Good morning everyone 大家上午好
Welcome to 欢迎来上
the Basic and Clinical Pharmacology 基础临床药学课程
In this class I am going to talk about 在这节课里我主要是讲
the introduction to toxicology 毒理学引言
and the occupational 职业和环境毒物
and environmental toxicants 职业和环境毒物
First of all let me give you one example 我先讲一个例子
So let us look at these two pictures 让我们来看一下这两张照片
This is taken from the same person 这是在五个月内来自于同一个人
within five months 这是在五个月内来自于同一个人
Do you know who he is 你们知道他是谁吗
He is Viktor Yushchenko 他是维克多·尤先科
the third president of Ukraine 乌克兰的第三任总统
from 2005 to 2010 从2005年到2010年间
So how can we image the person 那么我们如何能够想象这个人
has been changed so much 在短短的五个月里变化了这么多
within five months 在短短的五个月里变化了这么多
Actually the first photo 事实上第一张照片
was taken on July 3 2004 拍摄于2004年7月3日
In September 2004 在2004年9月份
he was poisoned by one of 他中了最烈性的化学毒物之一二噁英
the most potent chemical dioxin 他中了最烈性的化学毒物之一二噁英
And then five months later 五个月之后
he was becoming the picture 他变成了
taken at the right side 右边这个照片里的样子
So from his case we can see 所以从他的事例中我们可以看到
the toxic compound can have 有毒物质可以严重影响人类
severe effects on human 有毒物质可以严重影响人类
and also on animals 和动物
Sometimes it can cause death of people 有时候它会造成人的死亡
The first question we may ask about is 我们想问的第一个问题也许是
what the toxicology studies 毒理学研究什么
Toxicology is the study of poisons 毒理学是研究化学物理物质
or the adverse effects of chemical 对活生物的毒性或者不利影响
and physical agents on living organisms 对活生物的毒性或者不利影响
basically on human or animals 在人类或者动物上
So the main topic here is 所以主题是
chemical and physical agents 化学和物理物质
We need to study the poisonous 我们要学习这些物质的毒性
or the adverse effects and other effects 或者不利影响和其他影响
for these agents 这些物质
Actually toxicology has been developed 事实上毒理学已经发展了
for a long time and has more than 很长一段时间而且已经超过了
five thousand years’ histories 5000年的历史
For example on about 2700 BC (before Christ) 例如在公元前2700年
Chinese journals have already recorded 中国草本已经记载了
plant and fish poisons to people 一些植物和鱼对人的毒性
Between 1900 and 1200 BC 在公元前1900年到1200年之间
Egyptian documents have instructions 埃及的文件记录已经有
for collection preparation 收集 准备
and administration of more than 和使用超过800种医疗和有毒食谱的说明
800 medical and poisonous recipes 和使用超过800种医疗和有毒食谱的说明
In about 800 BC 在大约公元前800年
Hindu medicines have included notes on 印度医药里已经标注
poisons and antidotes which can be used 毒药以及可以使用的解药
to eliminate or reduce the effects of poisons 来消除或者减少毒药的影响
For 50-100 AD 从公元50到100年
the Greek physicians have classified 希腊医师已经分类了
over 600 plants animals and mineral poisons 超过600种植物动物以及矿物毒物
So between 50-400 AD 在公元50到400年间
Romans have already used poisons 罗马人已经使用毒药
for killing people for execution for prisoners 来杀死囚犯
or assassination for political opponents 或者是暗杀政治对手
One of the examples we can see 我们可以来看一个例子
at that time is for a great thinker Socrates 当时的伟大思想家苏格拉底
So he is a great thinker in Greek 他是希腊伟大的思想家
He taught radical ideas to the youth 他对年轻人讲一些激进的想法
and he was against the government 他反对政府
Eventually the government 最终政府
used a compound from a plant 使用了从植物中提取中的成分
shown in the right side of this image hemlock 就是右边这张图中的毒芹
and killed him 毒死了他
In about 1200 AD 在大约公元1200年
Spanish scholars wrote first-aid books 西班牙学者写了急救书
for poisonings poisons and their antidotes 是关于毒药和它们的解药
So in about 1500s 在大概16世纪的时候
A Swiss physician called Paracelsus 一位叫做帕拉塞尔苏斯的瑞士医生
He defined the toxicology for the first time 第一次定义了毒理学
and defined how the difference 定义了物质
between the therapeutic effect of a drug 治疗作用和毒性的不同点
and the toxic effect of the substance 治疗作用和毒性的不同点
What he said is 他说
‘All the substances are poisons: “所有的物质都是毒物：
there is none which is not a poison 没有一样没有毒
The right dose differentiates 只有正确的剂量可以使得
a poison from a remedy’ 药物不成为毒物”
