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3rd Year > Toxicology Exam 1 > Flashcards

Toxicology Exam 1 Flashcards

1
Q

The father of toxicology and what he states

A

Paracelsus (1493-1541)

He states “all substances are poisons; there is none which is not a poison”

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2
Q

Xenobiotic

A

any substance, harmful or not (e.g., poison or drug), that is foreign to a given biological system

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3
Q

Poison

A

any agent that impairs health or destroys life

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4
Q

Toxin

A

poisonous substance of biological origin

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5
Q

Toxicant

A

poisonous substance of human origin (ex: drugs)

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6
Q

Dose

A

amount of exposure (level of exposure)

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7
Q

Toxic/Toxicity

A

the degree to which something is poisonous

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8
Q

Risk

A

probability that exposure will cause harm

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9
Q

Toxicokinetics

A

study of the movement of xenobiotics in the body

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10
Q

Toxicodynamics

A

study of the interaction of xenobiotics with biological tissue

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11
Q

Biometabolism/biotransformation:

A

chemical alteration of xenobiotics by biological processes (how the body effects toxins)

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12
Q

Sources of Potential Poisons - 11

Exposure to Toxins

Exposure to Elements

Exposure to Pollution

A

Nature (poisons microorganisms, animals, plants, radiation)

Combustion of fossil fuels (acid rain, mercury, lead)

Agriculture (i.e., farming – pesticides)

Mining (anthropogenic activity – heavy metals)

Manufacturing products/processes/waste (e.g., PCBs, dioxin)

Construction products (e.g., asbestos, lead)

Pharmaceuticals (e.g., use and disposal of expired medicines)

Food additives (e.g., colorings, preservatives)

Cosmetics (e.g., makeup, hair dyes, shampoos)

Domestic (e.g., fire retardants, pesticides)

Household products (cleaners, solvents, detergents containing phosphorus, paint products containing lead, machine/auto supplies, garden supplies)

Insect repellants (e.g., DEET, N,N-diethyl-meta-toluamide)

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13
Q

Fields of Toxicology - 6

A

Medical Toxicology: subspecialty of medicine and evaluation of poisoned patients

Pharmaceutical Toxicology: evaluation of toxic potential of new or current drugs

Forensics Toxicology: analysis of biological samples for the presence of toxins

Occupational Toxicology: exposure to toxic hazards in workplace

Environmental Toxicology: toxic substances in environment

Regulatory Toxicology: development, modification, or application of regulations

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14
Q

Government Influence on Toxicology Public policy decisions regulatory action & safety - 5

A

U.S. Environmental Protection agency (EPA)

Food and Drug Administration (FDA)

Occupational Safety and Health Administration (OSHA)

Center for Disease Control and Prevention (CDC)

Environmental Protection Agency (EPA)

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15
Q

Toxicology

A

study of poisons on biological organisms

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16
Q

4 Primary Sites/Routes of Exposure

A

Lungs – Inhalation

Gastrointestinal (GI or “gut”) – oral ingestion

Skin – Topical absorption (can penetrate through the skin)

Injection – Parenteral

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17
Q

Injection – Parenteral

A

Intramuscular (IM)
Subcutaneous (SC)
Intravenous (IV)
Intraperitoneal (IP)
Intradermal (ID)

Intravenous IV > lungs > Intraperitoneal IP > Subcutaneous SC > Intramuscular IM > Intradermal ID > GI > skin

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18
Q

Rate of absorption of xenobiotics influenced by route of exposure

A

Intravenous IV > lungs > Intraperitoneal IP > Subcutaneous SC > Intramuscular IM > Intradermal ID > GI > skin

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19
Q

Influences on Rate

A

Epithelial cell layers of lungs, GI, and skin

Chemical nature of xenobiotics

These influences do not apply to parenteral route

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20
Q

Duration of Exposure

A

Acute: short-term -> single and high dose

Chronic: long-term -> multiple and low dose

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21
Q

Nature of Responses

A

Location
- Local: at site of exposure
- Remote: distant from site of exposure

Onset (latency)
- Time it takes for response to occur after exposure
- Rapid - (ex: food poisoning)
- Slow (delayed) - (ex: cancer like smoking takes decades)

