影響毒物在生物體內所表現的毒性作用之因素：

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1 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)

2 Dose-Response Relationship: As the dose of a toxicant increases, so does the response.
4 RESPONSE 0-1 NOAEL 2-3 Linear Range 4 Maximum Response 3 2 1 DOSE DOSE DETERMINES THE BIOLOGICAL RESPONSE

3 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

4 (short-term exposure)
Acute Toxicity: (short-term exposure)

5 Chronic Toxicity: (repeated exposures)

6 Routes of Entry: Oral = Ingestion by mouth Dermal = Skin exposure
Inhalation = Absorbed by lungs Ocular = Eye exposure

7 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。

8 Dermal Exposure Variables
Area Rate* forehead forearm abdomen palm scrotum ball of foot *Absorption rate compared to forearm, which is 1.0 mjweaver,1997

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

10 (TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin)
種、品系間之差異 世紀之毒"Dioxin" (TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin) Organism LD50(micrograms/kg) Guinea pig (male) 0.6 Guinea pig (female) 2.1 Rabbit 115 Monkey (female) <70 Rat (male) 22 Rat (female) 45-500 Mouse (male) <150 Dog (male) 30-300 Dog (female) >100 Frog 1,000 Hamster 1,157 Data from article in Scientific American, February 1986.

11 解毒酵素活性不同 Rate: cat > rat > rabbit Oxalate
Oxalate's toxicity results from its complexing of magnesium and calcium ions, making them unavailable.

12 對毒物有不同的解毒機制 Dogs, Cats o-aminophenol Rats, mice Aniline p-aminophenol

13 對毒物有不同的解毒機制 Malathione Malaoxon is a potent cholinesterase inhibitor

14 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 vomit 5.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

15 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 point 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 than 1%, it is referred to as a mutation.

16 Acetylation & genetic polymorphism
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

17 性別

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19 Age Some enzymes are age-dependent P450 monooxygenase
Glucuronosyltransferase, UDPGA Glutathione transferase Some are not Acetylation or sulfate conjugation (adult=newborn)

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21 (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、indoles potent inducers DDT, PCB 3.影響毒物的吸收。 鈣、鐵影響鉛、鎘的吸收

22 (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

23 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

24 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

25 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

26 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nitrosamines 2.     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 reductase PAHs↑CytP448( aryl hydrocarbon hydroxylase) 代謝酵素抑制劑如isoniazid、 piperonyl butoxide協力精抑制MFO

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