Teratogenicity sensitivity

Table 7.6 Comparison of maximum periods of teratogenic sensitivity for various organs/systems in humans...

Exposure effects Inhalation (general) Respiratory irritation Ingestion Skin/eye irritation Skin and respiratory sensitization Mutagenicity Teratogenicity Carcinogenicity ... 

Miltefosine, an alkylphosphocholine derivative, is a new antileishmanial drug and the first effective oral treatment of visceral leishmaniasis. However, there are concerns regarding teratogenicity, rapid emergence of resistance, and variable cure rates, possibly due to species differences in drug sensitivity. The mechanism of action of miltefosine is not known. 

FIGURE 44-1. Embryonic development. (Reprinted, with permission, from Moore KL, The Developing Human. New York Elsevier, 1874 p 96 copyright 1974.) The horizontal bars represent potential sensitivity to teratogens. The pink areas represent the more critical times. 

The data from the only available animal study (Prigge and Greve 1977) indicate that inhaled lead is not teratogenic. However, it impaired heme synthesis in both rat dams and fetuses. In this study, dams were exposed to 1, 3, or 10 mg lead/m3 (chemical species not provided) throughout gestation (days 1-21). Maternal and fetal ALAD were inhibited at all exposure levels in a dose-related manner, and fetal (but not maternal) hematocrit and body weight were decreased at the 10-mg/m3 lead level. These results suggest that the fetuses were more sensitive to lead-induced toxicity than were the dams. 

Currently, only the Hydra system incorporates a measurement of toxicity to the adult to provide a comparison of the sensitivity of the embryo with that of the adult (Johnson et al., 1988). However, the Hydra screen has not been fully validated as being predictive of results in mammals, and has fallen from favor. Thus, a major goal of research directed toward developing an in vitro teratogen screen should be to find a simple yet appropriate measure of toxicity unrelated to development. This would allow the comparison of the dose for a 50% effect (ED50) on developmental toxicity as measured in vitro to an ED50 for adult toxicity in vitro. The validation... 

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-... 

Residue must be < 0.1 ppm in meat and < 10 ppb in milk and eggs. + - If teratogenic activity is demonstrated, the safety factor is 1,000 may also be < 100 when human exposure data are available or when a sensitive measurement is used to set a no-effect concentration. 

Segment 11 teratogenicity study. This concentrates on the most sensitive part of gestation, from the time of implantation imtil major organogenesis is complete. This is the period during which a test substance is most likely to cause malformation of the embryo. Exposure of the mother to the test substance is usually confined to this period. Conventionally, the study is conducted in rats and rabbits. Rabbits are intolerant to antibiotics and the mouse is an acceptable alternative in most cases. 

Toxicology. Benomyl causes dermatitis and dermal sensitization in experimental animals it is a reproductive toxin and teratogen. 

Most drugs and chemicals pose a threat to the developing fetus. An estimated 4 to 5% of developmental defects in humans result from prenatal exposure to drugs or environmental chemicals. This is particularly important, since women with irregular menstrual cycles may be exposed to teratogens and enter the sensitive period of organogenesis before pregnancy is suspected. 

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