Actually for a drug at very low dose 事实上一个药物在很低的剂量下
it can have benefit effect 可以有治疗作用
and can help us to fight disease 可以帮助我们抵抗疾病
However when we increase the amount of dose 然而当我们增加剂量的时候
then this compound the drug 这种药物
will be a toxic compound 将成为有毒物质
and will have a severe adverse effect 可能对人的身体产生严重的不良反应
on human body 可能对人的身体产生严重的不良反应
So when toxicology become scientific discipline 毒理学在1815年成为一门科学学科
it has happened in 1815 毒理学在1815年成为一门科学学科
until a Spanish physician Orfila 一位西班牙医生奥尔菲拉
established toxicology 把毒理学
as a distinct scientific discipline 作为一个独立的科学学科
In the 20th Century 在20世纪
there are many developments in toxicology 毒理学得到了很大的发展
However I will only briefly 我将简要的介绍一点
talk about one issue here 我将简要的介绍一点
Here I want to mention about Paul Ehrlich 这里我想提及保罗·埃利希
He developed a staining procedure 他发展了染色的过程
to observe cells and tissues 来观察细胞和组织
And then pioneered the understanding 而且率先认识了
how toxicants can influence living organisms 毒物是怎样影响生物体的
Because of his scientific achievement 因为他卓越的科学成就
he received the Nobel Prize 他获得了1908年的诺贝尔生理学或医学奖
in Physiology or Medicine in 1908 他获得了1908年的诺贝尔生理学或医学奖
These images showed 这些照片显示的是
he was working in his office 他在办公室里工作
and also doing experiment in his lab 以及在实验室里做实验
As well as a result 后来
he observed from the microscope 他从显微镜里观察到
how the toxicants can affect the living cells 毒物是怎样影响生物体的
So in the 1950s the poisons led to 在20世纪50年代毒物使得
the public awareness 公众意识到
about the environmental issues 对环境的影响
At that time a writer called Rachel Carson 那个时期有个作家叫做雷切尔·卡森
She wrote a book called Silent Spring 她写了一本叫做《沉寂的春天》的书
In this book she documented many pesticides 在这本书里她记录了很多的农药
and herbicides which have deleterious effects 和对生物体一些有害的除草剂
on the living animals 和对生物体一些有害的除草剂
Then this book made publics aware 后来这本书使得公众意识到
about the potent effects 在农业和工业中使用的毒物的影响
used in agriculture and in industry 在农业和工业中使用的毒物的影响
After that the public know about 在公众知道这些之后
the deleterious effects of the toxicants 知道了毒物的有害影响后
and then led to the creation of the US 使得美国建立了美国
Environmental and Protection Agency 环境保护署
In the next few minutes I am going to talk about 下面几分钟我将讨论
the basic concepts in Toxicology 毒理学的一些基本概念
The first of two concepts I am going to talk about 我要讲的第一个概念是
is the Dose Makes the Poisonous 剂量导致毒性
For example if we have apparent 如果我们有
nontoxic material or chemicals at low dose 在低剂量下无毒化学物质
it is completely nontoxic 完全没有毒性
and at high dose it will become toxic 在高剂量下它会变得有毒
For example we use table salt 例如我们每天在食品原料里使用食盐
in food ingredient every day 例如我们每天在食品原料里使用食盐
However when the salt concentration 但是当盐的浓度
reaches much high level 达到一个很高的水平时
for example if we take 4 g/kg of body weight 如果我们每kg体重食用4g的盐
then the salt becomes lethal 那么盐会致命
It means too much of a good thing 这意味着一个好的东西如果量太大
can be bad things 会变成坏的东西
The second concept is highly toxic chemicals 第二个概念是毒性非常高的化学物质
can be life saving compound 当我们在一个合适剂量使用时可以变成救命的物质
when we give it in an appropriate dose 当我们在一个合适剂量使用时可以变成救命的物质
It means the poisons are not harmful 这意味着有毒物质
at a sufficiently low dose 在一个足够低的剂量时不会对人体有害
One of the examples I would like to talk about 我想要讲的一个例子是
is arsenic trioxide 砒霜
This is we know a very toxic compound 我们知道这是一个有毒物质
Think about history there 我们来回顾一下历史
is a French leader called Napoleon 有个法国领袖叫拿破仑
Some people suspected 有人怀疑
he was killed by arsenic trioxide 他是死于砒霜中毒
However nowadays in about 50 years ago 然而在大约50年以前
some people found that 有人发现
we can use Arsenic trioxide to cure some cancers 我们可以使用砒霜来治疗一些癌症
such as acute promyelocytic leukemia 如急性早幼粒细胞白血病
Here I would like to briefly discuss 现在我将简要的讨论一下
the dose of the chemicals and the response 化学物质的剂量以及
of the human body to adverse effect 人体对不良作用的反应
