Binding to a plasma protein might _______ toxicity and _______ half-life.

decrease; increase

Nitroglycerin is a drug that is used to treat angina (chest pain). When administered orally, it has poor bioavailability and thus it is typically administered sublingually (under the tongue). What is bioavailability and how might this route administration affect the bioavailability of nitroglycerin?

Bioavailability describes the proportion of a substance that is absorbed into the blood, and drugs that are ingested may have lower bioavailability due to the first-pass effect. If nitroglycerin is delivered sublingually it bypasses first-pass metabolism.

Explain why it is dangerous to take NSAIDS and ACE-inhibitors at the same time.

Certainly! Let’s delve into the intricate details of how NSAIDs (nonsteroidal anti-inflammatory drugs) and ACE inhibitors impact renal function, specifically focusing on the efferent and afferent arterioles.

1. Efferent and Afferent Arterioles:
   • The kidneys have specialized blood vessels called arterioles that play a crucial role in regulating blood flow within the glomerulus (the filtering unit of the kidney).
   • The afferent arteriole supplies blood to the glomerulus, allowing it to be filtered.
   • The efferent arteriole carries blood away from the glomerulus after filtration.
2. Angiotensin II and Its Effects:
   • Angiotensin II is a hormone that constricts blood vessels and plays a central role in blood pressure regulation.
   • In the kidney, angiotensin II constricts both the afferent and efferent arterioles.
   • However, it preferentially increases efferent resistance ¹.
   • Why? Here are some factors:
     • The efferent arteriole has a smaller diameter initially, so further constriction at this site leads to a greater increase in resistance compared to the afferent arteriole.
     • Angiotensin II stimulates the release of nitric oxide from the afferent arteriole, minimizing constriction at that site.
     • Angiotensin II also minimizes vasoconstriction at the afferent arteriole via angiotensin II type 2 receptors, resulting in vasodilation¹.
3. ACE Inhibitors and Efferent Arterioles:
   • ACE inhibitors (angiotensin-converting enzyme inhibitors) block the conversion of angiotensin I to angiotensin II.
   • By doing so, they reduce the production of angiotensin II.
   • As a consequence, efferent arteriolar vasoconstriction is inhibited.
   • This helps maintain or even raise the glomerular filtration rate (GFR) by stabilizing or increasing intraglomerular pressure².
4. NSAIDs and Afferent Arterioles:
   • NSAIDs inhibit the synthesis of prostaglandins.
   • Prostaglandins play a protective role in the kidney by dilating the afferent arteriole.
   • When NSAIDs are taken, they reduce the ability of the afferent arteriole to dilate.
   • Consequently, intraglomerular pressure decreases, potentially leading to ischemia and acute renal failure³.
5. Clinical Implications:
   • Understanding these mechanisms is crucial for healthcare professionals.
   • On tests, pay attention to:
     • Which drug impacts prostaglandins (NSAIDs) and which impacts angiotensin II (ACE inhibitors).
     • The specific effects on efferent and afferent arterioles.
     • How these alterations influence glomerular filtration and renal function.

Remember, the kidneys are intricate organs, and maintaining their delicate balance is essential for overall health.

Toxicology

Is the study of the adverse effects of chemical on living organisms

is the branch of science concerned with the nature effects and detection of poisons

Ebers Papyrus

oldest medical toxicologist documented

20th century is

where toxicology become a real thing

Paracelsus

made important improvements on dosages

Ebers Papyrus

One of the oldest known writings (1500 B.C.)

Contains information on many recognized poisons

Bioavailability

• In pharmacology, bioavailability refers to the percentage of an administered drug that reaches the systemic circulation.
• When a medication is administered intravenously, its bioavailability is 100% because it directly enters the bloodstream.
• However, when a medication is administered via other routes (such as oral ingestion), its bioavailability is lower due to factors like intestinal absorption and first-pass metabolism.
• Mathematically, bioavailability is expressed as the ratio of the area under the plasma drug concentration curve (AUC) for the extravascular formulation (e.g., oral) to the AUC for the intravascular formulation (e.g., intravenous).

