【正文】 Causes of cancer癌癥發(fā)生原因? mutations in oncogenes or tumor suppressor genes. 遺傳致癌基因或腫瘤抑制基因突變? These mutations result in alterations in the expression 。oncogene.H173。ofcodonmutationaassociatedismouse(DMBA)genotoxinof ras族原遺傳致癌基因和 p53腫瘤抑制基因? Forsuppressorp53 and family參與控制細(xì)胞增殖和分化的關(guān)鍵性基因? and cell regulation in genesgenes cellsynthesisreplicativetimerelativelywithinmustthedivisionbyofandofTheextrapolation.methodswithonlydeterminedcannotthisextent低劑量的致癌引發(fā)物表現(xiàn)出明顯的低程度危害。risk.butathusinitiatingdoses(閾值指當(dāng)所用的劑量低于該值時(shí)不會(huì)產(chǎn)生某種效應(yīng) measurableanotrelated)? aadditivethusirreversiblehavesmall(initiation)? irreversible(metastasis)引發(fā) (progression)? 轉(zhuǎn)移 (promotion)? 發(fā)展 (initiation)? 促進(jìn) cancer形成癌癥的四個(gè)階段? 引發(fā) stages致腫瘤原所處范圍及位置影響誘變性Fourofandthemutagenicityexists strong that bee has173。173。structures.byarepounds, categories for predict basis reasonablyprovideappearactivityGenotoxic Carcinogens （一）遺傳性毒性致癌物 遺傳毒性致癌物? NongenotoxicofMTD）twotolerableadosesofstudies致癌試驗(yàn)? low制定法規(guī)時(shí)通常是依各種致癌效應(yīng)而定 toxicforeffectsforappropriatelyusuallycarcinogenstowithdecision不可逆性人體癌癥的產(chǎn)生具有 :cancerofThe這種物質(zhì)在人體暴露劑量下的風(fēng)險(xiǎn) arewhichdosesatthetohumanssafedosetoextremelyitanimalbefoundhasacontaminant Pesticides and contaminants may reach the fetus by placental transfer and may also be transferred to the newborn postnatally with the breast milk. 母乳喂養(yǎng)的嬰兒可能會(huì)攝入高劑量化合物Cause 原因：the halogenated aromatic hydrocarbons that accumulate in fat, may be via breast milk. 某些化合物（尤其是脂肪組織中蓄積的鹵化芳香烴）主要通過(guò)乳汁分泌途徑進(jìn)行排泄., dioxins in human milk exceed the ADI 母乳中存在的二氧芑 Carcinogenicity二、致癌性? If afterfewexpressedareBut other forgenerally that same by are certain? Foryoungsensitivearecases大腦阻擋層）還沒(méi)有發(fā)育好4) a general vulnerability of rapidly growing tissues that is particularly important, for example, with regard to the developing nervous system 正快速生長(zhǎng)的重要組織最易受傷害，如發(fā)育中的神經(jīng)系統(tǒng)Differences between adult and fetus胎兒與成年人的差別 the fetus is more sensitive than adults 胎兒比成年人更易感染腫瘤 in173。? Additional factor is needed(normally 10)采用附加安全系數(shù)（一般取 10）? Why？newborn and very young infants may be particularly sensitive to the harmful effects of foreign chemicals新生兒和嬰幼兒對(duì)外來(lái)化學(xué)物特別敏感The cause:1)lack of development of enzymatic detoxifying mechanisms 新生兒和嬰幼兒的酶促解毒還沒(méi)有發(fā)育好2)inplete function of excretory ans 排泄器官的功能還不夠完善3)inplete development of physiological barriers such as the bloodbrain barrier 生理阻擋層（如血液 173。youngintoxicologicalbasedshouldinfantusedandinbelikelythatorforanestablishmentinanreevaluation lead should NewsafetyofnoAD1ADIbyis human of age theADI/TDI值確定時(shí)的 安全系數(shù)? The NOEL equivalent to the safe intake for animals is then divided by a safety or uncertainty factor to allow for possible differences between the test species and humans and for possible differences within the human population. 將動(dòng)物試驗(yàn)結(jié)果外推到人體時(shí)，需除以一個(gè)安全系數(shù)（即不確定因子）。