toxicologi materi
TRANSCRIPT
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Copyright 2008, The Johns Hopkins University and Michael A. Trush. All rights reserved. Use of these materials
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Absorption, Distribution,
and ExcretionMichael A. Trush, PhD
Bloomberg School of Public Health
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Section A
The Toxicological Process
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Definition
Toxicology is the study of poisons
Poisons are chemical/physical agents thatproduce adverse responses in biological
organisms
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What is there that
is not poison? All
things are poisonand nothing without
poison. Solely, thedose determines
that a thing is not
a poisonParacelsus (1493-1541)
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The Toxicological Paradigm
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Toxicokinetics Toxicokinetics is the quantitation of the time course of
toxicants in the body during the processes of
absorption, distribution, biotransformation, andexcretion or clearance of toxicants. In other words,toxicokinetics is a reflection of how the body handlestoxicants as indicated by the plasma concentration of
that xenobiotic at various time points
The end result of these toxicokinetic processes is abiologically effective dose of the toxicant.
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Toxicodynamics
Toxicodynamics refers to the molecular, biochemical, andphysiological effects of toxicants or their metabolites inbiological systems
These effects are result of the interaction of thebiologically effective dose of the ultimate (active) form of
the toxicant with a molecular target
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Molecular Targets Concept
The toxic action of a chemical is a consequence of thephysical/chemical interaction of the active form of thatchemical with a molecular target within the livingorganism
Continued
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Molecular Targets Concept
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Examples of Molecular Targets
Proteins
Arylhydrocarbon(Ah) receptorDioxin
HemoglobinCO
LipidsCarbon tetrachloride
DNAAflatoxin
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Dose-Response Concept
The magnitude of the toxic effect will be a function of theconcentration of altered molecular targets, which in turnis related to the concentration of the active form of thetoxicant( biologically effective dose) at the site where themolecular targets are located.
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The Toxicological Process
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The Toxicological Process
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Section B
Transport Process Mechanisms
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Membrane Transport
of Xenobiotics
The absorption, distribution, and excretion of xenobioticsinvolves passing through various cell and organmembranes.
This occurs through various transport mechanisms
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Membrane Transport
of Xenobiotics
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Xenobiotics:
Transport Mechanisms Factors affecting membrane transport of chemicals:
Molecular weight/shape
Charge
Lipid solubility
Membrane composition
Membrane thickness
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Types of Transport
Simple diffusion
Facilitated diffusion Active transport
Pinocytosis/receptor-mediated uptake
Filtration
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Types of Transport
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Characteristics of
Simple Diffusion Transport proceeds in the direction of the electrochemical
potential (concentration) gradient
Transport is not saturable at high concentration gradients
No structural specificity
No energy requirement Inherently symmetrical transport
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BOTH PASSIVE MEDIATED and
ACTIVE MEDIATED TRANSPORTINVOLVE the USE of CARRIER
PROTEINS
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Carrier-Mediated Transport
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Characteristics of
Passive Mediated Transport Transport proceeds in the direction of the electrochemical
potential (concentration) gradient
The process is saturable at high concentration gradients,i.e., there is a maximum rate of transport
Continued
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Characteristics of
Passive Mediated Transport Structural specificity (specific inhibitors)
No energy requirements Inherently symmetrical transport
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Characteristics of
Active Mediated Transport Transport can proceed against an electrochemical
potential (concentration) gradient
The process is saturable at high concentration gradients
Structural specificity
Requires cellular energy Asymmetrical transport
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Active Mediated Transport
The structure of the herbicide paraquat (A) and thepolyamines putrescine (B) and spermine (C)
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Pinocytosis/Phagocytosis/
Receptor Mediated Endocytosis
cell membrane
PINOCY
TOSIS
Pinocytic vessels
PHAGOCYTOSIS
pseudopods
Pinocytosis
chan
nel
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Filtration
Transport of solutes as a consequence of
bulk flow of fluid (aqueous) phase Glomerulus of kidney is a good example of
site where filtration occurs
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Section C
Toxicokinetics
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Systemic Kinetics: Outline
Physiological basis of toxicokinetics
Biliary excretion route for foreign compounds
Barriers
Major difference between a general (non-neural) and
brain capillary Excretion pathways
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Biliary Excretion Route For Foreign
Compounds
Image source: NIH/NIDDK. Public Domain.
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Systemic Kinetics: Barriers
Blood-brain barrier
Placenta Blood-testicular barrier
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Major Difference between a General
(Non-Neural) and a Brain Capillary
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Excretion Pathways
Respiratory excretion
Mucocilliary clearance Gastrointestinal excretion
Biliary excretion Entero-hepatic circulation Urinary excretion
Glomerular filtration Trans-tubular secretion
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Afferent arteriole
Efferent arteriole
Glomerulus
Bowmans capsule
Proximal tubule Water soluble
Lipid soluble
Filtered drugPassive
reabsorption
Excretion and/or further passive reabsorption
Unfiltered drug
Active
secretion
Renal Excretion of Chemicals
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Other Routes of Excretion
Milk
Sweat Hair
Nails Saliva
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Biological Half Life
The biological half-life(T1/2) is the time
required for some measure of the amountof a chemical in the body (for example,body burden, tissue concentration) todecrease to 1/2 its value at the beginningof the observational interval
Continued
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Section D
Toxicokinetics and PBK Modeling
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PBPK Modeling
Physiologically Based Pharmacokinetic (Toxicokinetic)
Purpose
To mathematically model how asubstance is absorbed, distributed, andmetabolized in the body to reduceuncertainties in determining theestimated dose
PBPK M d li
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PBPK Modeling
Source: Casarett & Doull, Chaps. 5 and 7, 1996 Continued
Tox, lec 1, slide 6
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PBPK M d li
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PBPK ModelingBlood Styrene Levels: Rat vs. Human
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Vinyl Chloride Metabolism
Covalent binding to proteins
H
C
C
H
Cl
H
O
Chloroacetaldehyde
GSH conjugation
P450
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Vinyl Chloride Exposure, Metabolism in Rats& the Incidence of Hepatic Angiosarcoma
Exposure g of VC per L of air g of VC metabolized/4 hr Incidence %
50 128 739 2
250 640 2435 7
500 1,280 3413 12
2,500 6,400 5030 22
6,000 15,360 5003 22
10,000 25,600 5521 15