影響毒物在生物體內所表現的毒性作用之因素：

主要 - 劑量 (dose)

暴露時間長短 (duration of exposure)

Dose-Response Relationship: As the dose of a toxicant increases, so does the response.

2

3

4

0 1 DOSE

RESPONSE

0-1 NOAEL2-3 Linear Range4 Maximum Response

DOSE DETERMINES THE BIOLOGICAL RESPONSE

Exposure: Duration

Acute < 24hr usually 1 exposure

Subacute 1 month repeated doses

Subchronic 1-3mo repeated doses

Chronic > 3mo repeated doses

Over time, the amount of chemical in the body can build up, it can redistribute, or it can overwhelm repair and removal mechanisms

Acute Toxicity:

(short-term exposure)

TIME: Minutes or Hours

Threshold Concentration

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SYMPTOMS

Chronic Toxicity:

(repeated exposures)

x

Threshold concentrat ion

SYMPTOMS

TIME: Weeks, months, years

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x

x

x

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Routes of Entry:

Oral = Ingestion by mouth

Dermal = Skin exposure

Inhalation = Absorbed by lungs

Ocular = Eye exposure

暴露途徑a. 呼吸道 : 氣體、分子小、脂溶性物質可由肺泡吸收，經由擴散 (CO 、 HCN) 或吞噬作用( 石綿、鉛 )b. 消化道 : 毒物隨食物飲水進入腸胃，重金屬需和必需金屬 ( 鈣、鐵 ) 競爭載體，不易吸收。c. 皮膚的表皮不易穿透，角質層阻擋水溶性物質之吸收，脂溶性物質則易穿透，角質層依身體之部位不同有差異，影響吸收速率。

Dermal Exposure Variables

Area Rate*

forehead 4.2forearm 1.0abdomen 2.1 palm 1.3 scrotum 11.8ball of foot 1.8

mjweaver,1997

*Absorption rate compared to forearm, which is 1.0

毒物的化學性質和活性1. The toxicity of mercury vapor differs greatly from methyl merc

ury. 

2. Another example is chromium.  Cr3+ is relatively nontoxic whereas Cr6+ causes skin or nasal corrosion and lung cancer.

3. The innate chemical activity of substances also varies greatly. Some can quickly damage cells causing immediate cell death. Others slowly interfere only with a cell's function

Ex. hydrogen cyanide binds to cytochrome oxidase resulting in cellular hypoxia and rapid death, nicotine binds to cholinergic receptors in the CNS altering nerve conduction and inducing gradual onset of paralysis

Data from article in Scientific American, February 1986.

OrganismLD50(micrograms/

kg)Guinea pig (male) 0.6Guinea pig (female) 2.1Rabbit 115Monkey (female) <70Rat (male) 22Rat (female) 45-500Mouse (male) <150Dog (male) 30-300Dog (female) >100Frog 1,000Hamster 1,157

世紀之毒 "Dioxin" (TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin)

種、品系間之差異

Rate: cat > rat > rabbit

Oxalate's toxicity results from its complexing of magnesium and calcium ions, making them unavailable.

Oxalate

解毒酵素活性不同

Dogs, Cats

Rats, miceAniline

p-aminophenol

o-aminophenol

對毒物有不同的解毒機制

Malaoxon is a potent cholinesterase inhibitor

對毒物有不同的解毒機制

Malathione

2. 生物轉化 (biotransformation) 有差異2-naphthylamine→2naphthyl hydroxyamine 導致 dog and human 膀胱癌acetylaminofluorene (AAF) 僅天竺鼠不 hydroxylation→不致癌 3. 對毒物的吸收、分佈與排泄有差異4. 生理功能有差異squill as a rodenticide, rats cannot vomit5. 解剖上的差異 BHA(butylated hydroxyanisole) 和 BHT(butylated hydoxytoluene) 引起大鼠前胃 (forestomach) 的腫瘤產生

個體差異多由於生物轉化酵素之遺傳差異

When the rate of sequence variation at a specific po

int in the DNA is more than 1% of a given population,

it is referred to as a polymorphism.