This curve showed the agent A 这个曲线显示物质A
has the adverse effect when the dose increased 当剂量线性增加时的不良影响
with a linear relationship 当剂量线性增加时的不良影响
So here we can see agent A 所以我们可以看到物质A
does not have a safe dose 没有安全剂量
So the question we want to ask is 我们想问的问题是
Is there such a thing as a ‘safe’ dose? 是否存在有“安全”剂量的物质？
The second example is the curve for agent B 第二个例子是物质B的曲线
At very low dose before this point 在这个点前是一个非常低的剂量
we can see even we increase 我们可以看到即使我们增加
the concentration of the compound B 物质B的浓度
then there is no observe adverse effect at all 也观察不到一点点的不良作用
It means below that curve 这意味着在这个值以下
the chemical compound is safe for people 这种化学物质对人体是安全的
When the concentration increases again 当浓度增加时
then the deleterious effect 那么有害影响
will be increased significantly 会随之快速增加
For most drugs we will have 大部分药物
this type of effect on human or animals 对于人类和动物都是这种类型的影响
This slide defined three parameters 这张幻灯片定义了三种参数
showing in the right image 在右边的图中给出
The first concept is the EDf 第一个参数是EDf
It is called the effective dose 这叫做有效剂量
for the f% of population 对f%的受试动物
It is a desired reversible response 这是所希望看到的可逆反应
This is why we can use this compound 这就是为什么我们可以用这种化合物
to treat disease 来治疗疾病
This is shown in the left curve of the image 这是图像左侧的曲线
The second parameter is called TDf 第二个参数是TDF
It is toxic dose for the f% of population 它是f%的受试动物的有毒剂量
It is an undesirable irreversible response 这是一种我们不希望的不可逆转的反应
This is what we do not need 这并不是我们所需要的
The response of the drug 这种药物的反应
is shown in the middle curve in the image 对应图中的第二条曲线
The third concept is the LDf 第三个参数是LDF
is called the lethal dose 在f%的受试动物中的致命剂量
for the f% of the population 在f%的受试动物中的致命剂量
This means the dose of a chemical 这意味着一种化学物质的剂量
which produces death in the f% of a population 在f%的受试动物中会导致死亡
of the tested animals regardless 在f%的受试动物中会导致死亡
how this compound is administered to the body 不管这种物质是如何进入身体的
The response curve is showed 其响应曲线显示
in the right side of the image LD 在图像的右边LD
Once we have these three parameters 当我们有了这些参数后
we can defined other terms 我们就可以定义其他
used to define the safety of the drugs 用于定义药物安全的术语
They are the Therapeutic Margin in short TM 它们是治疗窗 简称TM值
equals to LD50% - ED50% 等于LD50％减去ED50％
then the Therapeutic Index TI = LD50%/ED50% 其次是治疗指数TI为LD50%与ED50%的比值
the third one is Margin Of Safety 第三个是安全边界
in short MOS = LD5% - ED95% 简称MOS等于LD5%减去ED95%
the last one is Safety Index 最后一项是安全指数
in short SI = LD5%/ED95% 简称SI等于LD5%与ED95%的比值
This slide showed the LD50s of some compounds 这张幻灯片给出了一些化合物的LD50(半数致死量)
In the top of the list we can see alcohol and salt 在这份清单的上部我们可以看见酒精和盐
The LD50s for these two compounds 这两种物质的半数致死量
are very high normally they are nontoxic at all 是非常高的 通常它们一点毒性都没有
But remember if you like drink you can drink 但是记住如果你想喝酒你可以喝
but you should not drink too much 但是你不应该喝得太多
If it reaches a certain amount 如果达到一定程度的量
it will become lethal for human 它对人是致命的
For some chemicals or drugs 对一些化学物质或者药物
such as Aspirin and DDT have LD50s 250 mg/kg 比如阿司匹林和二硫苏糖醇的LD50是250 mg/kg
They are moderate toxic 他们有中等毒性
For other chemicals such as the compound 一些其他化学物质
I mentioned on the first slide Dioxin 如在第一张幻灯片里提及的二噁英
This compound is very toxic 这种物质是非常毒的
the LD50 is only 1 ug/kg 其半数致死量只有1 ug/kg
Other compounds such as the bee venom 其它物质如蜂毒
the LD50 is too low to detect 其半数致死量由于太低以致于检测不到
This slide showed the classification 这张幻灯片显示了
of general toxic compounds 常见毒物基于半数致死量的分类
based on the dosage of LD50 常见毒物基于半数致死量的分类
we can classify them to the following categories 我们可以把它们分成下面几种类型
Such as Practically nontoxic compounds 如事实上无毒的化合物
which have LD50 larger than 15 g/kg 其半数致死量大于15 g/kg
Slightly Toxic compounds 轻微有毒的化合物
and Moderately Toxic compounds 及中等毒性的化合物