NOEL實(shí)際上是一個(gè)觀察值，并不是試驗(yàn)數(shù)據(jù)推算結(jié)果safetydata.the part the derivedisvalue,anNOELreality, 觀察值 NOEL并不取決于試驗(yàn)組中動(dòng)物的數(shù)目，而更取決于劑量間的增量。 size.thethanofthedependentisthevalue效應(yīng)曲線的斜率? The173。dosage劑量間的增量或劑量 173。increment 如果供研究的動(dòng)物數(shù)目在毒性試驗(yàn)正常范圍內(nèi)，那么在確定 NOEL時(shí)，試驗(yàn)組大小對(duì)結(jié)果的影響是次要的。 .toxicityNOELdeterminingrolerelativelygroups試驗(yàn)組的大小? playsofthetoxicindicators be parameters more使用生化標(biāo)記物（例如，過(guò)氧化物酶增殖擴(kuò)散誘導(dǎo)物或有機(jī)磷酸酯殺蟲(chóng)劑的抑制物），可以提高靈敏度? anophosphateinhibition or proforenzymesuchare biochemical increased maygroup.theobservedtheextentontoxicologicalofThestudy若待試物質(zhì)在高劑量和低劑量之間的毒性動(dòng)力學(xué)或代謝特征存在明顯差異，應(yīng)該增設(shè)一個(gè)劑量水平。in be dose an low high between test of metabolickiictheexistsignificant? lowhighbetweensetshouldortoxicelicithighbe? The middle doseweight10%高劑量：應(yīng)該很高，即能夠誘發(fā)毒性癥狀，但又不會(huì)造成極端致命性的劑量.,excessivewithoutofelicithigh bestudy長(zhǎng)期試驗(yàn)的劑量選擇? the high dose levellong173。效應(yīng)曲線的斜率Dose173。劑量間的增量或劑量 173。responsetheslopeorbetween試驗(yàn)組的大小3.studiedtheSizeendpointtheSensitivitythreedeterminedistheprecision解釋?zhuān)篛ften the underlying mechanisms are not clear, but this phenomenon may arise from adaptation, resulting in the disappearance of an effect after longterm exposure.由于長(zhǎng)期暴露后某種效應(yīng)會(huì)消失，也就是說(shuō)這種現(xiàn)象可能是適應(yīng)性的結(jié)果。NOELs deduced from longterm studies are higher than those from shortterm studiesspecies. as as area to is sensitive測(cè)定 NOEL值對(duì)實(shí)驗(yàn)動(dòng)物的要求? theanimalsDemand神經(jīng)毒性? neurotoxicity觀察比較特殊的效應(yīng)? .,investigatedspecifictermtermofofthetarget毒性類(lèi)型theeffectsof一般用來(lái)確定：? indicateto:are不能用來(lái)確定 NOEL? Generally a establishment forconsidered are oral fromoralThe most important step 安全性評(píng)價(jià)中最重要的一個(gè)步驟：The determination of a noobservedeffect level (NOEL) based upon a consideration of the available toxicological data 以可能的有效毒性數(shù)據(jù)為基礎(chǔ)確定一個(gè)無(wú)作用劑量值（ NOEL） ）或每日容許攝入量（ TDI） d）Basicbwdefinition定義? the ADI or TDI is denned as an estimate of the amount of a pesticide residue or contaminant, expressed on a body weight basis, that can be ingested daily over a lifetime without involving an appreciable health risk, substances that accumulate in the body in specific ans should be very carefully evaluated. 以體重為基礎(chǔ)，評(píng)估人一生中每天可攝入的但不至于會(huì)對(duì)健康造成可覺(jué)察危害的農(nóng)藥殘留或污染物的數(shù)量 humans.animalsinducedthedifferencesprinciplemammalsleastexpectedtospeciesbetweenbiochemical假定：動(dòng)物體內(nèi)的作用機(jī)制也可能存在于在人體內(nèi)? physiologicalinbeexpectedalsoanimalsobservedoftheinassumedextrapolationhumans研究結(jié)果處理：將在動(dòng)物體內(nèi)產(chǎn)生的效應(yīng)外推到人體當(dāng)中Principlesdataof研究對(duì)象：動(dòng)物、微生物或組織及細(xì)胞Result:celltissuemicroanisms,entireendpoin研究目標(biāo)：各種不同毒性程度Object:different毒理學(xué)毒理學(xué)動(dòng)物實(shí)驗(yàn)Target:toxicologyit?to dose at andbesubstanceofhealth存在問(wèn)題? howquestion消費(fèi)者可能的攝入劑量對(duì)健康的危害 exposedmaythedoseathealthhumansstudiesoftherelevancedeterminesafetyofThepossible唯一解決途徑：只能盡可能地將含量降低，即將殘留物濃度降低到不會(huì)危及消費(fèi)者健康的水平。asasbe amoun