【正文】 e mortality 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 ., a 10% body weight reduction 例如 ， 能使體重減少 10%的劑量 。 ? The middle dose should be sufficiently high to elicit minimal toxic effects, or it should be set midway between the high and low doses. 中等劑量：也應(yīng)該很高 ， 能夠誘發(fā)產(chǎn)生最小毒性癥狀 ， 或者說(shuō)該劑量水平應(yīng)該位于高劑量和低劑量之間 。 ? if significant differences exist in the toxico kiic or metabolic profile of the test substance between the high and low doses, an additional dose should be included in the study 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 。 The sensitivity of the toxicological endpoint 毒性終點(diǎn)的靈敏度 ? depends on the extent of the phenomenon observed in the control group. 以對(duì)照組中觀察到的現(xiàn)象而定 ? Sensitivity may be increased if biochemical markers are used such as enzyme induction for peroxisome pro [iterators or enzyme inhibition for anophosphate insecticides. 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 ? These more sensitive parameters must be true indicators of toxic phenomena 并可作為毒性大小的指示劑 the size of animal groups試驗(yàn)組的大小 ? plays a relatively minor role in determining the NOEL in toxicity studies . 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 。 increment of dosage 劑量間的增量或劑量 效應(yīng)曲線的斜率 ? The observed value of the NOEL is more dependent on the increment of dosage than on the group size. 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 。 ? In reality, the NOEL is an observed value, which is not derived from the response part of the available data. 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 safety factors ADI/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 ） 。 ? Cause 原因： 1） differences in animals and humans 供試驗(yàn)的物種與人體之間存在的種群差異 2） differences in individuals 人與人之間存在的個(gè)體差異 ? a figure of 100 is applied. 將安全系數(shù)默認(rèn)為 100 * increasing factor安全系數(shù)需增大的情況： more relevant data are available 得到了較多的相關(guān)數(shù)據(jù) chronic studies have not been performed 還沒(méi)有完成慢性毒性試驗(yàn) toxicological data are missing 缺少毒性數(shù)據(jù) ? * decreasing factor during a uniform species response 安全系數(shù)需降低的情況： 具有相同的物種效應(yīng)時(shí) Factors effect on safety factors 安全系數(shù)的影響因素 ? Differences in toxico kiics and on susceptibility for both the animal species tested and for humans 供試物種和人體的毒性動(dòng)力學(xué)以及敏感性差異 ADI值的說(shuō)明 ? Normally the entire age range of the human population is covered by the ADI ADI以人類(lèi)整個(gè)年齡范圍而確定 ? The AD1 carries no guarantee of absolute safety ADI并不能保證絕對(duì)的安全 ? New knowledge should always lead to reevaluation of an ADI 隨著知識(shí)的不斷更新 ， 應(yīng)該及時(shí)更新 、 核定 ADI值 Special in infants 特例：嬰幼兒的 ADI/TDI值 ? The establishment of an ADI/TDI for pesticides or contaminants that are likely to be present in milk and cereals used for infant foods should be based on toxicological evaluation in very young animals評(píng)價(jià)嬰兒食品安全性時(shí) ， 應(yīng)該用幼小動(dòng)物為實(shí)驗(yàn)對(duì)象進(jìn)行的毒性評(píng)估 ， 從而確定 ADI/TDI值 。 ? 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 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 in some cases adults are more sensitive than young offspring. 在某些情況下成年人比嬰幼兒更敏感。 ? For example, certain nitrosamines are bioactivated by the same enzymes that are generally responsible for detoxifying other pounds. But these are fully expressed a few months after birth 有一種酶 ， 既能生物激活某些亞硝胺 ， 也能解毒其他成分 ， 但只在嬰兒出生后幾個(gè)月內(nèi)有活性 ， 隨后就不存在了 。 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 a contaminant or a pesticide has been found to be an animal carcinogen, it is extremely difficult to show 如果某種污染物或某種農(nóng)藥是某種動(dòng)物的致癌物，那么很難確定 : ? what dose is safe for humans 何種劑量對(duì)人體是安全的 ? to determine the risks at the doses to which humans are exposed 這種物質(zhì)在人體暴露劑量下的風(fēng)險(xiǎn) ? The characteristic of human cancer 人體癌癥的產(chǎn)生具有 : irreversibility 不可逆性 frequency 頻繁性 Regulatory decision making with regard to chemical carcinogens is usually and appropriately different for carcinogenic effects than for other toxic endpoints. 制定法規(guī)時(shí)通常是依各種致癌效應(yīng)而定 Carcinogenicity studies 致癌試驗(yàn) ? low numbers of animals較少的實(shí)驗(yàn)動(dòng)物 ? high doses of a carcinogen高劑量致癌物 ? maximum tolerable dose配給最大忍受劑量（ MTD） two groups of carcinogens 致癌物的分類(lèi) ? Genotoxic 遺傳毒性致癌物 ? Nongenotoxic 非遺傳毒性致癌物 Genotoxic Carcinogens （一）遺傳性毒性致癌物 ? Structureactivity relationships appear to provide a reasonably good basis to predict carcinogenicity for some categories of pounds, which are characterized by specific structures. 依靠化學(xué)物結(jié)構(gòu) 活性關(guān)系預(yù)測(cè)具有特定結(jié)構(gòu)化學(xué)物的致癌性 ? It has