Selected Examples of Developmental Toxicants

Ionizing radiation, microwaves, ultrasound, or hypothermia are the major physical agents that can affect the fetus via direct transmission through maternal tissues. In general, the dose required for a physical agent to cause detriment to the fetus surpasses that required to induce maternal toxicity. Mechanical impact or changes in temperature, unless extreme, are likely minimized by the hydrostatic pressure of the womb and maternal homeostatic capabilities. 

In general, the placenta is a poor barrier to xenobiotics and allows for bidirectional transfer of most substances. The majority of molecules cross the placenta via diffusion along a concentration gradient, the rate of which is a product of the agent s size, charge, lipid solubility, and affinity for other biomolecules. 

The maternal capacities that provide a homeostatic environment and metabolic deactivation of potential toxicants, along with the repair and regenerative capabilities of the embryo/fetus, are believed to impart a threshold phenomenon to developmental toxicity. The supposition of a threshold implies that a maternal dose exists at which a toxicant will elicit no adverse effect on the conceptus. This is in contrast to the threshold principle of carcinogenesis, which assumes that exposure to any amount of carcinogen, even a single molecule, can potentially lead to cancer. 

The typical dose-response curve for a developmental toxicant is steep and covers less than one to three orders of magnitude below the dose that kills or malforms half the embryos. However, the threshold and shape of a dose-response curve for a particular teratogen may differ, depending on the gestational time of exposure and the type of embryotoxicity that is measured. Furthermore, the dose at which an agent causes malformations may be above, below, or equivalent to the embryolethal threshold. Toxicants that cause little or no maternal toxicity, even at elevated doses, but adversely affect the conceptus are especially dangerous (e.g., thalidomide, diethylstilbestrol). 

Approximately 1200 chemicals have been shown to be teratogenic in experimental animals. However, less than 40 physical, chemical, or infectious agents are known to produce birth defects in humans (Table 34.3). Five xenobiotics known to be 

---

Another possible use of in vitro developmental toxicity tests would be to select the least developmentally toxic backup from among a group of structurally related compounds with similar pharmacological activity [use (2) in the list above], for example, when a lead compound causes malformations in vivo and is also positive in a screen that is related to the type of malformation induced. However, even for this limited role for a developmental toxicity screen, it would probably also be desirable to have a measure of the comparative matemotoxicity of the various agents and/or information on the pharmacokinetics and distribution of the agents in vivo. 

The first step in the laboratory study of developmental toxicity is determination of the substance to be tested. This might be straightforward in drug or pesticide registration studies because only a single pure compound is of concern. In the case of complex mixtures, however, selection of the test substance(s) for the particular condition(s) and route(s) of exposure can be very difficult. For example, gasoline, diesel fuel, or aviation fuel each contain more than 250 diverse hydrocarbons, which change with source of the crude oil, the products are formulated differently... 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

There are considerable data on the chronic toxicity of NP in laboratory animals. The focus of these investigations has typically been evaluation of the potential reproductive and developmental effects of NP, due to its ability to modulate estrogen receptor-mediated responses. Many endpoints are not consistently observed across studies. Some of this variability may be due to differences in the conditions, design, and other test-specific variables of the toxicity tests. For example, since phytoestrogens are abundant in most laboratory animal feeds (such as found in soy and alfalfa) and are known to modulate estrogen receptor-mediated responses, phytoestrogens may be confounding factors as a result of the feed selection. 

The classification of category 1, 2, or 3 cannot take into account the extremely variable potential for developmental toxicity. Therefore, in some countries efforts are being made to implement a better differentiation system. The German MAK commission, for example, classifies the developmental toxic substances in 3 additional groups on the basis of the occupational exposure levels (OEL). A classification has to be done if a developmental toxic effect can occur at the concentration of the established occupational exposure level. As a consequence of the fact that the concentration of the OEL is mostly much lower than the lowest effect concentration (LOEL) for developmental toxicity, many substances classified as developmental toxic substances do not show this property at the OEL. Figure 3.12 shows some selected chemicals which do not cause concern at the OEL. 

---