and Very Toxic compounds 及高毒性化合物
which have LD50 between 50 to 500 mg/kg 其半数致死量在50到500 mg/kg之间
Some of them are defined 他们中的一些被定义为
as Extremely Toxic and the last category is Supertoxic 剧毒 最后一种是超级毒物
these compounds have LD50 below 5 mg/kg 这些物质的半数致死量小于5 mg/kg
The last five compounds listed in the previous slides 在前面的幻灯片中列出的最后五个化合物
belong to the last category they are very toxic 属于最后一类 他们都是很毒的
So what is the effect of the toxic compounds 那么什么是有毒的化合物
different toxic compounds have different effects 不同的有毒化合物对人类和动物有不同的作用
on human and animals 对人类和动物有不同的作用
For example arsenic or cyanide can cause death 例如砷或氰化物可导致死亡
Ozone or lead can cause organ damage 臭氧或铅会导致器官损伤
and UV light can cause mutagenesis 紫外线会导致基因突变
We can look at the image the skin of the person 在图上我们可以看到此人的皮肤
has been significantly changed 已经发生了明显的改变
after strong and long time UV treatment 在受到强烈和长时间的紫外线照射后
Other chemicals such as Benzene 其它的化合物譬如说苯
and asbestos are carcinogenesis 和石棉都是致癌物质
Thalidomide can cause teratogenesis effect 沙利度胺可引起致畸作用
In the next few minutes I am going to talk about 在接下来的几分钟内我将谈谈
the molecular mechanisms of the toxicants 毒物的分子机制
There are six categories of mechanisms 毒理有六大类机制
for toxicology 毒理有六大类机制
So the first one is the Adverse Drugs Reactions 第一种是药品不良反应
called ADRs 简称ADRs
ADRs are notoriously unintended responses 药品不良反应是
occurring at therapeutic doses 发生在治疗剂量时的已知的不想要的反应
and account for about 5% 在约占所有急性住院的5%
of all acute hospital admissions 在约占所有急性住院的5%
There are two categories 共分两大类
One is Type A is called augmented ADRs 一种被称为A型的增强型药品不良反应
and the other is Type B bizarre ADRs 另一种是被称为B型的怪异药品不良反应
The type A has following effects A型有如下影响
The effects are related to 其影响与我们已知的药理学
the known pharmacology but undesirable 有关系但却是我们不希望看到的
It is very common it is also related to 这种作用很常见
the dose given to the patients 它与病人给药剂量有关
and it can be predicted 并且它是可预测的
However bizarre ADRs have the following effects 然而怪异药品不良反应却有如下影响
These effects are unrelated to 这些影响与已知的药理学没有关联
known pharmacology 这些影响与已知的药理学没有关联
These effects are very rare 这些反应非常罕见
and can not be predicted 并且不可预测
they are often idiosyncratic 它们常常是特异体质性的
That is why sometimes the bizarre ADRs 这也是为什么有时候怪异性药品不良反应
are more dangerous than the type A ADRs 比增强型药品不良反应更加危险的原因
Some examples for Type A and Type B ADRs 这里有一些A型和B型药品不良反应的例子
are showing at the right side of this table 在右边的表格里
So the second mechanism 第二种机制
is linked to receptors ion channels and enzyme 同受体离子通道和酶有关
they can mediate the toxicity 它们可以调节化合物的毒性
of the chemical compounds 它们可以调节化合物的毒性
There are four major families for receptors 受体主要有四大家族
The first one is Ligand 第一种是配体
can be gate ion channels ionotropioc receptors 可以是门控离子通道受体
and voltage gated ion channels 电压门控离子通道
The second group is G-protein coupled receptors 第二种是G蛋白偶联受体
The third one is enzyme-linked receptors 第三种是可调节酪氨酸激酶活性的酶联受体
regulating tyrosine kinase activities 第三种是可调节酪氨酸激酶活性的酶联受体
The forth one is nuclear receptors 第四种是一种核受体
which can regulate gene expression 能调节基因表达
The enzymes can also catalyze the metabolic 这种酶还能催化代谢
and catabolic pathways 并且分解代谢途径
If they are affected 如果它们受到影响
then the metabolism system in the human body 那么人体的代谢系统
will be significantly changed 将会显著改变
Other proteins including carrier proteins 其他蛋白包括载体蛋白
which can uptake or transport proteins 能够在细胞内外摄取或转运蛋白
in or out of the cells 能够在细胞内外摄取或转运蛋白
Some other proteins 一些其它蛋白
such as involved in vesicle release 如参与囊泡释放的蛋白
can also belong to this category 也属于这种类型
This table showed some toxins 这张表给出了一些
from plants and bacteria 来自植物和细菌的毒素
There are many many names showing here 这里面有很多很多的名称
Basically most of them block the RNA polymerase 基本上它们中的大部分阻断RNA聚合酶