Overdose

An overdose occurs when you take more than the recommended amount of something, often a medicine or drug. It can result in serious, harmful symptoms or even death. If you intentionally take too much of something, it is called an intentional or deliberate overdose ¹. In simpler terms, it’s like going beyond the safety limit and facing potentially severe consequences.

De Materia Medica

first book to talk about plant reproduction and plant poisons

Bioavailability

How much is actively poisoning you

Rapidity of the toxic response

onset of action

The effectiveness of the compound

potency

The degree of response of the parts of the body

specificity site of action

Complaints of victims

clinical signs and symptoms

Paracelsus

Dose makes the poison

published on the miners sickness and other disease of miners

Absorption

1. In Pharmacology:
   • Absorption refers to the process of assimilating substances across the intestinal epithelial cells or other tissues and organs.
   • It occurs through active or passive transport.
   • Absorption follows the digestion process and never precedes it.
   • For example, when you ingest a medication orally, its absorption occurs as it passes through the intestinal wall into the bloodstream or lymphatic system1.

Distribution

1. Distribution Process:
   • Distribution refers to how an absorbed chemical moves away from the site of absorption to other areas of the body.
   • After absorption (whether through the skin, lungs, or gastrointestinal tract), the toxicant enters the interstitial fluid.
   • From there, it can be distributed to various compartments within the body.

first scientific journal dedicated to toxicology

Archiv Fur Toxikologie

Mechanism of toxicology

identifies the cellular, biochemical, and molecular
mechanisms by which chemicals exert toxic effects on living organisms.

Descriptive toxicology:

direct toxicity testing which provides information for
safety evaluation and regulatory requirements

Regulatory toxicology:

deciding if (based on mechanistic and descriptive
toxicology data) a drug or another chemical has a low enough risk to be
marketed

• Forensic toxicology

focuses on the medicolegal aspects of the harmful effects
of chemicals

Clinical toxicology:

study of diseases caused by or uniquely associated with toxic
substances

Environmental toxicology:

focuses on the impacts of chemical pollutants in the
environment on biological organisms, mainly focused on nonhuman organisms.
Ecotoxicology: focuses on the impact of toxins on population dynamics in an
ecosystem

Developmental toxicology

the study of how exposure to chemicals before
conception, during prenatal development, or postnatally until the time of
puberty causes adverse effects on development. Teratology is the study of
defects in development between conception and birth

Reproductive toxicology:

the study of what happens to the male or female
reproductive system as a result of exposure to chemicals or physical agents

Toxicogenomics:

looks at the interaction between genes and toxicants in toxicity etiology

Transcriptomics

gene expression

Proteomics

protein expression

Metabolomics

small molecule metabolism and functions

Potential questions asked in toxicogenomics

How does a chemical affect genomic DNA, mRNA, or other RNAs?
• How does a chemical change epigenetics (methylation, acetylation, etc.)?
• How does a chemical influence gene expression?

Poison

any agent capable of producing a deleterious response in a biological
system

Toxic agents can be classified by their

physical state, chemical stability or
reactivity, general chemical structure, or poisoning potential

Toxin

toxic substances produced by biological systems

Toxicants

toxic substances that are a product of human activities

Lethal dose 50: LD50

The dose needed to produce death in 50% of
treated animals (short-term exposure dose)

Side effects that are always deleterious to humans are referred to

adverse, deleterious, or toxic effects of the drugs

• Chemical allergens:

an adverse immune response to a chemical (usually due to
previous exposure)

Chemical idiosyncrasy:

genetically related abnormal reactivity to a chemical

Delayed toxicity:

most toxic effects occur rapidly after a single administration of
a substance, but some can have delayed toxic effects. Example: carcinogens,
cancer 20-30 years after exposure

Site of action:

