Clinical:Developmental Toxicity

Developmental Toxicity

Developmental toxicity is the ability of certain chemical substances (e.g., thalidomide, ethyl alcohol, methylmercury), physical agents (e.g., ionizing radiation), and maternal disease states (e.g., diabetes mellitus) to act on the embryo or fetus prior to birth, or postnatally prior to puberty, to cause one or more manifestations of toxicity in developing offspring. These manifestations include growth retardation, abnormal anatomical development (malformations or variations), functional deficit, and death, individually or in combination. Growth retardation and functional deficit may also be secondary consequences of malformations, or they may be induced independently by the same or different mechanisms than those causing malformation or death. Developmentally toxic effects may be induced by exposure during pregnancy or by postnatal exposure of immature individuals until puberty. They may also result from parental exposure prior to conception. These outcomes can then become evident at any point in the life span of the organism.

Malformations vs. Variations

Malformations can be defined as permanent structural changes that may adversely affect survival, development, or function. Variations are divergences beyond the usual range of structural constitution that may not adversely affect survival or health, and they often represent temporary retardation of growth, development, or skeletal mineralization. Variations are also more common than malformations in both humans and laboratory animals. Making distinctions between malformations and variations can sometimes be difficult, because they exist on a continuum between the normal and the abnormal.

Related Terminology

Agents capable of causing developmental toxicity are referred to as “developmental toxicants,” and the study of developmental toxicity is referred to as “developmental toxicology.” In descriptions of the harmful effects of chemical or physical agents on developing systems, terms such as “embryotoxicity” and “fetotoxicity” have been used. These are legitimate terms, but they are most properly applied only to toxic insults occurring during the specified portion of the developmental process, i.e., during the embryonic or fetal period, respectively.

Additional terms include “teratogenicity,” which is used to mean the ability to produce malformations or “terata.” In the broader sense, teratogenicity has been used in the same way as developmental toxicity, but that usage is not as appropriate because an agent can be developmentally toxic without being teratogenic (i.e., capable of causing malformations). Agents that are teratogenic have been called “teratogens,” a label that is often misused, as it is dependent on factors such as level and timing of exposure and even on the specific organism being exposed.

Testing for Developmental Toxicity

Structural abnormalities (birth defects) and altered growth play an important role in developmental toxicology for several reasons. They appear to be useful endpoints to detect chemical toxicity, and they are easier to recognize than some other effects (e.g., subtle functional deficiencies). The ease of recognition, however, does not necessarily mean that birth defects are more important than other end points, such as lowered intelligence quotients or chronic alterations in the endocrine systems or behavior. Many birth defects can be linked to a specific period of development, thus enabling researchers to pinpoint the window of opportunity for toxic exposure. In laboratory settings, various patterns of exposure timing and dosing can be tested to obtain a whole spectrum of developmental effects such as delayed ossification at low dosages and skeletal malformations at high dosages. In contrast, human exposure to environmental chemicals usually represents a combination of exposure pathways, timing patterns, and doses. ^[1]

Testing for developmental toxicity has become a fundamental component of safety assessment for environmental chemicals. It encompasses the end points of fetal death, malformations, altered growth, and the much broader question of functional abnormalities. This last criterion is the most difficult to determine. It embraces a vast array of possibilities, most of which themselves comprise multiple indices; learning deficits, for example, describe a class of problems rather than a single problem. They may emerge clearly long after birth and then only in specific settings, such as the classroom. Functional measures also may be affected by lower exposure levels than other endpoints relied on as indices of developmental neurotoxicity. Fetal Alcohol Syndrome (FAS) offers an example of the progression from an emphasis on structure to an emphasis on function. In its original description, it featured craniofacial anomalies. With further investigation focused on the effects of lower levels of maternal alcohol intake than those evoking structural defects, a new syndrome, labeled Fetal Alcohol Effects, emerged. ^[2]

The goal of reproductive and developmental toxicity testing protocols is to assess the sensitivity of various processes and life stages to alterations brought about by exposure to the substance under study and to characterize the most vulnerable target tissue. Therefore, the highest dose of a chemical that is administered is generally the amount that would be expected to cause slight systemic toxicity, with lower dosages being spaced to encompass at least one level not expected to induce significant adverse effects. If the amount of toxicity exceeds a maximum tolerated dose (usually defined as a reduction on body weight of no more than 10% during the treatment period), caution must be applied in interpreting any adverse outcomes, as the effects could be confounded by excessive maternal systemic toxicity. It is important that appropriate sensitive end-points are evaluated, that exposures cover all of the known critical periods of development, and that sufficient sample sizes are used to ensure adequate statistical power to detect effects when present. Fetuses are examined for gross, internal soft tissue, and skeletal morphology, in utero mortality, and reduction in fetal weight.

Traditionally, two species, one rodent and one non-rodent, have been used for developmental toxicity testing for regulatory purposes. According to guidance from the U.S. FDA(Redbook 2000), the developmental toxicity test may be done as a stand-alone study, or it may be part of a multigeneration reproduction study. If it is combined with a reproduction study, assessment of teratological effects may be performed on either the first or second generation, but it is usually performed on the last litter of the generation to maximize exposure to the test agent. As part of a multigeneration study, the fetuses may be exposed to the test substance from conception. In a stand-alone study, treatment must begin early enough to include organogenesis for the species used and should continue to the day prior to the expected day of parturition. If the test substance is believed to have the capacity to alter the rate of its own metabolism through induction of metabolizing enzymes or as a result of damage incurred by the liver, then consideration should be given to evaluating the teratogenic potential of the compound by using a separate study. Studies to be used for regulatory purposes should be conducted according to Good Laboratory Practice Regulations (GLPs), and animals should be cared for, maintained, and housed according to the recommendations contained in the Guide for the Care and Use of Laboratory Animals. ^[3]

Further guidance for the design, conduct, and interpretation of tests for developmental toxicity can be found in these references:

Hood, R. D. (Ed.). 2006. Developmental and Reproductive Toxicology, a Practical Approach. CRC Press, Boca Raton, FL, 1168 pp.

OECD. 2007. Draft guidance document on mammalian reproductive toxicity testing and assessment. OECD Environment, Health and Safety Publications, Series on Testing and Assessment, No. 43.

U.S. EPA. 1991. Guidelines for Developmental Toxicity Risk Assessment. Federal Register 56:63798-63826.

References

1. ↑ Hansen, H et. al. "Public health challenges posed by chemical mixtures." Environmental health perspectives 106 (1998): 1271-80 - Abstract
2. ↑ Weiss, B. "Vulnerability of children and the developing brain to neurotoxic hazards." Environmental health perspectives 108 (2000): 375-81 - Abstract
3. ↑ Guide for the Care and Use of Laboratory Animals. Institute of Laboratory Animal Resources. (1996). Guidelines for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.