“ 二噁英”污染与人类健康

袁占鹏 Ph.D.

武汉大学公共卫生学院2011.11.4

E-mail: zpyuan@whu.edu.cn电话： 6875 9982 ； QQ ： 1520357237

目的• 以“二噁英”为例了解一类（种）污染物

从来源到公共卫生的系统考量

• “ 二噁英”是什么？• 来源• 对环境的污染与在环境中的变迁• 暴露途径• 代谢与分布• 毒性及其机制• 公共卫生考量 — 健康危害与对策

内容

“ 二噁英”• 是二噁英和二噁英样物质的统称

– Polychlorinated dibenzodioxins, PCDDs– Polychlorinated dibenzofurans, PCDFs– Polychlorinated biphenyls, PCBs

• 2,3,7,8-tetrachlorodibenzo-p-dioxin– 2,3,7,8-TCDD ，常简称 TCDD 或 dioxin– 是“二噁英”类物质的典型物– 俗称二噁英

TCDD

Dibenzo-p-dioxin

PCDDs

• Chlorine atoms are attached to this structure at any of 8 different places on the molecule– At positions 1–4 and 6–9– There are 75 PCDD congeners

PCDFs （呋喃）

• Polychlorinated dibenzofurans

– 2,3,7,8-tetrachlorodibenzofuran

PCBs （多氯联苯）

• Theoretically 209 different PCB congeners are possible, although only about 130 are found in commercial PCB mixtures

小结• HAHs – halogenated aryl hydrocarbons

（卤代芳香烃）– PCDD/Fs, PCBs

Note: 卤代芳香烃– Chlorine ( 氯 ) and Bromide ( 溴 )

• Along with Polycyclic aryl hydrocarbons （ PAHs, 多环芳香烃）

• Form aryl hydrocarbons (AHs) family

10

The term dioxin or dioxins is used almost exclusively to refer to compounds from the above groups which demonstrate the same specific toxic mode of action associated with 2,3,7,8-TCDD.

Incidents of contamination with PCBs are often reported as Dioxin Affair since it is this toxic characteristic which is of most public and regulatory concern.

“ 二噁英”的理化特性• 高挥发性• 高脂溶性• 高绝缘性• 高（化学）稳定性

Dioxins and dioxin-like compounds (DLC) are by-products of various industrial processes, except for occasional purposeful production, and are commonly regarded as highly toxic compounds that are also called persistent organic pollutants (POPs).

来源

• 自然过程形成• 人为产生

– 商品– 工业活动的副产品

PCDD/Fs 的历史• 工业化前低剂量“二噁英”即存在于环境

中– 自然燃烧– 地质过程：火山爆发等

• 最早产生副产品“二噁英”的工业活动– 1848 年德国 Leblanc Process （卤碱生产）

• 最早有意合成是在 1872 年

PCBs 的历史• 1930 年代首次合成• 1946 年 Monsanto 最早开始商业合成

– 利用其绝缘性、高稳定性和良好的导热性– 变压器、电容器散热

自然过程形成

• 深林火灾– PAHs

• BaP

– HAHs• dioxin

• 火山爆发– HAHs

• Dioxins/Furans, PCBs

– PAHs

工业活动

• 卤碱工业 Leblanc Process– HAHs

• 造纸业– 氯气用于纸浆漂白

• Dioxins (TCDD), Furans, PCBs, etc.

工业活动（续）• 废物焚烧• 商业合成

– PCBs, Herbicides (Agent Orange)

• 塑料工业– PVC

• 冶金业– HAHs

• Dioxins, furans, and PCBs

Major Sources

According to the most recent US EPA data• Combustion sources

– municipal waste incinerators

• Metal smelting• Refining and process sources• Chemical manufacturing sources • Natural sources • Environmental reservoirs

Concentration profile of PCDD in a 2001 sediment core from Esthwaite Water, Cumbria, UK

“ 二噁英”在环境中的变迁

影响因素• 来源性质

– 热过程– 常温过程

• 物理不稳定性– 易于光裂解 (photolytic)

“ 二噁英”的环境变迁 (1) 热过程

• 高稳定性和挥发性– 释放到大气中– 随大气运动扩散

• 常附着在有机颗粒上• 随雨、雪沉降地表

– 在土壤里浓度高– 空气中次之– 但因其化学稳定而不易代谢，且由于高脂溶性

而在动物脂肪组织中富集而浓度最高

“ 二噁英”在大气中的分布与沉降

“ 二噁英”的环境变迁 (2) 常温过程

• 随工业废物（水）进入环境– 流经的土壤

• 附着在颗粒有机腐质上– 环境生物

• 沉降到水底– 淤泥 (sediments)