Local (place of initial contact) vs systemic toxicity. Target organs

Tolerance

prior exposure = decreased responsiveness to a toxic effect

Additive

2+2=4

Synergistic

combined effect of chemicals is much greater 2+2=20

Potentiation

0+2=10 one chemical doesn't do anything but can if something is mixed within it

Example: Isopropanol and carbon tetrachloride

Functional Antagonism

counter balance. opposite effects. 4+(-4) = 0

Chemical antagonism

Chemical reaction between two toxins that produce a less toxic effect

Dispositional antagonism

About how interference with absorption happens. Biotransformation. distribution. excretion

Receptor antagonism

Two chemicals bind at the same receptor chemical binds receptor

Major routes of exposure

Gastrointestinal tract (ingestion)
• Lungs (inhalation)
• Skin (topical, percutaneous, or dermal)

Acute

Usually single administration (or within 24 hours

Subacute

repeated exposure for 1 month or less

Subchronic

repeated exposure for 1-3 months

Chronic

more than 3 months

What does line A represent?

a chemical with very slow
elimination

What does line B represent?

A chemical with a rate of
elimination equal to its dosing

What does line C represent?

Rate of elimination faster than its
dosing frequency

What does the purple shading mean

the concentration of the
chemical that elicits a toxic response

Individual refers to

an individual organism

Quantal refers to

a population of organisms

• Individual dose-response relationship:

which describes the response of an individual organism to
varying doses of a chemical, often referred to as a "graded" response because the measured effect
is continuous over a range of doses

Quantal dose-response relationships:

all or none
• An individual in a population of organisms is
classified as either a responder or nonresponder

Effective dose (ED) is a

statistical
approach for estimating a population’s
response to a toxic exposure
• ED50 = 50% response level

similar ED 50 btu could have different dosage effects overall (range of error)

Assumptions in deriving the dose-response relationship

The response is due to the administered chemical (cause-and-effect
relationship)
2. The magnitude of the response is related to the dose
3. There is a quantifiable method of measuring and a precise means of
expressing toxicity
a) This means a given chemical could have multiple dose-response
relationships for different effects

TD

Toxic dose

LD

Lethal dose

ED

Effective dose

Therapeutic index (TI):

ratio of the dose for a toxic effect and dose needed to elicit a
therapeutic response

TI =TD50/ED50

ED50 = 50% response level of the effective dose

TD50= toxic dose is 50% of population

Chemical A is _______ potent than B
• Chemical C is _______ potent than D

More and more

Maximal Efficacy
• Chemicals A and B
• Chemicals C and D

Chemicals A and B = same

Chemicals C and D = c has a lower maximal efficiency then d

Selective toxicity

a chemical produces injury to one kind of living
matter without harming a different form of life.

• A lot of toxicity studies rely of experimental results being

applicable to humans, BUT responses can have qualitative and quantitative differences

Acute toxicity testing:

Daily examination of animals→ could watch for signs of
intoxication, lethargy, behavioral modifications, and number of animals that die over a set period

LD50 determined using 1+ routes of exposure and 1+ species
• Identify target organs and other clinical manifestations
• Identify species differences and susceptible species
• Establish the reversibility of toxic response
• Provide dose-ranging guidance for other studies

Subacute

monitoring effects of repeated doses, typically over a period of 14
days (used as an aid to establish doses for subchronic studies

Subchronic

Usually lasts at least 90 days. One of the main goals is to establish the lowest observed adverse effect (LOAEL) or the no observed adverse effect (NOAEL)

Chronic

6 months- 2 years, done similarly to subchronic tests. One of the main goals is often to evaluate potential oncogenicity

idiosyncratic reactions,

• diosyncratic reactions refer to unpredictable and unusual responses to a substance.
• These reactions occur rarely and are not dose-dependent.
• They are not related to the pharmacological action of the substance.
• Examples include severe allergic responses or unexpected adverse effects in specific individuals.

reversible vs irreversible toxic effects

• Reversible effects occur when the toxic effect disappears after exposure ends.
  • These effects are often associated with low doses or short-term exposure.
  • For instance, binge drinking of ethanol for one night or weekend.
• Irreversible effects persist or worsen even after exposure ceases.
  • These effects are usually associated with long-term and high-dose exposure.
  • Examples include carcinomas, teratogenic effects (in offspring), neuronal damage, and liver cirrhosis (common in alcoholics).

local vs systemic effects

• Local effects occur at the site of contact with the toxic substance.
  • Examples include injuries from strong acids or skin irritation caused by corrosive chemicals.
  • Inhaled toxic gases can also cause local effects in the respiratory tract.
• Systemic effects occur after the toxicant has been absorbed and distributed throughout the body.
  • The toxicant enters the systemic circulation and affects various organs and tissues.
  • Target organs may not always have the highest concentration of the toxicant.