inhibit the potassium calcium channels etc 抑制钾钙通道等
This slide showed several compounds 这张幻灯片给出了几种化学物质
from the animal venoms and toxin environments 来自于动物毒液和环境毒素
For example we can see the dendrotoxins 如我们可以看到曼巴毒素
can block the potassium channels 可以阻断钾离子通道
and agatoxin can block the calcium channels 漏斗网蛛毒素可以阻断钙离子通道
This slide showed the mechanism of 这张幻灯片给出了
a-bungarotoxin which is from the banded krait 来自金环蛇的金环蛇毒素的机理
How can it affect the ion channel process 它是怎么影响到离子通道的呢
So this compound actually 这个化合物实际上
can block the acetylcholine receptor (AChR) 能阻断乙酰胆碱受体
and then it can inhibit the ion channel flow 然后抑制离子通道
shown in the right side of this image 如右图所示
And eventually leads to paralysis 最终导致动物或人类的瘫痪和死亡
and death of animals or humans 最终导致动物或人类的瘫痪和死亡
The third mechanism of the toxicology 毒理学的第三个机制是
is the alteration of biochemical pathways 改变生物化学通路
For example cyanide 比如氰化物
can inhibit mitochondrial cytochrome c oxidase 能抑制线粒体细胞色素c氧化酶的活性
to prevent cellular respiration 从而阻止细胞呼吸
Carbon monoxide displaces oxygen 一氧化碳取代来自血红蛋白的氧气
from haemoglobin causing hypoxia 从而导致低氧
Under normal condition 在正常条件下
when we have oxygen supplies haemoglobin 当我们有氧供给时血红蛋白
can be gradually saturated 可逐渐饱和
However in the presence of carbon monoxide 然而当存在一氧化碳时
then haemoglobin can be quickly occupied 血红蛋白会很快被一氧化碳占用
by carbon monoxide 血红蛋白会很快被一氧化碳占用
It cannot carry oxygens 而无法携带氧
That is why even with 0.01% of carbon monoxide 这就是为什么即使空气中仅含0.01%的一氧化碳
in atmosphere it will cause headache 也会导致头痛
When the concentration is higher than 0.2% 当浓度超过0.2%
it can cause potential death for people 就可能导致死亡
The fourth mechanism for toxicology 毒理学的第四个机理
is linked to the organ-directed toxicity 与器官靶向毒性有关
For example lead compound can cause defects 比如铅化合物能造成中枢神经系统缺陷
on the central nervous system 铅化合物能造成中枢神经系统缺陷
which will have severe effects on children 这对儿童产生严重的影响
Isocyanates can cause immune system problems 异氰酸酯会引起免疫系统问题
ethanol and acetaminophen 酒精和对乙酰氨基酚
can cause liver damages 会导致肝损伤
and tobacco smoke asbestos 吸烟 石棉和
and ozone can cause respiratory tract problems 臭氧会引发呼吸道问题
UV lights as I mentioned can cause skin 我提过的紫外光会导致皮肤
and eye problems 和眼睛问题
metals can cause kidney dysfunctions 金属可引起肾功能异常
And other compounds 而且其他化合物
such as dibromochloropropane 如二溴氯丙烷
can cause problems in reproductive systems 可引起生殖系统问题
The fifth mechanism is linked to 第五个机理与
mutagenesis and carcinogenesis 突变和癌变相关
Mutagens are compounds which 诱变剂是能引发DNA突变的化合物
can cause DNA mutation 诱变剂是能引发DNA突变的化合物
This mutation can cause disease 这种突变会导致疾病的产生
If this process can make neoplastic cells 如果这个过程可以产生肿瘤细胞
the agent is termed a carcinogen 该化合物就被称为一种致癌物
There are two major classes of genes 有两大类基因是涉及致癌
which are involved in carcinogenesis 有两大类基因是涉及致癌
The first type is proto-oncogenes 第一类是原癌基因
which can promote cell cycle progression 它可以促进细胞周期的进程
For example the constitutive active growth factor 例如稳定活性生长因子
tyrosine-kinase receptors 酪氨酸激酶受体
can cause neoplastic transformation 能引起致瘤性转化
The second type here 第二种
is the tumor-suppressor genes 是肿瘤抑制基因
If these genes have mutation 如果这些基因有突变
then it can inhibit cell cycle progression 然后它可以抑制细胞周期的进程
For example the mutations 比如肿瘤抑制基因的突变
in tumor suppression genes 肿瘤抑制基因的突变
can produce p53 mutations 能导致p53突变
and cause many many cancers in human body 能在人体内引发很多肿瘤
The last one I would like to mention 最后我想提的
is teratogenicity 是致畸性
Actually those are compounds 事实上那些化合物
which can cause birth defects 能引发出生缺陷
during the development 在发育过程中
One of the cases I would like to mention to you 我想要向大家提的一个例子
is the thalidomide story 就是关于沙利度胺的故事
As we know thalidomide 众所周知沙利度胺
was used as a sedative in 1960s 在20世纪60年代是作为镇静剂使用的
However later on 然而后来