Persistence
- Reversible - food poisoning
- Sustained - cancer, brain damage

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22
Q

Dose response relationship - Links exposure to response:

A

Three key assumptions:
1) Level of xenobiotic at site of action is directly proportional to level of exposure (dose) - how much you have of the xenobitoic is directely proportional to how much you of a dose or how much you were exposed

2) Exposure causes toxicity
Assumes cause and effect

3) Magnitude of response is proportional to exposure level
Exposure-response relationship is quantitative
- how you react is directley based on how much you were exposed

Graded analysis: Measures the severity of response in individuals

Quantal analysis: Measures frequency of response in populations (Only two possible outcomes at a given dose
Response is all or none)

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23
Q

Quantal Dose-Response relationship: Uses in drug therapy and safety

A

Efficacy: maximum response elicited by xenobiotic - frequency and severity

Potency: dose range of xenobiotic

Therapeutic Index (TI): TI examines the therapeutic vs. toxic potential of drugs
Relates drug effect dose response to drug toxicity dose response

Margin of safety (MS): Better estimate of drug safety than TI

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24
Q

Interactions between xenobiotics: Additivity

A

Two poisons together produce maximal response that is equal to the sum of individual responses

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25
Q

Interactions between xenobiotics: Synergy

A

Two poisons together produce maximal response that is greater than the sum of individual responses

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26
Q

Interactions between xenobiotics: Potentiation

A

One poison has no response by itself but enhances the response of another poison

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27
Q

Interactions between xenobiotics: Antagonism

Three types of antagonism:

A

Functional Antagonism: Response of two xenobiotic counterbalance each other

Dispositional Antagonism: One xenobiotic affects absorption, distribution, or elimination of another

Chemical Antagonism: Response of one xenobiotic is neutralized by another through direct chemical interactions

28
Q

Disposition

A

The term disposition is from the verb ‘to dispose’ or to get rid of. In pharmacology, disposition refers to what happens to the drug after it enters the body, including distribution, and elimination processes.

29
Q

Disposition of Poisons
Four major components of Disposition

A

Xenophobic → Absorption → Distribution → Elimination

(ADME)
Absorption
Distribution
Metabolism (biometabolism or biotransformation)
Elimination

30
Q

Role in xenobiotic (foreign chemical in the body) exposure

A

ADME determines level of xenobiotic at site of action

Major determinant of toxic potential of poisons

31
Q

Factors affecting disposition of poisons

A

Dose

Chemistry of the xenobiotic itself (e.g., hydrophobicity)

Rate of absorption

Sequestration in non-target tissue (fat tissue, adipose, blood)

Biotransformation to active/inactive metabolite

Rate of elimination

32
Q

Toxicokinetics

A

Quantitative modeling of xenobiotic disposition

33
Q

Absorption: 3 key sites

Absorption is the process of movement of a xenobiotic from the external environment into the local interstitial fluid

A

1) Gastrointestinal tract (alimentary system)
- Digestion (breakdown of food)
- Absorption of nutrients
- Water absorption
- Xenobiotics include chemicals (e.g., weak acids/bases, organic) or particulates

2) Lungs (pulmonary system)
- Oxygen absorption
- Xenobiotics include gas, vapors of volatile liquids, aerosols, and particulates

3) Skin (dermis)
- Maintain body temperature
- Prevent dehydration
- Xenobiotics include oils, organic chemicals, venoms

34
Q

Elimination: 4 key sites Plus

A

1) GI tract
- Removal of digestion waste products (feces)

2) Liver (hepatic system)
- Dietary nutrient storage and processing
- Bile production (aids in lipid digestion in the GI tract)

