17.14: Toxicity Testing in Animals

Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence rate of a severe effect like cancer could represent 25,000 individuals in a large population, highlighting the stakes of accurate risk estimation from animal tests.

The process begins with determining the median lethal dose (LD₅₀), which is the dose lethal to half the animal population tested. This is a crucial term in toxicology, as it helps us understand a substance's potency. The LD₅₀ is determined using two species and two routes of administration, one of which matches the expected human exposure. Over a 14-day observation period, scientists record mortality and check for symptoms of toxicity, such as intoxication and lethargy.

The substances then undergo a 90-day repeated exposure test involving at least three doses. This study is tailored to the route intended for human exposure, and it includes comprehensive health monitoring and ends with detailed pathological examinations of the animals' organs and tissues.

Long-term or chronic studies conducted alongside human clinical trials assess the duration-dependent effects of exposure. Depending on the intended duration of human use, these studies might last from six months to two years. They are crucial for evaluating the carcinogenic potential of substances like pesticides, pharmaceutical drugs, and industrial chemicals, and other long-term health impacts like teratogenicity (congenital malformations), perinatal and postnatal toxicity, and fertility effects. These studies provide valuable insights into the potential risks associated with these substances, helping us make informed decisions about their use.

Toxicity tests in animals assume that adverse effects observed in laboratory animals apply to humans. This comparison is made after adjusting for body surface area and other physiological differences.

Usually, testing involves fewer animals than the potentially large human populations at risk. As a result, animals are exposed to higher doses to predict the effects of lower doses in humans.

Initially, toxicity tests estimate the LD₅₀, or dose lethal to half of the population in two animal species via two routes of administration.

Post single dose, animals are monitored for 14 days for morbidity, intoxication, lethargy, behavioral changes, and mortality.

Next, animals undergo repeated exposure toxicity tests for 90 days, involving three different doses, monitoring of health parameters such as weight changes, and detailed pathological examination of organs and tissues.

Long-term or chronic toxicity studies are conducted in parallel to clinical trials.

They assess chemicals' carcinogenic and teratogenic potential, along with their perinatal and postnatal toxicity, and fertility effects.