Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents).
Toxicology studies using 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. Studies in pregnant animals are used to determine the risk of birth defects and other reproductive effects. There is no question that whole animal teratology studies are helpful in raising concerns about the reproductive effects of drugs and chemicals, but negative animal studies do not guarantee that these agents are free from reproductive effects. There are examples in which drug testing was negative in animals (rat and mouse) but was teratogenic in the human (thalidomide), and there are examples in which a drug was teratogenic in an animal model but not in the human (diflunisal). Testing in animals could be improved if animal dosing using the mg/kg basis were abandoned and drugs and chemicals were administered to achieve pharmacokinetically equivalent serum levels in the animal and the human. Because most human teratogens have been discovered by alert physicians or epidemiology studies, not animal studies, animal studies play a minor role in discovering teratogens. In vitro studies play an even less important role, although they are helpful in describing the cellular or tissue effects of the drugs or chemicals. One cannot determine the magnitude of human risks from these in vitro studies. Performing toxicology studies on adult animals is performed by pharmaceutical companies, chemical companies, the Food and Drug Administration, many laboratories at the National Institutes of Health, and scientific investigators in laboratories throughout the world. Although a vast amount of animal toxicology studies are performed on pregnant animals and numerous toxicology studies are performed on adult animals, there is a paucity of animal studies using newborn, infant, and juvenile animals. This deficiency is compounded by the fact that there are very few toxicology studies performed in children. That is 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. Although many studies reveal that the infant and the developing animal have difficulty in metabolizing drugs and are more vulnerable to the toxic effects of environmental chemicals, there are exceptions that indicate that infant 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 to environmental toxicants is not valid. For animal toxicology studies to be useful, animal studies have to use modern concepts of pharmacokinetics and toxicokinetics, as well as method-of-action studies to determine whether animal data can be used 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, because the oncogenesis is the result of peroxisome proliferation, a reaction that is of diminished importance in humans. Scientists can use animal studies to study the toxicokinetic and toxicodynamic aspects of 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, maximum permissible exposures, and toxic effects can be estimated but have to be interpreted with caution when applying them to the human. Well-performed epidemiology studies are still the best method for determining the human risk and the effects of environmental toxicants.
Brent
Robert L
RL
Thomas Jefferson University, Alfred I. duPont Hospital for Children, Laboratory of Clinical and Environmental Teratology, Wilmington, Delaware 19899, USA. rbrent@nemours.org
D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D002648:Child; D005260:Female; D005333:Fetus / Q000187:drug effects; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D007231:Infant, Newborn; D023421:Models, Animal; D011247:Pregnancy / Q000187:drug effects; D014116:Toxicology / Q000379:methods
D015386:Hazardous Substances