3) Lungs
- C02 elimination

4) Kidneys (renal system)
- Urine production and metabolic waste removal
- Maintenance of blood volume, salt content, pH

Lymphatic system Lymph
- Drainage of fluid with waste from organs
- Returns wastes to blood for elimination via liver/kidneys
- Immune system (lymph nodes)

35
Q

Distribution: Requires the circulatory system

A

Heart

Blood vessels
- Arteries: carry oxygenated blood to tissues
- Veins: carry deoxygenated blood away from tissues
- Capillaries: nutrient/waste exchange in tissues

Blood
- Composed of fluid, protein, and cells
- Distribution of nutrients to tissues (e.g., O2, glucose)
- Removal of metabolic waste from tissues (e.g., CO2, lactate)

36
Q

Disposition of Poisons: Transport Mechanisms - Cell/Membrane barriers

A

Barrier property of cell (plasma) membranes

Cell membranes are lipid bilayers composed of glycerol phospholipids

Cell membranes are semipermeable selectivity barriers

Hydrophobic (does not like water) fatty acid groups efficiently repel hydrophilic molecules

Hydrophilic/polar (likes water) head group can antagonize hydrophobic molecule penetration to some extent

37
Q

​​Two general transport mechanisms across cell barriers

A

1) Passive transport
Simple diffusion
Filtration (between the cell)

2) Specialized transport - charge molecules
Facilitated diffusion
Active transport

38
Q

Passive Transport - Simple diffusion

A

Paracellular diffusion (between the cell)

Transcellular diffusion (through the cell)

Two driving forces work together: Brownian motion
and Concentration gradient

39
Q

Xenobiotic transport depends on two major chemical properties that are unique to each xenobiotic

A

Lipophilicity vs. polarity (hydrophobicity)
- measured by LogP
- low lipophilicity is low log p

Charge (hydrophilicity)
- measured by pKa

Values provide some predictive information regarding type of transportation (paracellular vs. transcellular)

40
Q

Passive Transport (requires water) - Filtration(movement water from blood into the tissue): endothelial cells

A

Occurs in capillary beds of circulatory system

Depends on endothelial cell type/connections

Three types of endothelial cells that line capillary vessels
Continuous: tight junctions (Ex skin, lung, GI, brain)
Discontinuous: no tight junctions (Ex many capillaries)
Fenestrated: holes (Ex kidneys, liver)

Two driving forces
1) Blood pressure: determined by the heart
2) Osmotic pressure: determined by albumin in blood

Filtration is determined by water flowing out of the tissue

41
Q

Facilitated diffusion

A

Driving force is concentration gradient
Requires Solute Carrier (SLC) proteins

Characteristics of SLCs
- Reversible
- Involved in influx/absorption
- Involved in efflux/excretion
- Transport endogenous or xenobiotic molecules
- Molecules transported can be anionic, cationic, or organic in nature

SLCs are a large family of transporter proteins that are classified by substrate transported

42
Q

Specialized - Active Transport: ATP - Binding Cassette transporters (ABC)

A

Transport against a concentration gradient

Driving force is cellular ATP

Types of active transport channels
- Sodium-potassium ATPase
- Sodium-calcium exchanger
- Calcium pumps
- ABC transporters

Are plasma membrane proteins

Split up into Gut, Liver, Kidneys, Brain, Placenta, Testis

ABC transporters hydrozole ATP to get energy

43
Q

Specialized transport - Active Transport: MDR protein

Multidrug-resistant protein (MDR)/P-glycoprotein (P-gp)

A
  • Primarily transports xenobiotics out of cells/tissues/body (efflux/excretion)
  • Endothelial cells “pump” xenobiotics back into blood
  • Target cells pump xenobiotics back into interstitial fluid
  • Performs a protective role by preventing xenobiotic from reaching its target
  • Mice lacking MDR/P-gp had 50-fold increase in accumulation of a substrate xenobiotic in brain
  • The LD50 for a substrate xenobiotic was also decreased >70-fold in mice lacking MDR/P-gp
44
Q