LD50

• The LD50 represents the dose of a substance (usually a drug or chemical) that is lethal to 50% of the population exposed to it.

ED50

• The ED50 represents the dose of a drug that produces a therapeutic effect in 50% of the population.

potency

• Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of its maximal effect.

maximal efficacy

• Efficacy (also known as maximal efficacy) represents the maximum effect that can be expected from a drug.

• Differentiate between individual and quantal dose-response relationships and understand their graphical representation

Certainly! Let’s explore the differences between individual dose-response relationships and quantal dose-response relationships, along with their graphical representations:

1. Individual Dose-Response Relationships:
   • Individual dose-response relationships focus on the graded response of an individual to varying doses of a drug or substance.
   • These relationships are continuous and represent the effect of different doses on a specific individual.
   • The response can be measured on a graded scale, such as blood pressure, pain relief, or enzyme activity.
   • Graphically, an individual dose-response curve shows how the response changes with increasing doses of the drug.
   • The x-axis represents the dose (usually in logarithmic scale), and the y-axis represents the graded response (e.g., pain relief score, enzyme activity level).
   • The curve may exhibit features like potency, maximal efficacy, and slope ¹.
2. Quantal Dose-Response Relationships:
   • Quantal dose-response relationships focus on the binary outcome (either present or absent) in a population exposed to varying doses of a drug.
   • These relationships are discrete and represent the rate of occurrence of a specific effect (e.g., toxicity, adverse event) in a group of individuals.
   • The response is typically categorized as either responders (those who exhibit the effect) or non-responders (those who do not).
   • Graphically, a quantal dose-response curve shows the percentage of responders at different doses.
   • The x-axis represents the dose, and the y-axis represents the percentage of responders.
   • The curve may exhibit features like the median effective dose (ED50), which represents the dose at which 50% of the population responds².
3. Graphical Representations:
   • Graded Dose-Response Curve:
     • !Graded Dose-Response Curve
     • This curve depicts the graded response (e.g., pain relief) as the dose increases.
     • It shows the potency, maximal efficacy, and slope of the drug’s effect.
   • Quantal Dose-Response Curve:
     • !Quantal Dose-Response Curve
     • This curve represents the percentage of responders in a population.
     • The ED50 (dose at which 50% respond) is a key point on this curve.

In summary, individual dose-response relationships focus on an individual’s graded response, while quantal dose-response relationships analyze binary outcomes in a population. Both provide valuable insights for drug dosing and safety considerations.

Ultimate toxicant

could be original chemical or
a molecule generated during biotransformation
of the toxicant

Absorption

the transfer of a chemical from the site of exposure into the
systemic circulation (blood)
• Sometimes there are transporters
• Most chemicals go through epithelial barriers via diffusion

Factors that influence absorption:

Surface area of exposure
• The characteristics of the epithelial layer where the toxic substance is being absorbed
• Lipid solubility

Presystemic elimination:

during transfer to systemic circulation
• Example: GI track

•Distribution:

exit blood and reach site(s) of action

Mechanism facilitating distribution to a target

Porosity of the capillary endothelium
• Specialized transport across plasma membranes
• Accumulation in cell organelles
• Reversible intracellular binding

• Mechanisms opposing distribution to a target

• Specialized barriers
• Distribution to storage sites
• Association with intracellular binding proteins (nontarget)
• Export from the cell membrane

