Lecture 10

Chapter 4 of Textbook

Factors That Influence Toxicity

Selective Toxicity 选择毒性 Much less toxin is needed to kill a small insect than a considerably larger mammal if everything else being equal.

There is an inverse relationship反比关系 between the weight of an animal and its surface area表面面积 ; the small the animal, the larger its surface area per gram of weight.

Percutaneous absorption rate 表皮吸收速度

Same area and same weight, A and B, but which one has larger surface area?

Percutaneous absorption rate 透皮吸收速度

The insecticide, DDT (dichlorodiphenyltrichloroethane) is about equally toxic to insects and mammals when given by injection, yet when applied externally it is considerably more toxic to insects.

This toxicity is due not only to the difference of surface area to body weight ratio, but also to the fact that the chitinous exoskeleton几丁质外骨骼 ,甲壳素 of the insect is more permeable to DDT than unprotected mammalian skin.

Percutaneous absorptionanimal test

chitinous exoskeleton

Metabolic Pathways代谢途径 Metabolic-pathway differences among species may provide another rationale 基本原理 for achieving selective toxicity. Refer to textbook for examples.

Enzyme Activity 酶活力

In some cases metabolic pathways may be the same for several species, but the enzymes that carry out certain reactions may differ. Refer to textbook for examples.

Xenobiotic-Metabolizing Systems

Selective toxicity also may be based on differences in xenobiotic-metabolizing systems. For instance, the insecticide malathion 马拉硫磷 , upon being converted by cytochrome P-450 to malaoxon, becomes an inhibitor of acetylcholinesterase. It is nearly 38 times less toxic when given orally to rats than applied topically to houseflies.

Figure 4.3 Conversion of malathion to malaxon

Toxicity Tests in Animals

•Acute toxicity test•Subchronic toxicity test•Chronic toxicity test (cancer study)

Oral toxicity testing force-feeds strong chemicals

Acute toxicity test

It is for the determination of LD50. Groups of animals (5-10 males and an equal number of females per group) are treated with a chemical at three to six different dose levels. The number of animals that die within 14 days is tabulated. The weight of the animals and any changes in their behavior are noted. At the end of the experiment the survivors are sacrificed and all animals (including the control group) are examined for pathological changes.

Subchronic toxicity tests

It invloves daily administration of the compound to be tested to groups of males and females at three dose levels: the maximum tolerated dose (MTD), lowest observable adverse effect level (LOAEL), and no observable effect level (NOAEL). MTD is chosen so that it does not exceed LD10. Usually two species and frequently two routes of exposure are tested, one being the same as the expected human exposure. The duration of the test vary between 5 to 90 days. Mortality, weight, and behavioral changes are noted. Blood chemistry measurements are performed prior to, halfway through, and at the end of the experiment. Subsequently, all the animals are sacrificed for pathologic study病理学 .

Species Differences物种差异 When using animal assay data for predicting human toxicity, the goal is to minimize species differences. Unfortunately, this is frequently difficult to achieve. Even with a single class, such as mammals, metabolic differences among species may be considerable.

Compartments of the gut wall with some species differences indicated

The US Food and Drug Administration (FDA 美国食品药品管理局 ) requires a toxicity study in two unrelated species (usually rats or mice and dogs) before an approval of phase 1 clinical trials (I 期临床试验 ) is granted. Phase 1 clinical trials are designed to test the toxicity of a new drug in human patients.

Phase I Clinical Trials Logo Ward 病房

Exposure Mode 暴露模式 In any evaluation of the toxicity of environmental and industrial compounds, it is important that the test animals be exposed to the presumed toxin in a manner similar to the anticipated human exposure.

Exposure Model for Electroplating Process电镀厂

The typical course of infection传染病

Individual Variations个体差异 in Response to Xenobiotics

1.Environment and Endocrine 内分泌腺 Factors

•The recurrent 重复 exposure of the same toxins in the environment.

•Personal diet habits

•The hormonal 激素 status of an individual

2. Genetic Factors

Some individuals are endowed with天生具有 genetic characteristics designated as hypersensitivity and hyposensitivity.

Influence of Age

In general, both developing and aging organisms are more susceptible to the toxic effects of xenobiotics than young adults. This increased susceptibility is probably due to the fact that very young individuals have not fully developed sufficient levels of detoxifying enzymes解毒酶 and the levels of these enzymes have decreased in aging individuals. An insufficiently developed immune system 免疫系统 in children and depressed immunity in aged organisms may also play a role.