暴露途径

• 呼吸暴露– 汽车尾气

• 食物暴露– 一般人群– 特殊人群暴露—哺乳

• 事故性暴露• 废物场暴露

食物暴露

• The major sources of human exposure (96%) are– Animal fats found in meats

– Full fat dairy products – Fatty fish (herring, mackerel, salmon,

sardines, trout, tuna)

http://upload.wikimedia.org/wikipedia/commons/f/f9/Dioxin_chart.png

空气暴露

• Breathing incineration gases released from medical, municipal, and hazardous waste incinerators

• Breathing gases released by industrial processes from paper mills, cement kilns, and metal smelters

职业暴露

• People who perform the following types of work can be exposed to dioxins– Production and handling of certain chlorinated phenols

(such as 2,4,5-trichlorophenol or pentachlorophenol [PCP]) – Production or handling of chlorinated pesticides, such as 2-

4-dichlorophenoxyacetic acid (2,4-D) and other herbicides – Chlorinated pesticide application – Pressure treatment of wood with PCP and handling of PCP-

treated wood – Production of chlorinated paper at pulp and paper mills – Operation of municipal solid waste or hazardous waste

incinerators – Hazardous waste clean-up operations

其它暴露

• 事故性暴露 (accidental exposure)– Seveso, Italy (dioxin, 1976)–台湾食用油污染 (PCBs, 1960s)

• 废物场暴露• 婴儿哺乳

– Children are passed substantial body burdens by their mothers, so breast-feeding increases the child's body burden

分布、代谢与排泄

• 代谢–微不足道

• 分布– 脂肪成分：肝及其它脂肪组织

• 排泄–缓慢

• The estimated half-life for highly chlorinated dioxins (4-8 chlorine atoms) in humans ranges from 7.8 to 132 years

“ 二噁英”毒性

• Dioxins refer to such a broad class of compounds that vary widely in toxicity– the concept of toxic equivalent (TEQ) has been de

veloped to facilitate risk assessment and regulatory control.

– Toxic equivalent factors (TEFs) exist for selected congeners of dioxins, furans and PCBs

– The reference congener is the most toxic dioxin 2,3,7,8-TCDD which per definition has a TEF of one

• 急性毒性– 消化系统脏器损伤、皮肤损伤等– 免疫毒性、神经毒性（行为变化）

• 慢性毒性– 消瘦症 (wasting syndrome)– 发育毒性 (developmental toxicity)– 生殖毒性 (reproductive toxicity – teratology)– 肿瘤发生 (carcinogenesis)– 免疫毒性 (immunotoxicity, immunological tox.)– 神经毒性 (neurotoxicity, neurological tox.)

AH 毒性机制

• 绝大多数 AHs 的毒性（如果不是全部）是通过 AH 的受体 (AhR, Aryl Hydrocarbon Receptor) 介导的 (Hankinson, 1995)

• 问题–许多毒性得不到满意的解释

AhR信号通道

XRE promoter gene (CYP1A1)

Translation

Increased expression CYP1A1 protein

Increased expression of other gene products

+

AhR/Arnt heterodimer

mRNA

IC

+

AhR 的功能

• 动物感测细胞外信号和环境压力的一员– PAS (Per-AhR/Arnt-Sim)家族

• Per – circadian• Arnt – AhR• Sim – Drosophila single-minded, an orthologue of Arnt,

essential for midline differentiation

• AhR主动物的适应与对污染物的毒性反应• 正常生长发育和免疫细胞的重要调节因子• 也是一些生理平衡的重要调节因子

AhR pathway participants

90

X XAP2/AIP

HSP90 x 2

L

L

Exogenous ligand

Endogenous ligand

AhR Arnt AhRR

IC Initiation complex

NuNu

Nucleosomes

Nuclear proteins?

XRE promoter gene (ie.CYP1A1)

Target DNA

AhR信号通道调节

+

XRE

mRNAX

Translation

+XRE promoter gene (AhRR)

mRNA

IC

AhRR

Proteosome degradation

抑制调节

AhR信号通道与其它通道的交互作用

http://www.helsinki.fi/science/dentenv/dioxin.html

持久与短暂 AhR激活

持久与短暂 AhR激活

AhR 活力的调控• Rapid receptor degradation (2)

– Ubiquitination – proteosomal degradation– Only happen in SUSTAINED AhR activity

• The action of an AhR Repressor (AhRR) (3)

• Agonist depletion through an enzymatic negative feedback loop (5)

• The evolution of multiple mechanisms to suppress sustained AhR activity implies that its prolonged signaling is physiologically deleterious.