Excretion

removal of the xenobiotic from the blood
• Major excretory organs: kidney and liver
• Note excretion is a physical mechanism, biotransformation is a chemical mechanism for
eliminating toxic substance

Reabsorption

Toxic chemicals are filtered and then reenter into the blood
through diffusion
• Example: toxicants delivered to the GI tract by biliary, gastric, and intestinal excretion can be
reabsorbed by diffusion across intestinal mucosa
• Dependent on lipid solubility (harder to get rid of fat soluble because they absorb easily)

Biotransformation

the biochemical modification of a chemical compound

Toxication (or metabolic activation):

Biotransformation to harmful products
• Conversion into electrophiles, free radicals, nucleophiles, or redox-active reactants

Detoxication

biotransformation that eliminate the toxicant
• Detoxication of toxicants with no functional groups, nucleophiles, electrophiles, free radicals,
protein toxins

Most common targets:

nucleic acids (especially DNA), proteins, and membranes

The toxicant reacts with the target and adversely affects its function
• Reaction types:

non covalent, covalent interactions, hydrogen abstraction, redox reactions, enzymatic reactions

The toxicant reaches effective concentrations at the

target site

The toxicant alters the target in a way that is mechanistically

related to observed toxicity

Molecular repair

Repairing proteins (molecular chaperones, other enzymes, or mark for degradation if beyond repair)
• Lipids
• DNA (direct repair of covalent modification by enzymes, excision repair, nonhomologous end
joining)

Cellular repair

• Autophagy→ removing and degrading damaged cellular components like organelles
• Regeneration of damaged axons

Tissue repair

Apoptosis and regeneration (replacement of cells and extracellular matrix)

Adaptation

A harm-induced capability
of an organism for increased tolerance to
the harm itself
• Decrease delivery of toxicant to target
• Decreased susceptibility of the target
• Increased capacity for repair
• Strengthened mechanisms to compensate for
toxicant-induced afflictions

Examples of toxicity resulting from inappropriate repair and
adaptation

Tissue necrosis (tissue cell death—injury overwhelms/disables repair
mechanisms)
• Fibrosis (excess extracellular matrix deposition with abnormal composition)
• Carcinogenesis
• Failure of DNA repair, failure of apoptosis, or failure to terminate cell proliferation

Delivery

Delivery in relation to toxicology encompasses several critical aspects. Let’s explore them:

1. Forensic Toxicology and Criminal Justice Delivery:
   • Forensic toxicology involves the study of poisons and their effects on biological systems, especially in the context of legal and criminal investigations.
   • It plays a crucial role in criminal justice delivery by providing evidence related to toxic substances.
   • Forensic toxicologists analyze biological samples (such as blood, urine, or tissues) to detect drugs, toxins, or chemicals.
   • Their findings are used in court proceedings to establish whether a substance contributed to an individual’s health condition or death¹.
2. Post-Mortem Investigations:
   • Forensic toxicology is applied in post-mortem examinations to determine if excessive drug intake occurred and whether it played a role in a person’s demise.
   • Toxicologists identify substances in tissues and assess their impact on the deceased individual.
   • This information aids in understanding the cause of death and may have legal implications.
3. Environmental Toxicology and Public Health Delivery:
   • Toxicology also extends to environmental health.
   • It helps assess the impact of pollutants, chemicals, and hazardous substances on ecosystems, wildlife, and human populations.
   • By understanding toxic effects, regulatory agencies can develop policies and programs to limit exposure and prevent negative health outcomes².
4. Risk Assessment and Safety Delivery:
   • Toxicologists evaluate the risks associated with exposure to various substances.
   • They assess safe exposure levels, establish guidelines, and recommend safety measures.
   • This information is crucial for public health delivery, ensuring that individuals are protected from harmful substances.

In summary, toxicology plays a vital role in delivering justice, safeguarding public health, and understanding the impact of toxic substances on individuals and the environment.

