Transcript Environmental Health and Toxicology

Environmental Health and
Toxicology
Chapter 2 Review of Pharmacologic Concepts
Food vs Poison
A long time ago, we believed there are only two
basic types of substances:
• Beneficial 有益 one (foods and medicines);
• Harmful 有害one (causing sickness and death and called
poisons)
Today, modern science states that all substances
have a whole spectrum 大范围of activities,
ranging from beneficial to neutral to lethal 致命.
“the right dose differentiates 区分a poison and a remedy
救药 ”
Dose Response Relationship
A famous admonitions 劝告 in toxicology
“In all things there is a poison, and there is
nothing without a poison. It depends only upon
the dose whether a poison is poison or not.”
Paracelsus (1493 – 1541)
Determination of Toxicity
Biological systems used, for example:
• Growth inhibition抑制生长 of a cell 细胞 culture
培养液
• Mutagenesis突变形成,
• Bacterial colony counter菌落计算器
• Death of an animal, eg. mouse, insects, etc.
** end points chosen depend on the goal of the
experiment.
Dose-response relationships
• Intoxication process is mass-driven (the higher
the dosage, the bigger the response)
•  chemicals absorbed per time
•  amount to reach target site (organs)
•  exposure (oral, skin)
•  toxic effects (individual variation)
Calculation parameters
Toxicity of a chemical is related to:
• Size of the organism exposed;
– Units per kilogram of body weight or per square
meter of body surface area.
– Eg. mouse vs. rat; kid vs. adult
• Dose in terms of concentration 浓度, not mass
– mass unit per volume(g/mL), or in molar units
(molarity, eg 3 M)
% Response vs dose, mg/kg
• Cumulative 累积dose-response curve
• S-shaped curve
• At very low dose, biodegradation 生物降解or
elimination 自动排泄dominate主要支配 – no
response in organism
• The highest dose that still produces no
response is NOEL (No Observable 观察Effect
Level)
• The lowest dose to give the response is
termed Toxic Threshold 门槛.
Lethal dose 致命量
• Lethal dose or lethal concentration – at which
the response of the test animals is death
• If the response is a non-lethal response, the
dose is termed as effective dose (ED) or
sometimes call a toxic dose (TD)
Other Terms
• NOELs (no observable effect level) exist for
any chemicals
– Proven by the natural toxicants that make up our
daily diet.
• LD50 – at this concentration, 50% of test
organisms die
Response frequency % vs Dose
• Each individual 个体 organism is toxicologically
distinctive 独特because of variations变化 in its
absorption, metabolism and response.
• For a given dose, some variation in response is
expected 期望.
• Bell-shaped 铃 curve of normal probability 或然率
• Hypersensitive 反应过敏organisms respond at the low
dose end and resistant organisms at the other.
Response frequency % vs Dose, mg/kg
敏感
顽强
Probability vs cumulative
(log对数) dose
 The dose-response relationship is linear 直线.
 The probability point at 50% response is the
median, and the corresponding dose is median
effective 有效 dose (ED50)
 If the response is death, the ED50 becomes the
median lethal dose (LD50)
 LD50 of a chemical – is the dose will kill a statistical
50% of a test population.
 Toxicity of a chemical varies amongst species due
to different size, metabolic ability and exposure
condition.
Probability vs cumulative (log) dose
Potency 效力of a compound
• The compound with the smaller LD50 value is
the more potent one.
• Some may have a reversed 反向toxicity
relationship as LD value vary.
– Refer to curve
– A is more toxic than compound B at the LD50
concentrations, but less toxic at the LD20
concentrations.
Potency of a compound
Margin 边缘 of safety
• Slope 倾斜度 is steep 陡峭– a small increase in the
dose may produce a significant 明显change in
toxicity.
• The shallower the slope, the greater is the margin of
safety.
• ** this expression is NOT the same as therapeutic
治疗index 指数(LD50/ED50) in clinical 临床toxicology,
where the margin of safety represents a spread
between an effective dose ED50 and a toxic dose
LD50
Biphasic 两阶段dose-response curve
of chemicals
• Happens in those organism that requires small
amounts of the chemical for the normal 正常
functioning 活动, and yet at high concentration
produce toxicity, e.g. vitamin A, niacin (vit B),
selenium硒, and some heavy metals such as copper
and cobalt .