it is found that this compound can cause defect 发现这个化合物能引发
showing in the right side of this slide 如这张幻灯片的右图所示的缺陷
for example birth defects on the feet legs 例如腿足手的出生缺陷
and also on hands 例如腿足手的出生缺陷
Actually later on people found 事实上后来人们发现
that this compound has two different enantiomers 这个化合物有两个不同的对映异构体
and these two enantiomers 这两个对映异构体
have different functions 有不同的功能
Here is a little bit history about thalidomide 这是一些关于沙利度胺的故事
This compound was synthesized in 1950s 这个化合物在20世纪50年代合成
When it was tested in all the animals at that time 在当时所有试验过的动物中该化合物都没有毒性
there was non-toxic effect 没有毒性
Then this drug was introduced in 1956 然后这个药物就在1956年被使用
as sedative to reduce nausea 作为镇静剂来缓解孕期恶心
and vomiting during pregnancy 和孕期呕吐
In 1961 thalidomide became 在1961年沙利度胺成为
the best-selling sleeping pill 最畅销的安眠药
in West Germany and the United Kingdom 在西德和英国
However once it was taken 然而当它被
by the pregnant women 怀孕妇女服用时
then thalidomide produced teratogenic effects 沙利度胺产生了致畸作用
in 100% of foetuses exposed 在100%的3-6周妊娠期的胎儿
between 3-6 weeks of gestation 在100%的3-6周妊娠期的胎儿
There is an estimated about 8,000-12,000 infants 约有8000-12000名婴儿
born with birth defects caused by thalidomide 出生时就患有沙利度胺引发的缺陷
However only about 5,000 of them 然而只有其中的5000名
survived beyond childhood 活过童年
After this disaster 在这次灾难之后
the United States and European countries 美国和西方国家
implemented drug testing new rules 实施了药物检测的新规则
Although this drug is toxic for people today 尽管这个药物至今对人类而言是有毒的
this drug is still useful for some of the disease 但还是对有些疾病有效
For example it can be used to treat leprosy 比如它能用于治疗麻风病
and multiple myeloma 和多发性骨髓瘤
This table showed us the effect of toxic drugs 此表给出了对胎儿发育有影响的有毒药物
on the fetal development 对胎儿发育有影响的有毒药物
The first stage is the blastocyte formation 第一阶段是囊胚的形成
It is within 16 days of the gestation 它在妊娠的16天内
Some cytotoxic drugs such as alcohol 一些细胞毒性药物如酒精
can affect the cell division at this stage 可以在这个阶段影响细胞分裂
The second stage is the organogenesis 第二阶段是器官
It is between 17-60 days 它在17-60天
Some of the teratogens 有些致畸药物
such as thalidomide retinoids and warfarin 如沙利度胺 维甲酸和华法林
can affect cell division migration differentiation 可以影响细胞分裂 迁移和分化
and even cause death 甚至导致死亡
The third stage is the maturation stage 第三阶段是成熟期
In that stage alcohol nicotine and steroids 在这一阶段酒精尼古丁和类固醇
can affect cell division migration differentiation 能影响细胞分裂 迁移和分化
and even cause death 甚至引发死亡
In the next few minutes I will briefly mention 在接下来的几分钟内我将简要地讲解
the occupational and environmental toxicology 职业和环境毒理学
The goals for the occupational toxicology 职业毒理学的目的在于
are to deal with the chemicals found 处理在工作场所发现的化学物质
in the workplace 处理在工作场所发现的化学物质
to identify the chemicals and the agents 识别这种环境中的化学品和试剂
in that environment 识别这种环境中的化学品和试剂
to identify the acute and chronic diseases 鉴别它们能引起的急性和慢性疾病
that they can cause 鉴别它们能引起的急性和慢性疾病
And to define the conditions under which 并且定义安全使用的条件
they may be used safely 并且定义安全使用的条件
Also it studies to prevent the absorption 同时它研究预防这些化学物质有害剂量的摄入
of harmful amounts of these chemicals 同时它研究预防这些化学物质有害剂量的摄入
Sometimes the environmental toxicology 有时候环境毒理学
also defines and carries out programs 也制定和执行计划
for the surveillance of exposed workers 来监测接触的工人
and the environment in which they work 和工人工作的环境
The goals for the environmental toxicology 环境毒理学的目的在于
are to deal with the potentially deleterious impact 处理环境中的化学物质对生物体潜在的有害影响
of chemicals in the environment 处理环境中的化学物质对生物体潜在的有害影响
on living organisms 处理环境中的化学物质对生物体潜在的有害影响
And to study the toxic chemicals 并研究有毒化学品对空气 土壤和水的污染
in air soil and water pollution 并研究有毒化学品对空气 土壤和水的污染
To identify chemicals 鉴定
used in the agricultural environment 在农业中用作杀虫剂的农药化合物
as pesticides or in food processing 在农业中用作杀虫剂的农药化合物
