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The Dose-Response
Relationship
Introduction
• The need to establish some criteria to base the relative safety of
chemicals is essential.
• Acute toxicity studies are the most commonly performed studies for
obtaining information on the effects of chemical exposure. They are
short-term, relatively inexpensive tests with death of the test animal
being the useful observed effect.
• The groups are observed for 14 days, and the number of deaths in each
group is recorded.
Acute Toxicological Studies (3)
• LC50 is a measure of chemical toxicity resulting from inhalation. LC
means “lethal concentration” and the subscript has the same meaning as
described previous for LD. The unit of measure for the LC50 is usually
expressed as part per million (ppm).
Chronic Toxicological Studies (1)
• Chronic toxicity tests may be performed over a period of months, years,
or the lifetime of the test animal. Doses of the toxic substance are
selected to assure that most of the animals will survive the entire time
the study is performed.
• Males and females of the same species may respond differently to the
same substance.
• In reality
– Several different routes
– Exposure to more than one chemical at a time
– Greater genetic variability in a larger population – the range of
responses to a given chemicals more diverse.
– The collective interactive effect of all these factors on toxicity
makes it difficult to establish a cause-effect relationship.
Dose-Response Curves (1)
• The major purpose for performing acute and chronic toxicity studies is
to establish a cause-effect relationship between exposure to a toxic
substance and an observed effect in order to determine a safe exposure
level.
• A curve can be drawn that illustrates the relationship between the dose
administered and the observed response. This curve is referred to as
the dose-response curve.
• lowest-observed-adverse-effect-level (LOAEL)
– Lowest concentration or amount of a substance, found
by experiment or observation, which causes an adverse
alteration of morphology, functional capacity, growth,
development, or life span of a target organism
distinguishable from normal (control) organisms of the
same species and strain under defined conditions of
exposure.
Terminology Associated with
Dose-Response Curves (3)
• Frank-effect level (FEL)
– Level of exposure that produces unmistakable and
irreversible effects (such as impairment or mortality)
at statistically significant increased severity or
frequency.
– The level where overt effects are observed is referred to
as the Frank-effect level.
Threshold Dose
• Dose below which no adverse effects are observable in a
population of exposed individuals.
• NOAEL approach
– Identify the adverse effect that occurs at the lowest dose
– Determine the NOAEL or LOAEL for that endpoint
– Divide NOAEL/LOAEL by uncertainty factors
Acceptable Daily Intake
• ADI estimated (maximum) amount of an agent, expressed
on a body mass basis, to which a subject may be exposed
over his lifetime without appreciable health risk (also TDI,
tolerable daily intake)
• Default values:
UFinterspecies = 10 , UFhuman variability = 10
Additional Uncertainty Factors
• Sometimes applied:
– UFLOAEL-NOAEL = 3 or 10
– UFsubchronic-chronic = 3 or 10
– UF database insufficiences = up to 10
• Interspecies variability
– The variability in response between species is primarily the result
of the evolution of different biological mechanisms involved in the
metabolism of toxic substances.
– The differences in toxicity may be due to the rate at which
metabolism occurs, or whether metabolism produces chemical
intermediates more toxic than the parent compound.
• For example, the pesticide malathion is metabolized at a different rate in
mammals than in insects. In mammals, the chemical intermediates are rapidly
metabolized to deliver end products that are excreted from the body. In insects
metabolize malathion more slowly and produce a chemical intermediate ---
malaoxon --- that is toxic to the insect.
• Methanol intoxication results in ocular damage and blindness. However, in
other species methanol is less toxic and the symptoms associated with human
intoxication are not observed.
• Rats do not have a vomiting reflex. Rodenticides, such as squill, are more
effective if they are ingested because the rat can not discard the substance by
vomiting.
Intraspecies (individual) variability
• Additive effects
– An additive effect occurs when the combined effect of
the two chemicals is equal to the sum of the effects of
each individual chemical.
• Synergistic effect
– A synergistic effect occurs when the observed effects are
greater than what would be predicted by simply
summing the effects of each individual chemical.
Chemical Interactions (3)
• Antagonistic effects
– Antagonistic effects are the basis on which antidotes are
developed to counteract the effects of toxic substances
that enter the body.
– Antagonistic effects occur when the sum of the effects of
each individual chemical is less than the sum of the
effects for both chemicals.
Chemical Interactions (4)
• Four major types of antagonism
– Functional antagonism
• It refers to a type of reaction two chemicals have on a specific
physiological function in the test organism, usually producing
counterbalancing or opposite effects.
– Chemical antagonism
• It may be referred to as chemical inactivation. This type of
interaction is the result of a reaction between two chemicals to
produces a less toxic product.
– Dispositional antagonism
• The toxic substance is either transformed into a less toxic
substance or it is eliminated from the body more rapidly, then
the observed effects will be less than the expected ones.
Chemical Interactions (5)
– Receptor antagonism
• It occurs when two chemicals require binding to the same
receptor in order to exert their effect. The result is that when
the two chemicals are administered together the observed effect
is less than the sum of the effects for each chemical.