• Concentrations higher than the normal range cause
toxicity. If the concentration is lower than the
normal range, the organism suffers from a deficiency
缺乏 that alters normal functions.
Biphasic dose-response curve of chemicals
Factors affecting quantitative response
• The duration of exposure
– Acute toxicity – exposure to single dose over a
short period of time (24-96h)
– Acute toxicity is greater (LD50 is smaller) upon
subacute 亚急性(a few days) or chronic
(longer-term)
• Absorption route
– Respiratory exposure produces the highest
toxicity
– Dermal exposure is lower toxicity than oral
exposure
Other factors
• Presence of impurities
– Synergism 合作– toxicity of the mixtures is greater
than the sum of the individual toxicities, e.g.
inhibition 抑压 of the detoxification 解毒 of other
eg. Alcohol + sleeping pills
– Antagonism 对抗– toxicity of the mixtures is less than
the sum of the individual toxicities, e.g. interfere the
other’s receptor
eg. Alcohol + rice
Toxicokinetics毒代动力学
• Initial 初段 absorption – can be rapid快速
• Equilibrium 平衡 is reached
– When intake = metabolism + elimination
• Stop exposure --- decline in body content
• Re-exposure 再接触--- new equilibrium will be
established again.
Toxicokinetics
Basline=底线 uptake=吸入 equilibrium= 平衡 depuration=排毒
Reversibility 可逆性 of Toxicity
• In most cases, toxicity induced 引发 by a chemical is
essentially 实质上reversible;
• Individual will recover 康复 when the toxin is
removed by excretion 排泄 or inactivated 阻止活性
by metabolism 生陈代谢;
• Sometimes toxicity is irreversible不可逆性, when the
organs have been damaged too far, enzyme 酶is
irreversibly inactivated;
• Toxin may deprive 剥夺an organism of a vital 重要
substance, and recovery has to await 等待
resynthesis 重新制造of this substance.
Concept of Receptors 受体
• Some chemical nonspecifically 不明确地denature 改
变本性 protein蛋白质, dissolve the tissue 组织
chemical burns;
• Some toxins interact 互相影响with specific
components of the tissue, thus perturbing 扰乱
normal metabolism; i.e. the concept 槪念 of
receptors.
• Receptors are proteins. Some have enzymatic activity
and some serve as “transport vehicles媒介” across
the cellular membranes 细胞膜.
• Some plasma proteins 血蛋白 may not act as specific
receptors, but act as a binding 粘结protein of
chemicals.
Xenobiotics外来物 is a general designation of chemical
compounds foreign to the organism
Mode模式 of Entry of Toxins
1. Percutaneous route (skin)
2. Repiratory route (breathing)
3. Oral route (eating or drinking)
循环系统 Circulatory System
Extracellular細胞外
interstitial fluid 组织液
Percutaneous (skin) Route
• Important route for human and animal exposure to
environmental toxic chemicals;
• Three possible routes of skin absorption:
– Diffusion 扩散 through the epidermis 表皮into the
dermis真皮
– Entry through sweat ducts汗腺;
– Entry along the hair-follicle毛囊orifices 孔
• Outermost 最外边 layer of epidermis (Stratum corneum) is
made up of several layers of dried, flattened keratinocytes
角质化细胞, no vascularization 血管分布, no metabolic 新
陈代谢activity
• Lower basal layer of epidermis has high metabolic activity
and is capable of biotransformation 生物转换of
xenobiotics
Percutaneous route
• All entry of substances occurs by passive 被动 diffusion;
• Polar 极性substances via the protein filaments and nonpolar
substances via the lipid matrix基体;
• Hydration 水合作用of the stratum corneum 角质层 increases its
permeability 浸透for polar substances;
• pH of the solution applied to the skin affects permeability;
• Pretreatment 预先处理of the skin with e.g. dimethyl sulfoxide,
methanol, ethanol, hexane, acetone, in particular a mixture of
chloroform and methanol increase the permeability of the skin.