that may persist as residues or ingredients 或食品加工中食品里存在的残留物或成分
in food product 或食品加工中食品里存在的残留物或成分
Here I would like to briefly mention hazard and risk 在这里我想简要地提及危害和风险
Hazard is the ability of a chemical agent 危害是指一个化学品能
to cause injury in a giving situation or setting 在指定的情况和环境下造成的伤害
the conditions of use 其使用条件
and its exposure are primary considerations 和接触是主要考虑因素
It includes the inherent toxicity 包括固有毒性
and the amount of chemicals 和人体对化学物质的摄入量
absorbed to the body 和人体对化学物质的摄入量
Risk here is defined as the expected frequency 在这里风险是指因接触化学或物理试剂而产生不良效应的预期频率
of the occurrence of an undesirable effect 在这里风险是指因接触化学或物理试剂而产生不良效应的预期频率
arising from exposure to a chemical or physical agent 在这里风险是指因接触化学或物理试剂而产生不良效应的预期频率
There are mainly three routes 主要有三种接触毒物的途径
for exposure of toxicants 主要有三种接触毒物的途径
They are inhalation skin contact and oral ingestion 吸入 皮肤接触和口服
Here are some of the properties 我们可以用一些性质
we can estimate the potential hazard of a compound 来估测化合物的潜在危险
The first one is the degradability 第一个是降解性
If a compound is poorly degradable 如果化合物难降解
then it may exist in human bodies for a long time 那么它可以在人体中长期存在
For examples such compounds 例如这样的化合物
are organic pollutants polychlorinated biphenyls 有机污染物多氯联苯
which are highly hazard 是非常危险的
The second property is the mobility 第二个性质是流动性
If a chemical is highly mobile 如果一个化合物在空气 水和土壤中有很高的流动性
through the air water and soil 如果一个化合物在空气 水和土壤中有很高的流动性
then it will have more adverse effect 那么它将产生更多的不良影响
It will affect more people 也会影响更多的人
The third property is bioaccumulation 第三个是生物积累
For example some of the compounds 比如一些化合物
such as lipophilic substances such as DDT 如脂溶性物质DDT
It can accumulate in the body fat showing 它能在体内脂肪中蓄积
in the upper part of this image 如这张图片的上半部分所示
When an animal grows from childhood to the adult 当一个动物从童年生长到成年
then this kind of chemicals 这种化合物
will accumulate in their body 将在其体内累积
The fourth one is biomagnification 第四个是生物放大作用
This is a process that a chemical can be transported 这个过程中化合物可以在不同动物之间转移
from different animals to other animals 化学品可以在不同动物之间转移
That is why if a compound 这就是为什么如果一个化合物
has biomagnifications properties 具有生物放大作用
then it will accumulate in large animals 它将会在大动物
and even in human 甚至人类体内累积
There are five major pollutants 主要有五物种污染物
They are air pollutants solvents pesticides herbicides 包括空气污染物 溶剂 杀虫剂 除草剂
and environmental pollutants 和环境污染物
I will briefly introduce them in the next few slides 在下面几张幻灯片中我将简要介绍它们
The first one is air pollutants 首先是空气污染物
Carbon monoxide accounts for ~52% 一氧化碳约占空气污染物的52%
of the air pollutants 一氧化碳约占空气污染物的52%
It can bind to the oxygen binding sites 它能结合到血红蛋白的氧结合位点形成碳氧血红蛋白
of hemoglobin to form carboxyhemoglobin 它能结合到血红蛋白的氧结合位点形成碳氧血红蛋白
Brain and heart are the most affected organs 脑和心脏是受影响最大的器官
The second one is sulfur oxide 第二个是硫氧化物
It accounts for about 14% of the air pollutants 约占空气污染物的14%
It can form sulfurous acid with moisture 它可以形成亚硫酸
and can cause irritant to eyes to respiratory tract 会刺激眼睛和呼吸道
and also affect skins 也会影响皮肤
The third one is nitrogen oxides 第三个是氮氧化物
It accounts for about 14% of air pollutions 它占空气污染物约14%
It can damage type I and II alveolar cells 它可以破坏I型和II型肺泡细胞
cause pulmonary edema or death 从而引起肺水肿或死亡
The next one is ozone 下一个是臭氧
The chemical formula is O3 化学式是O3
It occurs in earth atmosphere 它存在于大气层中
around high-voltage electrical device 高压电气设备或臭氧生产设备的周围
or ozone producing devices 高压电气设备或臭氧生产设备的周围
This is an irritant of mucous membranes 这具有粘膜刺激性
can irritate upper respiratory tracts 能刺激上呼吸道
cause deep lung irritation pulmonary edema 引起肺刺激肺水肿
and so on 等等
The last category is hydrocarbons 最后一类是碳氢化合物
It accounts for about 14% 约占14%
and the particulate matter 和颗粒物
it is called PM 即PM
