Download 劑量與毒性

Introduction to Toxicology
• Toxicology (毒物學) can be defined as that
branch of science that deals with poisons, and
a poison can be defined as any substance that
causes a harmful (有害的) effect when
administered (施藥), either by accident or
design, to a living organism.
• Poison is a quantitative (量) concept (概念),
almost any substance being harmful at some
doses but, at the same time, being without
harmful effect at some lower dose (劑量).
Between these two limits there is a range of
possible effects, from subtle (微微的) longterm chronic (慢性) toxicity to immediate
lethality (致命性).
• Vinyl chloride (氯乙烯) may be taken as an
example. It is a potent hepatotoxicant (肝毒劑)
at high doses, a carcinogen with a long latent
(潛伏的) period at lower doses, and
apparently without effect at very low doses.
• Clinical drugs are even more poignant
examples. Aspirin (acetylsalicylic acid，乙醯
水楊酸), for example, is a relatively safe drug
at recommended doses and is taken by
millions of people worldwide. At the same
time, chronic use can cause deleterious effects
on the gastric mucosa (胃粘膜), and it is fatal
at a dose of about 0.2 to 0.5 g/kg.
• The importance of dose is well illustrated by
metals (金屬) that are essential in the diet but
are toxic at higher doses. Thus iron (鐵),
copper (銅), magnesium (鎂), cobalt (鈷),
manganese (錳), and zinc (鋅) can be present
in the diet at too low a level (deficiency), at an
appropriate level (maintenance), or at too
high a level (toxic).
• Even medications often found at a pharmacy
or grocery store shelves have a dose at which
toxicity occurs.
• For example, Vitamin C (as well as some of the
other compounds in citrus fruit) will cause
diarrhea (腹瀉), stomach upset (反胃), and
even vomiting (嘔吐), if ingested in extremely
large amounts.
• While this might be toxicity, no one would
suggest that vitamin C should never be used
for therapeutic benefit.
• All substances have what is termed an LD50 (半
數致死劑量). This is the dose that, when
administered to a large group of animals (or
humans), will cause lethality (death) in 50% of
that group.
• If the LD50 is less than the average therapeutic
(治療的) dose, then toxicity occurs before
therapeutic effects and the substance should
be avoided (避免).
• If the LD50 is much greater than the
therapeutic dose, then the substance is very
safe and can be administered to a patient in
large amounts without fear of toxicity.
Units used to measure chemicals in
the environment
• ppm: parts per million
1 cent in $ 10, 000
ppb: parts per billion
1 cent in $ 10, 000, 000
ppt: parts per trillion
1 cent in $ 10, 000, 000, 000
Important Relationship
• For water at STP (standard temperature [0℃]
and pressure [15psi])
• 1cc = 1ml = 1g
• 1 liter of water = 1 kg
• 1 mg / kg = 1 ppm
• 1 mm3 / liter = 1 ppm
• 1 mg / liter = 1 ppm
Measures of Toxicity
• Toxicity of chemicals is determined in the
laboratory.
• The normal procedure is to expose test
animals by ingestion, application to the skin,
by inhalation (呼吸), gavage (胃管), or some
other method which introduces the test item
into the body.
• Toxicity is measured as clinical “endpoints (
試驗終點指標)” which include:
• Mortality (death) (死亡)
• Teratogenecity (birth defects) (致畸性)
• Carcinogenicity (cancer) (致癌性)
• Mutagenecity (DNA damage) (致突變性)
The Median Lethal Dosage
(LD50 and LC50)
• LD50
• The dose of a chemical which produces death
in 50% of a population of test animals to
which it is administered by a specified
method.
• Normally expressed as mg/kg (milligrams of
substance per kilogram of animal body
weight)
• LC50
• The concentration of a chemical in air or water
which produces death in 50% of an exposed
population of test animals in a specified time
frame.
• Normally expressed as mg/kg (milligrams of
substance per liter of air or water [or as
ppm])#
Routes of exposure (暴露途徑)
• There are three primary routes by which
organisms are exposed to certain material
(solvents, pesticides, )：
• Oral (口服) ：Taken in through the mouth and
passes through gastrointestinal tract.
• Dermal (皮膚)：Most common route of
human exposure.
• Inhalation (呼吸)：Breathed into the lungs
through nose or mouth.#
Duration of Exposure (持續暴露時間)
• Three terms are commonly used to describe
the duration of doses：
• Acute (急毒性)：Application of a short-term
[generally less than a day] dosing.
• Chronic (慢性)：Repeated exposure to a
chemical in doses regularly applied to
organism for a time greater than half of its
life-expectancy.
• Subchronic (亞慢性)：
• Toxic symptoms are expressed after repeated
applications for a timeframe less than half the
life expectancy of the organism – but more
often than a single dose or multiple doses
applied for only a short time.
• The less you need to cause a toxic effect, the
more toxic the substance is. Thus, an LD50 of
15 mg/kg is more toxic than is one of 250
mg/kg.
• Organisms can’t differentiate between “natural”
and “synthetic” chemicals.
• “synthetic (合成)” does not mean toxic or poisonous.
• “natural (天然)” does not mean safe or even low risk.
• Chemicals must evaluated in their biological context of
behavior in organisms.
• Mode of action, not source, is the concern and
informed the users of pesticides.
• Most herbicides act on biological pathways (代謝途徑)
not present in humans.#
Insecticides (殺蟲劑)
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TCDD (Dioxin)
Parathion (巴拉松)
Nicotine (尼古丁)
Carbaryl (加保利)
Malathion (馬拉松)
0.1 mg/kg
13.0 mg/kg
50.0 mg/kg
270.0 mg/kg
370.0 mg/kg
Herbicides (除草劑)
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Paraquat (巴拉刈)
2,4-D (二四地)
2,4-DP (N/A)
Triclopyr (三氯比)
Dicamba (N/A)
Hexazinone (N/A)
Glyphosate (嘉磷塞)
95 mg/kg
375 mg/kg
532 mg/kg
630 mg/kg
755 mg/kg
1,690 mg/kg
4,320 mg/kg
Highly Toxic (劇毒)
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•
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Botulinus toxin (肉毒)
Dioxin (戴奧辛)
Parathion
Nicotine
0.00001 mg/kg
0.1 mg/kg
13.0 mg/kg
50.0 mg/kg
Moderately Toxic (中等毒)
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•
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Paraquat
Caffeine
Carbaryl
Marathion
2,4-D
95 mg/kg
200 mg/kg
270 mg/kg
370 mg/kg
375 mg/kg
Are all substances toxic?
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All are toxic to some degree.
Sugar has an LD50 of 30,000 mg/kg.
Ethanol has an LD50 of 13,700 mg/kg.
Even water has a recognized LD50 of slightly >
80,000 mg/kg.
• All materials should be treated with care and
proper respect!!!