu/kg BW early in pregnancy adversely affects fetal central nervous system development (Aaseth and Norseth 1986). In humans, no definitive data are available on whether copper can cause birth defects however, incubation of human spermatozoa with metallic copper results in loss of sperm motility (Aaseth and Norseth 1986). 

Earl, F.L., Miller, E. and Van Loon, E.J. (1973). Teratogenic research in beagle dogs and miniature swine. The Laboratory Animal in Drug Testing Fifth Symposium, Internal Committee on Laboratory Animals (Spiegel, H., Ed.), pp. 233-247. 

In laboratory animals, TCDD administered in suitable doses has produced a wide variety of toxic effects, including a wasting syndrome (severe weight loss accompanied by reduction of muscle mass and adipose tissue), thymic atrophy, epidermal changes, hepatotoxicity, immunotoxicity, effects on reproduction and development, teratogenicity, and carcinogenicity. The effects observed in workers involved in the manufacture of 2,4,5-T (and therefore presumably exposed to TCDD) consisted of contact dermatitis and chloracne. In severely TCDD-intoxicated patients, discrete chloracne may be the only manifestation. 

This is a sedative drug with low adult toxicity, which proved to be a very potent human teratogen, causing phocomelia (shortening of the limbs) and other defects when taken between the third and eighth week. In some cases, only a few doses were taken, but on the critical days (e.g., days 24-27 for phocomelia of arms). It is not readily reproducible in laboratory animals (e.g., rats). Mechanism is unknown, but a metabolite suspected, possibly produced by cytochrome P-450. A number of metabolites are produced and some chemical breakdown occurs. Phthalylglutamic acid metabolite is teratogenic in mice. Thalidomide may acylate nucleic acids and polyamines. The S-enantiomer is more embryotoxic than the R-enantiomer. 

Recent studies have indicated that humans may be exposed to 2,3,7,8-tetrachlorodibenzo-p- dioxin(2,3,7,8-TCDD), a toxic and teratogenic substance in laboratory animals (1). A fraction of beef fat samples from cattle known to have grazed on pasture treated with herbicide 2,4,5-T (which contains trace quantities of 2,3,7,8-TCDD) have been reported to contain low part per trillion (ppt) levels of 2,3,7,8-TCDD (2,3) Two studies of bovine milk reported no detectable chlorodioxins however (4,5). Combustion processes have been reported to produce chlorinated dioxins which enter the air as fly ash and soot (6.7.8). Three different studies of human milk have been carried out by various workers to determine if humans contain detectable concentrations of 2,3,7,8-TCDD (9,20,22). 

---