• Permeability of skin is not uniform统一
• Percutaneous absorption is a time-dependent process, with
passage through the stratum corneum as the rate-limiting
reaction.
Respiratory Route
• Respiratory system consists of three regions:
– Nasopharyngeal鼻咽
– Tracheobronchial气管与支气管
– Pulmonary肺部
• Nasopharyngeal canal is lined by ciliated 纤毛epithelium through which
mucous glands粘液腺 are scattered分散.
– The role is to remove large inhaled particles and to increase the
humidity and temperature of inhaled air
• Tracheobronchial region consists of the trachea, bronchi, and bronchioles
细支气管
– These are branched between the nasopharyngeal and pulmonary
regions;
– Lined with ciliated epithelium and mucus-secreting goblet cells杯状细
胞
– Propel 驱使 foreign 外来 particles from the deep parts of the lungs to
the oral 口腔 cavity, either expelled 排出with the sputum 痰 or
swallowed吞下.
Respiratory Route
• Pulmonary region consists of respiratory bronchioles,
alveolar ducts肺泡管, and clusters 群 of alveoli;
– Alveoli – as little bubbles about 150-350 µm in diameter, for the gaseous
exchange between the environment and the blood
– Total alveolar surface area of human lung is 35 m2 during expiration 排气
and 100 m2 during deep inhalation深呼吸.
– Toxins exert their harmful action either by damaging respiratory tissue or
by entering the circulation and causing systemic 全身toxicity.
• The amount of a toxin delivered to the lungs depends on
the concentration of the toxin in the air and on the
minute volume of respiration
– Minute volume is a product of tidal volume潮气量 and the number of
breaths 呼吸per minute.
Respiratory Route
Fick’s law D = Cd x S/MW-1/2 x A/d x (Pa- Pb)
D: diffusion rate; Cd: diffusion coefficient; S: solubility of the gas
in blood; MW: molecular weight; A : surface area; d: thickness
of the membrane; Pa and Pb: partial 部分pressure of the gas in
the inspired 吸入air and in the blood.
Respiratory Route
Toxicity depends on the size of the particles:
• Particles larger than 5 µm
– Deposit in nasopharyngeal region, expelled 排出 by
sneezing 喷嚏or propelled into the oral cavity.
• Particles 2-5 µm in size
– Deposit in tracheobronchial region, cleared by the
mucociliary escalator电动扶梯, expelled in the sputum or
swallowed
• Particles 1 µm or smaller
– Deposit in alveoli, removed by mucociliary escalator, or
enter lymphatic system淋巴系统
Oral route
• Mouth and esophagus食道
– Short retention time停留时间, no significant
absorption
• Stomach 胃 (gastric acid 胃酸)
– Toxicity can be altered 改变 by influencing影响
absorption or modifying修改 the chemicals
• Depend upon whether compounds are administered 加
入 with food or directly into the empty stomach
Oral Route
• Small Intestine 小肠
– Most food absorption takes place
– Xenobiotics (foreign chemicals外来化学品) may enter the
body via the carrier systems for nutrients or via passive
diffusion
– Lipid-soluble organic acids and bases are absorbed by passive
diffusion only in nonionized form.
– Particles of several nanometers 纳米in diameter can be
absorbed from the gastrointestinal tract by pinocytosis胞饮作
用 and enter the blood circulation 血液循环via the lymphatic
system
– Absorbed compounds may enter the circulation either via the
lymphatic system, then to blood, or via the portal circulation 肝
静脉 to liver.
Translocation移动 of Xenobiotics
• Absorbed xenobiotics must be transported by the blood before
reaching the target 目标cells
• The time to the onset of toxicity depends on how quickly plasma
levels of the toxic compound may be achieved.
• The capillary walls have pores 毛孔of up to 0.003 µm (3 nm纳米)in
diameter between them.
• The water-soluble compounds of up to 60,000 molecular mass
enter and exit the bloodstream by filtration 过滤through these
pores.
• The velocity 速度of diffusion decreases rapidly with increasing
molecular radius半径.
Translocation of Xenobiotics
• Lipophilic 嗜油脂compounds diffuse easily through capillary
walls.
• Their diffusion velocity is related to their lipid-water partition
coefficient.
