Congenital effects toxicity

Developmental Effects. Evidence from human studies on congenital anomalies as an end point (Emhart et al. 1985, 1986 McMichael et al. 1986 Needleman et al. 1984) indicate no association between prenatal exposure to low levels of lead and the occurrence of major congenital anomalies. This conclusion is further supported by developmental toxicity studies conducted in rats and mice these studies provide no evidence that lead compounds (acetate or nitrate) are teratogenic when exposure is by natural routes (i.e., inhalation, oral, dermal). Intravenous or intraperitoneal injection of lead compounds (acetate, chloride, or nitrate) into pregnant rats, mice, or hamsters, however, has produced malformations in several studies reviewed by EPA (1986a). 

Pyrimethamine, in combination with sulfadiazine, is first-line therapy in the treatment of toxoplasmosis, including acute infection, congenital infection, and disease in immunocompromised patients. For immunocompromised patients, high-dose therapy is required followed by chronic suppressive therapy. Folinic acid is included to limit myelosuppression. Toxicity from the combination is usually due primarily to sulfadiazine. The replacement of sulfadiazine with clindamycin provides an effective alternative regimen. 

Prolonged contact between toluene and human skin may cause nonallergic contact dermatitis. Human exposure to toluene also causes nervous system symptoms and signs and excessive exposure may cause adverse effects on the kidney and liver. Adverse effects on the nervous system have been observed in experimental animals. In studies of spontaneous abortion, perinatal mortality and congenital malformations in humans, the numbers of cases were small and the mothers had also been exposed to other substances. Embryotoxicity that generally occurs concurrently with maternal toxicity has been seen in some studies in mice and rats but not rabbits (lARC, 1989a). 

Genetic and Neonatal Toxicity. The ability of heavy metals readily to cross the placenta and disrupt nucleic acids coupled with the high sensitivity of the fetus and neonate increases the potential dangers of congenital and neonatal toxicity. In mammalian leukocyte cultures, chromosomal aberrations have been reported with lead (112), arsenic (113), mercury (114), and methylmercury (115). Charbonneau, et al. (116) reported a lack of mutagenic effect for methylmercury. 

An example of an effective teratology profile is one in which the terms BIRTH , CONGENITAL , DEVELOPMENT , LITTER , OFFSPRING, or PROGENY should not cause a hit unless one of the following terms also appears in the record — ABNORMAL , ANOMAL , DEFECT , DEFORM , MALFORM , or TOXIC . The latter terms should not cause a hit unless one of the former terms also appears. 

Such a dichotomy cannot be resolved in a generic manner. Although it may be advisable that chronic effect results be obtained from both a rodent and nonrodent, the selection of appropriate species for chronic toxicity tests should be based upon practical reasons and the results of previously conducted studies. In some cases, testing with a single species may provide sufficient data for assessing test chemical hazards. Strains of test animals should be well characterized for commonly found diseases and their resistance, and should be free from congenital defects. 

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