When the incidence of a variant sequence is less th

an 1%, it is referred to as a mutation.

• Rapid and slow acetylators– Various mutations result in decreased

enzyme activity or stability– Incidence of slow acetylators

• 70% in Middle Eastern populations; 50% in Caucasians; 25% in Asians

– Drug toxicities in slow acetylators• nerve damage from dapsone; bladder cancer in

cigarette smokers due to increased levels of hydroxylamines

Acetylation & genetic polymorphism

性別

AgeSome enzymes are age-dependent

P450 monooxygenaseGlucuronosyltransferase, UDPGAGlutathione transferase

Some are notAcetylation or sulfate conjugation (adult=newborn)

( 四 ) 營養狀況1. 改變混合功能氧化酵素 (mixed function oxidase system MFO) 的活性缺乏必需脂肪酸、蛋白質或維生素 A 、 C 、 E ，高糖飲食→↓混合功能氧化酵素的活性hexobarbital 、 aminopyrine ( 經 MFO 代謝 )黃麴毒素、四氯化碳 ( 由 MFO 活化 )2. 誘發混合功能氧化酵素的產生食物含 strong inducers 黃樟素 (safrole) 、 xanthines 、 indolespotent inducers DDT, PCB3. 影響毒物的吸收。鈣、鐵影響鉛、鎘的吸收 

( 五 ) 疾病1. 肝臟 - 影響生物轉化2. 腎臟 - 影響排泄及代謝3. 心臟 - 影響肝臟、腎臟之循環均會增加化合物的毒性

環境因素物理因素1. 溫度 - 影響生物轉化之速率2. 大氣壓力 - 主要來自氧張力的改變3. 日光週期 - 酵素活性亦具生物時鐘4. 輻射線照射社會因素 : 如飼養方式 - 一籠幾隻、籠架及墊料種類

化學物質相互作用1.    加成作用 (additive) ：兩種化學物質一起暴露所產生的影響等於單獨暴露產生的影響之和， 2+3=5 ，大多數的有機磷農藥2.    協同作用 (synergistic) ：兩種化學物質一起暴露所產生的影響大於單獨暴露產生的影響之和， 2+3=20 ，四氯化碳和乙醇之肝毒性3.    強化作用 (potentiation) ：原本不具毒性的化學物質，與另一具毒性之化學物質一起暴露，明顯增強其毒性，0+2=10 ，不具毒性的化學物質抑制毒物的代謝酵素4.    拮抗作用 (antagonism) ：兩種化學物質一起暴露，兩者互相干擾其作用或其中之一受干擾 4+6=8 ； 4+(-4)=0 ； 4+0=1

化學性拮抗作用 - 兩種化學物質發生反應，產生毒性較弱之產物。如重金屬與螯合劑 chelator

功能性拮抗作用 - 兩種化學物質對同一生理參數產生相反的作用

競爭性拮抗作用 -agonist 和 antagonist 作用於同一受體非競爭性拮抗作用 - 化學物質之毒性被另一化學物質所阻斷，但不作用於同一受體

Organophosphate vs. atropine

作用機制1.     化學反應 - 如亞硝酸鹽 Nitrites 和胺 amines在胃中形成亞硝胺 nitrosamines2.     改變吸收 - 如用牛奶解毒3.     競爭取代與血漿蛋白結合4.     競爭受體或轉運系統5.     改變排泄 - 如改變尿液之酸鹼度 - 酸性尿液→↑鹼性物質排泄6.     抑制或誘發代謝酵素 -誘發劑 inducers 如 phenobarbital-↑liver weight, SER, cyt P450, NADPH-cyt C reductasePAHs↑CytP448( aryl hydrocarbon hydroxylase)代謝酵素抑制劑如 isoniazid 、 piperonyl butoxide 協力精抑制 MFO