• The entry of a compound into the blood does not necessarily
ensure it will arrive unchanged at its target site.
– Inactivated in liver, excreted into the bile and returned to the
gastrointestinal tract
– Could be reabsorbed and back to the liver – called
enterohepatic circulation肠肝循环
• Blood plasma has a limited metabolic capacity, involving
hydrolytic and transaminating enzymes
• Some xenobiotics may be temporarily inactiviated by bounding to
plasma 血浆 protein.
Cellular 细胞的 Uptake吸入
• According to the fluid 流体mosaic model流体镶嵌模型, the
plasma membrane consists of two layers of lipids with their
hydrophobic疏水性 ends facing each other.
• The hydrophilic亲水的 ends face the aqueous
environment of the interstitial 空隙 fluid on one side and the
interior of the cell on the other side.
• Two types of proteins are embedded into this structure.
– Peripheral proteins do not penetrate through the
membrane and can be removed without disrupting 使混乱
its integrity完整性.
– Integral 完整proteins extend 延伸across the width of the
membrane, responsible for the transport of compound
across it.
Cellular Uptake
Four mechanisms of passage through the cell membrane:
• Water and small organic and inorganic molecules diffuse through
the small pores in the membrane (0.2-0.4 nm)
• Lipid-soluble molecules diffuse easily through the lipid bilayer in
the direction of the concentration gradient浓度梯度 (from high
concentration to low concentration).
• Transported across the membrane by specialized enzymatic
processes that exhibit saturation kinetics
– Energy-independent, transport occurs in the direction of the
concentration gradient, called facilitated diffusion
– Require energy input, transport occurs against 相反the
concentration gradient, called active transport主动运输 (energy
required)
Distribution 分布 between plasma 血浆 and tissue
组织 (Pharmacokinetics药代动力学 )
• Solutes are freely 自由exchangeable交换 between plasma
and the interstitial fluid, thus the concentration of a
xenobiotic in tissue is proportional to that of the free
xenobiotic in plasma.
• The proportionality factor is expressed in terms of an
apparent volume of distribution (VD)
• Large VD indicates easy uptake吸收, whereas a small VD
indicates poor uptake of a compound by the tissue
• However, the true picture is complicated 复杂by the
binding of a xenobiotic to plasma protein or its deposition
排到 in fat脂肪.
Distribution Between Plasma and tissue
e.g. animal is injected intravenously 静脉注射 with chemicals:
• Concentration of the compound in plasma is determined at
frequent time intervals
• The peak concentration occurs immediately after the injection
• Concentration decrease with time through two processes:
uptake by tissue (αphase) and elimination from plasma
(βphase)
• Elimination include urinary excretion, fecal excretion,
excretion by exhalation, excretion with sweat, or metabolism.
Distribution between plasma and tissue
• Plasma clearance清除
– Represents the volume of blood plasma cleared of
a xenobiotic in one minute
• Blood-brain barrier血脑屏障
– Related to impaired 受损 permeability of the
blood capillaries毛细管 in brain tissue
– Lipid solubility of a toxin is an important factor in
the penetration 穿透of the blood-brain barrier
Storage储藏 of Chemicals in the Body
• In general, a compound will accumulate 累积 in the
body after repeated intake if its elimination or
biotransformation 生物转化 is slower than the
frequency of uptake.
• Some compounds are stored in the body in specific
tissues. Such storage effectively removes the material
from circulation and thus decreases the toxicity of the
compound.
• Repeated doses of a toxic substance may be taken up
and subsequently stored without apparent toxicity
until the storage receptors become saturated; 
toxicity suddenly occurs.
E.g. lipophilic compounds such as halogenated
hydrocarbons DDT (dichlorodiphenyltrichloroethane), PCBs (polychlorinated
biphenyls), etc. stored in fat without apparent
harm to the exposed organism.
Accumulate in the food chain食物链 . Eventually,
the storage capacity 容量of an organism at the
end of the food chain may be exceeded超过.
Toxin may be released into circulation and
causing harmful effects.
During starvation饥饿, fat deposits are mobilized
for energy. Stored toxins are then released,
causing sickness or death