持久与短暂激活• G1 arrest

Sustained +Transient –

• Constitutively active AhR (CA-AhR)– Marked incidence in gastric tumors– It is tempting to speculate that CA-AhR may a

ctually suppresses normal growth in the stomach and liver thereby conferring a growth advantage upon any transformed cells in the tissue

• Transient and sustained AhR activation affect the transcriptome differently– culminating in distinct biological responses to

receptor activation– highlights the importance of tightly regulating

AhR signaling

• Suffice it to say that sustained AhR activity invokes a homeostatic disequilibrium– underscored by a dramatically altered transcri

ptome.

Conclusions

其它重要效应

• 机体 /细胞的氧化还原稳态改变– 活性氧 (reactive oxygen species, ROS) 水平增高

• ROS– 分子和细胞氧化损伤

• DNA, RNA, Protein, peroxidization of lipids, organelles

– 组织氧化损伤– 免疫抑制（损伤），等

DNA损伤 — 种类与修复

DNA损伤修复模型

DNA双链断裂• DNA Double SStrand Breaks (DSBs)

• 一种 DNA损伤– 最严重– 直接产生

• UV

– 间接产生•未能修复的 DNA损伤使其在复制时受阻而产生

DNA SB RepairNature, 411:366-374, 2001

DNA DSBs只是损伤的产物吗？

• No!– They operate in diverse biological settings

• V(D)J– Generating immune-receptor diversity

• Production of gametes for sexual reproduction– Meiosis I (减数 ) and II. Sister chromatin exchange p

roceeds M I, involving Spol I that bound DSBs

• Telomere homeostasis and ageing

– Transportable Elements

端粒稳态与老化DDR protein Role at normal telomeres

MRN Telomere length regulator, role in end processingATM, CHK2 and ATR Maintain telomere length, phosphorylate Shelterin-

complex components, possible roles in telomerase activationand recruitment

Ku and DNA-PKcs Telomere components and telomere-length regulators, possible telomere-capping functions

RAD9–RAD1–HUS1 (9-1-1) Telomere component and telomere-length regulator; aids telomerase recruitment/activation

Nucleases EXO1, FEN1, Processing of telomeric termini to promote XPF/ERCC1 and Apollo telomerase action; regulate telomere integrityPARP1 Potential telomere-length regulatorBRCA1 Telomere maintenanceRPA Telomere component, in telomerase recruitmentWRN Maintains telomere structure and functions in

telomere replicationRAD51D and other HR proteins Regulate telomeric integrity

DNA损伤与疾病• 癌症与 DNA损伤“亲密”关联

– HAHs cause ROS elevation)

• Neurodegenerative disorders– Remember Sim? And AhR belongs to PAS?

• Immune deficiencies and infertility– mutations in NHEJ factors yield B- and T-cell imm

une deficiency– Spermatogenesis

• Genome Instability in Other Heritable hDiseases

健康危害与对策• 致癌• 非致癌• 对策

健康危害• 致癌

– TCDD, a Group 1 carcinogen by the Int’l Agency for Research on Cancer (IARC)

– US EPA• Potential human carcinogen ’94• non-cancer effects (reproduction and sexual de

velopment, immune system) may pose an even greater threat to human health

• No threshold dose ’00

健康危害• 非致癌危害包括

– Developmental abnormalities– Central and peripheral nervous system pathology– Thyroid disorders – Damage to the immune systems– Diabetes– Exposure to dioxins changes the ratio of male to f

emale births among a population • More females are born than males

– etc.

对策• 预防和控制“二噁英”暴露

– Proper incineration of contaminated material is the best available method of preventing and controlling exposure to dioxins

• 高温 >850°C

– 预防食物污染• 食品加工质量控制• 食品安全监控

• 个人如何减少“二噁英”风险– Trimming fat from meat and consuming low fat dairy pr

oducts– A balanced diet (adequate fruits, vegetables etc.)

Identify and measure dioxins in the environment and food

• The quantitative chemical analysis of dioxins requires sophisticated methods– Time consuming– Capital consuming: > US$1700/sample

• Advocate for biological-based methods– Use for screening– Confirm by chemical analysis