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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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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


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


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

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