Digestive System: components

A

Gastrointestinal tract (GI) or Alimentary Tract:
- Continuous muscular tube
- Lined by specialized epithelial cell layer connected by tight junctions
- The lumen (inside the tube) is exterior to the body
- Contains commensal/mutualistic microbial flora (microbiome)

Accessory digestive organs:
-Liver/gallbladder: bile
- Pancreas: digestive enzyme/bicarbonate

Subdivision of the GI tract:
- Mouth (intake)/tongue
- Pharynx/esophagus
- Stomach
- Small intestine
- Large intestine (cecum)
- Colon
- Rectum and anus (output)

45
Q

Factors influencing GI absorption - 8

A
  • Gastric (stomach) and enteric (intestinal) mucosa
  • pH of GI lumen (e.g., ionization state)
  • Transit time
  • GI contents
  • Surface area of tubes
  • Blood flow (law of mass action)
  • Microbial biometabolism
  • Bile acids (lipophilic surfactant produced by liver)
46
Q

The stomach: gastric region of GI

A

Gastric mucosal layer: epithelial cell layer of stomach
- Specialized in acid production
- Food stimulates gastrin (hormone) released into the circulation
- Gastrin stimulates secretion of H+ by gastric mucosa cells
- Combines with Cl- in the stomach lumen to form hydrochloric acid (HCl)
- Very low pH (pH between 1 and 2)

Small surface area - Mucosa layer is relative smooth compared to the small intestines

*weak acids is favorable in stomach bc of pka and ph - stomach breaks down proteins which are charged

47
Q

Small Intestines: enteric region of GI

A

Pancreas
- Pancreas is an accessory organ of GI
- Produces bicarbonate buffer and digestive enzymes
- Secretes >1 liter of juice per day into the duodenum of the small intestines (first section after stomach)
- Higher pH above 6

Large surface area
- Enteric mucosal layer are epithelial cells lining the GI
- These cells are specialized in absorption
- Villi structure of wall and microvilli of enterocytes * Increased 600-fold over stomach

*weak bases are more absorbed in small intestine

48
Q

Summary for pH influence on GI absorption

A

Absorption of weak acids is more favorable in stomach

However, absorption of weak acids can occur in the small intestines due to large surface area and the action of transporter proteins

Absorption of weak bases is most favorable in intestines

49
Q

Anatomy of the respiratory tract

A

Upper respiratory tract: nose/mouth, nasal passage, pharynx, trachea

Lower respiratory tract: Lungs
- Bronchi/bronchioles (airways)
- Alveoli (air sacs)

50
Q

Chemical nature of xenobiotics

A

Gases: carbon monoxide, nitrogen dioxide, sulfur dioxide,
ozone, radon

Vapors: volatile liquids such as formaldehyde, chloroform,
and certain anesthetics

Aerosols/particles: water droplets, coal dust, asbestos, smoke

51
Q

Lung Absorption: Gas/vapor

A

Gas/vapor absorption involves partitioning between two phases, atmosphere (gas) and body water (aqueous)
* Diffusion vs. Solubility: diffusion is not rate-limiting
* Limited by physical process of dissolving in aqueous medium (cellular/interstitial fluids and blood plasma)

The partition coefficient is unique trait for a given gas (i.e., chemical constant) - Partition coefficient reflects rate of absorption of gases/vapors
* Low solubility gases: Perfusion-limited gases/vapors
* High solubility gases: Ventilation-limited gases/vapors

52
Q

Lung Absorption: Aerosols/particles

A

Aerosols: xenobiotics dissolved in liquid droplets
Particles: solids dispersed in air (e.g., smoke/smog,
dust/asbestos, plant pollens)

Deposition in the respiratory tract (upper vs. lower) is influenced by size (i.e., diameter) of particles

