Developmental toxicants examples

The first is a rule-based system, which makes predictions for untested agents by drawing upon the human interpretation of toxicity data and biological information. That is, it captures, organizes, and applies scientific expertise that relates chemical structures with developmental toxicity. Examples of commercially available rule-based approaches include HazardExpert,23 Deductive Estimation of Risk from Existing Knowledge (DEREK),24... 

Short- to medium-term exposure has shown neurotoxicity, developmental toxicity, immunotoxicity, and endocrine disruption to be relevant end-points. Table 24 summarizes the critical studies for each compound and identifies NOAELs or LOAELs. The degree of each of the toxic end-points differs across the group as a whole. For example, tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. 

Additionally, there are specialized studies designed to address endpoints of concern for almost all drugs (carcinogenicity, reproductive or developmental toxicity) or concerns specific to a compound or family of compounds (local irritation, neurotoxicity, or immunotoxicity, for example). When these are done, timing also requires careful consideration. It must always be kept in mind that the intention is to ensure the safety of people in whom the drug is to be evaluated (clinical trials) or used therapeutically. An understanding of special concerns for both populations should be considered essential. 

To demonstrate that a developmental effect is secondary to a particular parameter of maternal toxicity, it is necessary but not sufficient to show that all mothers with developmental toxicity also had maternal toxicity and that the severity of the developmental effect was correlated with the maternal effect. An example of such a correlation is shown in Figure 8.8, in which a drug-induced effect on maternal... 

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. 

Toxicologists nowadays take a broad view of developmental toxicity they consider not only structural but also functional abnormalities to qualify as adverse, as long as they were produced as a result of exposures incurred in utero. Thus, for example, the developmental effects of chronic alcohol abuse by pregnant women, known as fetal alcohol syndrome (FAS), are characterized not only by the presence of certain craniofacial abnormalities, but also by a variety of disabilities such as shortened attention span, speech disorders, and restlessness. Although fully expressed physical deformities included in FAS are associated with heavy drinking, debate continues on the level of alcohol consumption, if any, that is without these more subtle effects on behavior. 

Often several different toxic hazards (neurotoxicity, organ toxicity, developmental toxicity, for example) associated with the substance that is the subject of the risk assessment, each with its own dose-response characteristics, will emerge from the first two steps of the risk assessment. Which of these should become the principal basis for the final risk assessment. ... 

Additional factors may be applied if there are significant shortcomings in the available data that are a cause for concern. If, for example, data relating to the effects of a chemical during the developmental phase are absent, and there are reasons to suspect that the chemical could have such effects (it may, for example, be structurally related to a known developmental toxicant) an additional factor may be applied to the NOAEL. 

ICCVAM has evaluated alternative test methods for acute oral toxicity, genetic toxicity, biologies, immunotoxicity, dermal corrosion and irritation, ocular toxicity, developmental toxicity, pyrogeni-city, and endocrine disrupter effects (ICCVAM 2007). As examples, alternative test systems for dermal corrosion and irritation are described in the following text. 

Developmental toxicity, defined in its widest sense to include any adverse effect on normal development either before or after birth, has become of increasing concern in recent years. Developmental toxicity can result from exposure of either parent prior to conception, from exposure of the embryo or fetus in utero or from exposure of the progeny after birth. Adverse developmental effects may be detected at any point in the life span of the organism. In addition to stmcmral abnormalities, examples of manifestations of developmental toxicity include fetal loss, altered growth, functional defects, latent onset of adult disease, early reproductive senescence, and shortened life span (WHO/IPCS 2001b). 

DeSesso JM, Goeringer GG Developmental toxicity of hydroxylamine an example of a maternally mediated effect. Toxicol Ind Health 6 109-121, 1990... 

One way to circumvent such (unjustified) labeling is to try to prove a causal relationship between the maternal effects and those in offspring, thus trying to show that the latter ones are unspecific secondary consequences of the former ones. So for the sound interpretation of study results it is important to find a good balance between maternal and fetal effects. For example, if a 10% reduction in maternal net weight gain is accompanied by a comparable reduction in fetal weight, then this puts the fetal effects in the correct perspective and would not lead the experimenter to conclude that the compound is a (specific) developmental toxicant. On the other hand if in the same situation the number of fetal anomalies (in particular malformations) is increased, then this could most unlikely be explained as a consequence of maternal toxicity. 

To date, there is no consensus on the role maternal toxicity in developmental toxicology. Several publications and workshops have discussed this complex issue in order to get a better understanding of how to design and interpret developmental toxicity studies. Examples of workshops include European Commission... 

Developmental toxicity can be induced by different maternally mediated mechanisms, several examples relate to induction of disturbed embryonic oxygenation. However, such adverse fetal effects should be characterized as developmental toxicity even if it is mediated via maternal pharmacological mechanisms. The observed effects may, or may not, be relevant in the human exposure situation. If a company claims that the observed developmental toxicity is not relevant in the human, the regulatory authorities will expect the company to provide appropriate and convincing evidence to that effect (e.g., mechanistic studies together with kinetic data). 

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