Transcript Toxic Responses of the lung

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 absorption
animal 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.