Mucociliary escalator: alveolar macrophages phagocytose
(“cell eating”) larger particles and transport them to the
upper respiratory tract

Alveolar dust plaques/nodules: alveolar macrophageinduced collagen fiber deposition resulting in long-term
retention of particles in the lower respiratory tract

Efficiency depends on the solubility or dissolution in lung
fluids (i.e., the lower the solubility the longer the retention time) - The more soluble a compound is in the liquid phase, the less time it will spend being carried along by the gas

53
Q

Anatomy of the skin

A

Two major layers of skin: epidermis (outer-most) and dermis (inner)

Stratum corneum
* Semi-solid outer
surface
* Most important barrier
of skin
* Limits absorption of
most xenobiotics and
loss of body water

54
Q

Absorption through stratum corneum: size and lipophilicity

A

Absorption directly through stratum corneum occurs via simple diffusion

Penetration of xenobiotics is proportional to lipophilicity and inversely proportional to molecular weight

Small highly lipophilic xenobiotics (e.g., organic
solvents/oils) may be able to penetrate the stratum corneum readily
- Molecules >400 Da exhibit poor percutaneous
penetration)
- Charged and polar xenobiotics do not penetrate directly
through stratum corneum (however, appendages later)

Absorption of xenobiotics is inversely related to thickness of stratum corneum layer
- Thickness of stratum corneum in various regions of body
surface: Palm > back of hand > forehead > Scrotum

55
Q

Disposition of Poisons: Distribution
Overview

A

Distribution is the systemic movement of xenobiotics within the body away between the site of absorption and target tissue
- Requires the circulatory and lymphatic system
- The rate of distribution is determined by three factors:
1) Blood flow
2) Transport from organ capillary beds into organ interstitial
fluid
3) Affinity for target tissue

Xenobiotics have the potential to distribute to different
compartments of total body water
* Plasma: liquid fraction of unclotted blood after removal of
blood cells
* Interstitial water: extracellular space in organs
* Intracellular water: cytoplasm of cells

56
Q

Sequestration/accumulation of xenobiotics in
tissues

A

Sequestration in compartments can hinder distribution
* Xenobiotics may have an affinity for tissue other than their target organ of toxicity
Sequestered xenobiotics may persist in body for long durations (e.g., years)
* May provide protection by diminishing distribution to
target organ
* May hinder drug therapy by ↓ potency/efficacy
* May be released from sequestered site (delayed toxicity)

57
Q

Four major sites of xenobiotics sequestration:

A

1) Plasma proteins
2) Body fat
3) Keratinized tissue/hair
4) Bone

58
Q

Sequestration/accumulation of xenobiotics in
tissues: Plasma

A

Binding of xenobiotic is reversible
* koff/kon determine the extent to which a xenobiotic is free - k on affinity higher k off affinity lower
KD quantitative measure of binding affinity
The lower the KD, the higher the affinity: kon > koff

Plasma albumin is a receptor for many xenobiotics
Lipophilicity is important chemical determinant of albumin binding affinity
* The high the LogP, the lower the Kd

Albumin is important for filtration

Xenobiotics with higher affinity may outcompete for binding of xenobiotics with lower affinity
Xenobiotic displacement of endogenous factor may cause toxicity

59
Q

Sequestration/accumulation of Xenobiotics in
tissues: Adipose tissue (body fat)

A

Made of adipocytes are fat storing cells in adipose tissue - Body fat is highly lipophilic
Sequestration can occur over long time periods
Reversible: mobilization of fat release xenobiotics

Body fat level is an important factor in xenobiotic sequestration in adipose tissue - the more body fat the more sequestration

60
Q

Sequestration/accumulation of Xenobiotics in
tissues: Keratinized tissue, hair, and fingernails

A

Selective bioaccumulation of xenobiotics
* Arsenic, lead, mercury - bad metals that can accumulate
Can provide a non-invasive biomarker for exposure to certain xenobiotics