– Sensitization
• Initial exposure to toxic chemicals does not always result in an
observable or measurable effect. However, subsequent
exposure to the same chemical may result in an observable or
measurable effect.
• Sensitization occurs as a result of the interaction of the body’s
immune system with the toxic chemical during the initial
exposure.
Chemical Interactions (6)
– Potentiation
• At first glance it would appear that synergism and potentiation
are the same. In A potentiation, only one of the chemicals has
an observable effect when administered alone.
[10]
Grain alcohol (ethanol) rat, oral 7,060,000,000 ng/kg
Melamine rat, oral 6,000,000,000 ng/kg
[12]
Table Salt rat, oral 3,000,000,000 ng/kg
[13]
Paracetamol (acetaminophen) rat, oral 1,944,000,000 ng/kg
[15]
Metallic Arsenic rat, oral 763,000,000 ng/kg
[17]
Aspirin (acetylsalicylic acid) rat, oral 200,000,000 ng/kg
[18]
Caffeine rat, oral 192,000,000 ng/kg
[22]
Cadmium oxide rat, oral 72,000,000 ng/kg
[23]
Nicotine rat, oral 50,000,000 ng/kg
[24]
Strychnine rat, oral 16,000,000 ng/kg
[25]
Arsenic trioxide rat, oral 14,000,000 ng/kg
[26]
Metallic Arsenic rat, intraperitoneal 13,000,000 ng/kg
[27]
Sodium cyanide rat, oral 6,400,000 ng/kg
[30]
Beryllium oxide rat, oral 500,000 ng/kg
[31]
Aflatoxin B1 (from Aspergillus flavus) rat, oral 480,000 ng/kg
[33]
Dioxin (TCDD) rat, oral 20,000 ng/kg
[37]
Polonium-210 human, inhalation 10 ng/kg (estimated)
human, oral, [38]
Botulinum toxin (Botox) 1 ng/kg (estimated)
injection, inhalation
Ionizing radiation human, irradiation 6 Gy
Typical Costs of Various Types of Toxicity Tests
Typical Testing protocols for Acute and Chronic
Toxicity Studies
Dose-Response Curve
LD50 Values of Organochlorine Pesticides
LD50 Values of Organophosphate Pesticides
Regional Differences of Dermal Absorption in Human Male
Toxicity of various Compounds to
Different Test Species
No-effect Levels on
a Dose-Response Curve
Acute Toxicity of N-hydroxy
acetylaminofluorene in Various Strains of Rats
Five Threshold Doses
• 美國環境保護署(EPA)對動物毒性實驗的反應程度確立了五種界限值(threshold),
用以評估毒性強弱而發展出各類毒性物質的每日允許攝取量。這五個界限值為:
• 一 ﹑沒有可觀察到的影響值(no-observed-effect level,NOEL)。
• 二﹑沒有可觀察到的不良影響值(no-observed-adverse-effect level,NOAEL)。
• 三﹑可觀察到有影響的最低值(lowest-observed-adverse-drrect level,LOEL)。
• 四﹑可觀察到有不良影響的最低值(lowest-observed-adverse-effect level,LOAEL)。
• 五﹑有直接顯著影響值(frank effect level,FEL)。
• 美國是以NOAEL值經過體重權衡後,除以安全因素而得到每日允許攝取量。而這一限
值就是表示,對設定毒性物質可允許它每天進入體內之總和量。
•
•
圖片連結-各種劑量反應關係 各種劑量反應關係 圖片連結-各種劑量反應關係
LOEL
• 最低作用值(LOEL,Lowest-observed effect level)
• 是指在研究人體或動物接觸某種物質時產生任何反應的頻率或嚴重性在生物學上顯著
增加的最低劑量。 相關名詞
• 最低作用值:不良效應級(有害作用劑量):最低濃度或數量的物質,通過實驗或觀察
發現,這會導致不利的改變形態,機能,生長,發育,壽命或生物體的目標分辨正常
(對照)的生物物種和同一菌株在規定條件下的暴露。 逆轉錄不利影響 , 最低的觀察
效果級別 , 不遵守,不利的效應級別 , 無觀測效應水平
• 在劑量反應曲線中,我們常常會應用到幾個相關名詞,包括:
• 無反應劑量(no-effect level, NEL)或無觀察反應劑量(no-observed effect level, NOEL
):無顯著反應的最低劑量。
• 最低觀察反應劑量 (最低作用值)lowest observed effect level,LOEL):可以觀察到反應
之最低劑量,不過此反應為次要之反應而非引起主要想要測量之反應。
• 無觀察危害反應劑量(no observed adverse effectlevel, NOAEL):一些非欲觀察之毒性
反應(危害性低)發生之劑量,但在高劑量下觀察得到的反應,在此劑量並不會出現
。 (無顯著危害的最高劑量,並非無反應而是與對照組無統計差異)
• 最低觀察危害反應劑量(lowest observed adverseeffect level, LOAEL):第一個可以觀
察得到危害反應的最低劑量濃度。
• 法蘭克反應劑量(frank effect level, FEL):引起嚴重危害反應發生之劑量稱之。 訂定