It accounts for ~4% 约占4%
For solvent pollutants there 溶剂污染物
are mainly two categories 主要分为两类
One is halogenated aliphatic hydrocarbons 一个是卤代脂肪烃
includes carbon tetrachloride chloroform etc 包括四氯化碳 氯仿等
These kinds of compounds 这些化合物
can cause central nervous system depression 可导致中枢神经系统抑郁
cause liver and kidney injury cardiotoxicity etc 造成肝肾损伤 心脏毒性等
The second group is aromatic hydrocarbons 第二组是芳香烃
such as benzene toluene xylene 如苯 甲苯 二甲苯
These compounds 这些化合物
can cause many deleterious effects 会造成许多有害的影响
mostly can cause cancer such as blood cancer 主要引发肿瘤 比如血癌
cause defects in central neural systems 导致中枢神经系统缺陷
For pesticides there are mainly four categories 杀虫剂主要分为四类
One is organochlorine pesticides 一个是有机氯农药
such as DDT and its analogs benzene hexachlorides 比如DDT和它的类似物苯六氯化合物
and so on 等等
These kinds of compounds 这些化合物
can interfere with inactivation 能干扰兴奋膜上钠通道的失活
of the sodium channel in excitable membrane 能干扰兴奋膜上钠通道的失活
and can cause rapid repetitive firing 引起大多数神经元快速重复放电
in most neurons 引起大多数神经元快速重复放电
can inhibit calcium ion transport 能抑制钙通道的转运
they are slowly degraded 它们降解很慢
and have bioaccumulation effect 具有生物累积作用
The second group is organophosphorus pesticides 第二组是有机磷农药
such as trichlorfon diazinon etc 如敌百虫 二嗪磷等
They can inhibit acetylcholinesterase 它们可以抑制乙酰胆碱酯酶
The last two groups are carbamate pesticides 最后两类是氨基甲酸酯类农药
and botanical pesticides 和植物源农药
Some of the examples 其例子有
are aldicarb aminocarb nicotine rotenone 涕灭威 灭害威 尼古丁 鱼藤酮
and pyrethrum 和除虫菊
This slide showed some of the herbicides 这张幻灯片显示一些除草剂
The first one is chlorophenoxy herbicides 第一个是氯代苯除草剂
Two of the examples are shown 这张幻灯片的上面给出了两个例子
on the top of this slide 这张幻灯片的上面给出了两个例子
2,4-D, 2,4,5-T 2,4-D, 2,4,5-T
There are multiple chlorine atoms 这些化合物有多个氯原子
in these compounds 这些化合物有多个氯原子
The next one is glyphosate 下一个是草甘膦
This is nonselective herbicide 它是非选择性除草剂
can cause eye and skin irritant 可引起眼睛和皮肤的刺激
and may cause death 也可能引起死亡
The structure is shown in the middle of this slide 结构显示在这张幻灯片的中间
So the third group is bipyridyl herbicides 第三组是联吡啶类除草剂
One of the examples is shown 在这张图的下方给出了一个例子
at the bottom of this image 在这张图的下方给出了一个例子
This kind of herbicide can accumulate in lung 这类除草剂可富集在肺部
and cause lung edema 并引起肺水肿
Here are some of the environmental pollutants 这儿是一些环境污染物
The first group actually also contains 第一类事实上也包含
lots of chlorine atoms 很多氯原子
such as polychlorinated biphenyls 如多氯联苯
Some of the examples are shown in this slide 这张幻灯片上给出了一些例子
such as TCDD and PCDD 比如四氯二苯并-p-二噁英和多氯二苯-p-二噁英
They can cause dermatologic problems 他们能引起皮肤问题
and elevate plasma triglycerides 并提高血浆中甘油三酯含量
Another group is endocrine disruptors 另一组是内分泌干扰物
They have estrogen-like 它们具有类雌激素
or anti-androgenic properties 或抗雄激素性质
have adverse effect on reproductive cancers 对生殖系统癌症有不良影响
The third one is asbestos 第三种是石棉
It can cause progressive lung disease 它可引起进行性肺疾病
In this class I have briefly 这节课我已经简要地
talked about the following things 讨论了以下内容
We need to know how toxicology is developed 我们需要知道毒理学是如何发展的
We need to know the brief history of the toxicology 我们需要知道毒理学的简要史
and what are the effective dose toxic dose 并知道一个化合物的有效剂量 有毒剂量
and lethal dose for a compound 和致死剂量
what are the therapeutic margin therapeutic index 什么是治疗窗 什么是治疗指数
margin of safety and safety index 以及其安全边界和安全指数
what are the types of toxic effects 毒副作用的类型
what are the molecular mechanisms of toxicology 毒理学的分子机制
what are the properties 估计潜在有害物质
for estimating potential hazards 估计潜在有害物质
what are the major air pollutants 主要的空气污染物
major toxic solvents pesticides herbicides 主要的有毒溶剂 杀虫剂 除草剂
and environmental pollutants 和环境污染物
Thank you very much 非常感谢
I would like to see you next class 下节课再见
Bye-bye 拜拜