61
Q

Sequestration/accumulation of Xenobiotics in
tissues: Bone

A

Made of fibrous matrix of hydroxyapatite - Ca2+ (calcium), PO (phosphate) -, OH (hydroxide)
Bone remodeling is continuously occurring naturally
- Osteoclasts: bone breakdown via osteolysis
- Osteoblasts: bone formation via mineralization
- Osteoporosis: wasting (e.g., long term weightlessness)

Sequestration of xenobiotics in bone tissue
* Storage is can be long-term and reversible
* Bone breakdown (resorption) can release sequestered
xenobiotics
* Exchange occurs at the bone interface

Xenobiotics in bone lead (Pb) and fluoride (F)
- lead can be toxic under certain conditions
- fluoride can be directly toxic

62
Q

Central nervous system: Blood Brain Barrier

A

CNS - brain, spinal cord, retina
BBB - Specialized endothelial cells, Continuous form of endothelial layer, Linked by tight junctions between cells, Maintains the interstitial ionic environment

No paracellular transport - no filtration occurs in brain
Dyes (very small molecules) penetrate the interstitial space of most tissues except the brain/spinal cord

Electrical resistance: measure of leakiness of endothelium

Partitioning of xenobiotics into brain
* Increases with increased lipid solubility
* Decreases with ionization/polarity

To get into the brain needs simple diffusion or solute carrier protiens - lipophilicity is important

ABC transporters
* Lumenal side of the endothelium
* Extrude xenobiotics (even those with high lipophilicity)
The BBB is a serious limitation on efficacy drug therapies for treatment of CNS maladies

63
Q

Why is diffusion of gases not rate limiting in the lungs?

A

Once a gas is dissolved in the liquid phase of the lungs, it can move by diffusion down its concentration gradient. However, it must be soluble in the liquid phase first. This is why solubility is rate limiting.

For a gas with low solubility in liquid, the concentration gradient will not be very strong because the concentration difference between the gas phase and liquid phase is small. This is why low solubility gases depend on blood perfusion, which carries what does dissolve away from the lungs. This will maintain the small concentration gradient so the gas can continue to dissolve in the liquid. Thus gases with low solubility are perfusion-limited.

64
Q

Does transcellular transport occur in the GI tract?

A

Paracellular transport is not possible through the epithelial cell barrier (and some endothelial cell barriers) because of the tight junctions between the cells. In other words, filtration is not an option. Of course, highly lipophilic xenobiotics can pass through the epithelial cell barrier by transcellular transport down their concentration gradient. On the other hand, xenobiotics with low lipophilicity (low solubility in the organic phase of the membrane) can still pass through these barriers via transcellular transport but require protein transports to do so. The GI tract epithelial cell layer possess these solute carrier proteins to aid in the transcellular transport of xenobiotics (and nutrients) with low lipophilicity.

65
Q

The concept of gas solubility

A

The more soluble the gas in the liquid the higher concentration of gas there is in the lungs are ventilation limited

Less soluble needs high perfusion rate (blood flow) for the gas to continue to be absorbed

The coefficient of solubility of gases is expressed as the ratio of the concentration of the gas in liquid (i.e. blood) divided by the concentration of gas in air [liquid phase]/[gas phase]. The greater the ratio (i.e., >1), the more soluble the gas is in liquid, and the higher the concentration of gas in the lung tissue (i.e., saturation of the tissue occurs at a much higher concentration of gas than lower solubility gases). Such gases are ventilation limited (i.e., how much is absorbed depends on how fast we can breathe in the gas). On the other hand, the lower the ratio (e.g., <1), the less soluble the gas is in liquid. In this case, saturation of the tissue will occur at a low concentration and prevent further increases in the concentration in the tissue. The lower the solubility the gas, the lower the tissue concentration will be when this occurs. Such gases will require a high perfusion rate (blood flow) for the gas to continue to be absorbed because the blood will carry the absorbed gas away maintaining a low tissue concentration (i.e., reduce the possibility of saturation).

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