The Selected Works of Robert Brent
Utilization of Juvenile Animals Studies to Determine the Human Effects and Risks of Environmental Toxicants During Postnatal Developmental Stages
Robert L. Brent, duPont Hosp for Children
DATE: January 2004
SOURCE: Birth Defects Research, Part B, vol71, pp. 303-320
ABSTRACT:
Toxicology studies utilizing animals and in-vitro cellular or tissue preparations have been used to study the toxic effects and mechanism of action of drugs and chemicals and to determine the effective and safe dose of drugs in humans and the risk of toxicity from chemical exposures. Testing in animals could be improved if animal dosing using the mg/kg basis was abandoned and drugs and chemicals were administered to compare the effects of pharmacokinetically and toxicokinetically equivalent serum levels in the animal model and human. Since alert physicians or epidemiology studies, not animal studies have discovered most human teratogens and toxicities in children, animal studies play a minor role in discovering teratogens and agents that are deleterious to infants and children. In vitro studies play even a less important role, although they are helpful in describing the cellular or tissue effects of the drugs or chemicals and their mechanism of action. One cannot determine the magnitude of human risks from in-vitro studies when they are the only source of toxicology data. Performing toxicology studies on adult animals is performed by pharmaceutical companies, chemical companies, the Food and Drug Administration (FDA), many laboratories at the National Institutes of Health and scientific investigators in laboratories throughout the world. While there is a vast amount of animal toxicology studies performed on pregnant animals and adult animals, there is a paucity of animal studies utilizing newborn, infant and juvenile animals. This deficiency is compounded by the fact that there are very few toxicology studies performed in children. That is one reason why pregnant women and children are referred to as “therapeutic orphans.” When animal studies are performed with newborn and developing animals, the results demonstrate that generalizations are less applicable and less predictable than the toxicology studies in pregnant animals. While many studies reveal that infants and developing animals may have difficulty in metabolizing drugs and are more vulnerable to the toxic effects of environmental chemicals, there are exceptions that indicate that infants and developing animals may be less vulnerable and more resilient to some drugs and chemicals. In other words, the generalization indicating that developing animals are always more sensitive (Table 1) to environmental toxicants is not valid. In order for animal toxicology studies to be useful, animal studies have to utilize modern concepts of pharmacokinetics and toxicokinetics, as well as “Mechanism of Action” (MOA) studies in order to determine whether animal data can be utilized for determining human risk. One example is the inability to determine carcinogenic risks in humans for some drugs and chemicals that produce tumors in rodents, When the oncogenesis is the result of peroxisome proliferation, a reaction that is of diminished importance in humans. Scientists can utilize animal studies to study the toxicokinetic and toxicodynamic aspects of drugs and environmental toxicants. But they have to be performed with the most modern techniques and interpreted with the highest level of scholarship and objectivity. Threshold exposures, NOAEL exposures and toxic effects can be determined in animals, but have to be interpreted with caution when applying them to the human. Adult problems in growth, endocrine dysfunction, neurobehavioral abnormalities and oncogenesis may be related to exposures to drugs, chemicals and physical agents during development and may be fruitful areas for investigation. Maximum permissible exposures have to be based on data, not on generalizations that are applied to all drugs and chemicals. Well-performed epidemiology studies are still the best methodology for determining the human risk and the effects of environmental toxicants. But performing these focused studies in developing humans will be difficult. So, at the present time the animal studies may be our only alternative for answering many questions with regard to specific postnatal developmental vulnerabilities.