Toxicokinetics

the quantitative study of absorption, distribution,
metabolism (biotransformation), and elimination

Some factors that affect the rate of absorption

How easily a toxic substance can cross a membrane (lipophilic? Uses a transporter? Ionized [pH
dependent])
• Route of exposure

Facilitated diffusion:

down the
concentration/electrochemical gradient.
Doesn’t require energy (some molecules like
glucose and amino acids can cross
membranes like this)

Active transport

against a gradient, selective
for certain chemical features, expends energy

Most toxicants cross membranes by

simple diffusion

Getting to the brain

Must cross the blood brain barrier
• Must cross the blood-cerebrospinal fluid barrier

Placental barrier

Numerous cell layers (~6) between fetal and maternal circulations that have different
transport proteins that may help protect the fetus from some xenobiotics

Route of exposure and absorption

Gastrointestinal tract
• Lungs
• Skin
• Other routes

How is Absorption measured?

• Level of chemicals in blood, urine, tissues
• Environmental tests-sample taken from surrounding media for fish, worms, shell-fish
• Computational modeling: QSAR-BCF: Bio-Concentration Factor –could be estimated in EpiSuite
• Radiolabeling monitoring 3H and 14C---generally considered as unequivoqually proof

Distribution

(going from the bloodstream throughout the body)

Volume of distribution (Vd):

the apparent volume of a biological fluid the
xenobiotic is diluted into

Storage sites include:

liver, kidney, fat, bone, and plasma protein

Distribution and plasma proteins as a storage depot

Some xenobiotics bind to plasma
proteins
• Once bound, they cannot cross capillary
walls (high molecular weight)
• This means there is less toxicant
immediately available for distribution
(usually these interactions are
reversible)
• Toxicity is typically only the result of
unbound xenobiotics

Elimination

Excretion
• Urinary excretion
• Fecal excretion
• Exhalation
• Cerebrospinal fluid
• Milk
• Sweat and Saliva

Toxicokinetics

the quantitative study of absorption, distribution,
metabolism (biotransformation), and elimination

If F < 1 then

then less than 100% of the administered dose reaches systemic
circulation

Most toxic substances aren’t delivered intravenously, and Bioavailability (F) describes

the extent of absorption (or the proportion of toxicant that enters
circulation)

Volume of Distribution (Vd):

the apparent volume of a biological fluid the
xenobiotic is diluted into
• Usually expressed in mL or L of blood, plasma, or plasma water

Clearance (CL):

the apparent volume of physiological fluid that is cleaned of a
toxicant per unit of time (i.e. mL/min)
• High clearance values = efficient and generally rapid removal of chemicals from
systemic circulation

The elimination rate constant (Kel) represents

the fraction of the amount of a
chemical that is removed from systemic circulation per unit of time.
• This is equivalent to elimination via clearance mechanisms over the volume distribution
(CL/Vd)
• So if CL= 10 L/hr and Vd = 100 L, then what is Kel?

10 L/Hr /100 L = 0.1 per hour

Because the percent of elimination over a given period of time is constant, it is more common to refer to an

elimination half-life (t1/2): the time it takes for the concentration
to reduce by 1/2

Cl= 10 Vd = 100

(0.693 * 100 )/10 = 6.93 hours

Toxicokinetics

the quantitative study of absorption, distribution,
metabolism (biotransformation), and elimination

Classic model:

chemicals move through the body as if there were
one or more compartments that have no apparent physiologic or
anatomical reality

Physiologic toxicokinetic models:

attempt to portray the body as an elaborate system of discrete tissue or organ compartments that are interconnected via circulatory system

Know how plasma proteins affect xenobiotic distribution

Certainly! Let’s explore how plasma proteins impact the distribution of xenobiotics (foreign substances, such as drugs or toxins) within the body:

1. Plasma Proteins and Xenobiotics:
   • In the bloodstream, xenobiotics can interact with various plasma proteins.
   • The most significant protein involved is albumin.
   • Albumin has high binding affinity for many xenobiotics due to its large size and hydrophobic pockets.
   • When xenobiotics encounter albumin, they can bind reversibly to it.
2. Effects of Plasma Protein Binding:
   • Reduced Free Concentration: When xenobiotics bind to plasma proteins, their free (unbound) concentration decreases.
   • Equilibrium: The non-bound (free) portion of xenobiotics is in equilibrium with the bound portion.
   • Buffering Effect: Plasma proteins act as a buffer, preventing sudden changes in xenobiotic concentration.
   • Transport: Bound xenobiotics can be transported throughout the body by the bloodstream.
3. Clinical Implications:
   • Altered Distribution: Plasma protein binding affects the distribution of xenobiotics to various tissues.
   • Competition: Different xenobiotics may compete for binding sites on plasma proteins.
   • Drug Interactions: Co-administration of drugs that bind to the same protein can lead to drug interactions.
   • Toxicity: If a xenobiotic is highly bound to plasma proteins, it may have limited access to target tissues (e.g., the brain), affecting its therapeutic or toxic effects.
4. Volume of Distribution (Vd):
   • The volume of distribution (Vd) describes how a drug or xenobiotic distributes within the body.
   • It considers both the free and bound fractions.
   • Standard values for a typical adult are:
     • Plasma volume = 3 liters
     • Extracellular fluid volume = 12 liters
     • Total body water = 41 liters

In summary, plasma proteins play a crucial role in determining the distribution of xenobiotics, affecting their availability to target tissues and potential toxic effects.

Distinguish between classic and physiologic toxicokinetic models

Certainly! Let’s delve into the differences between classic and physiologically based toxicokinetic (PBTK) models:

1. Classic Toxicokinetic Models:
   • Description: Classic toxicokinetic models describe the time- and dose-dependent processes of absorption, distribution, and elimination of a chemical substance and its metabolites in animals and humans.
   • Characteristics:
     • Compartmental: These models represent the organism as a set of compartments, each characterized physiologically or empirically.
     • Mathematical Functions: They rely on mathematical functions to fit concentration-time data and predict concentration-time courses of the parent chemical and metabolites, typically in blood or plasma.
     • Applications: Classic models are used for both repeated and continuous exposures.
     • Limitations: They do not account for detailed physiological and anatomical variations.
   • Examples:
     • One-Compartment Open Model: Describes concentration-time courses using a single compartment.
     • Two-Compartment Open Model: Incorporates two compartments to better represent distribution and elimination processes.
2. Physiologically Based Toxicokinetic (PBTK) Models:
   • Description: PBTK models quantitatively describe the absorption, distribution, metabolism, and excretion of chemicals across various exposure routes and doses in organisms.
   • Characteristics:
     • Physiological and Anatomical Data: PBTK models require detailed physiological, anatomical, physicochemical, and biochemical data.
     • Tissue-Specific Predictions: Unlike classic models, PBTK models can predict concentration-time courses in various tissues and organs.
     • Realistic Representation: They consider interspecies scaling and account for individual variability.
     • Applications: Widely used in toxicology studies and risk assessment.
   • Advantages:
     • Precision: PBTK models provide a more realistic representation of chemical behavior.
     • Predictive Power: They enable predictions beyond blood or plasma concentrations.
     • Customization: Can be tailored to specific chemicals and exposure scenarios.

In summary, classic models are simpler but lack physiological detail, while PBTK models offer a more comprehensive understanding of toxicokinetics by incorporating anatomical and physiological complexities^{1 2 3 4}.

The liver is the main organ facilitating

metabolic homeostasis
• Process/ delivery of nutrients absorbed
in the intestinal tract

The liver is the main organ where

exogenous chemicals are
metabolized for eventual excretion
into bile

Dual blood supply:

Heaptic artery from:

hepatic portal vein from:

Heart: (supplies oxygen rich
blood to the liver)

stomach and
small intestines

Steatosis

Fatty liver→ increased lipid content in liver cells
• Most common cause is insulin resistance, some toxicants (i.e. carbon tetrachloride, valproic acid)
• Bile duct damage
• Inflammation

Fibrosis

scaring when chronic liver injury overwhelms the capacity of the organ to repair

Liver cancers come from

chronic abuse of alcohol, androgens, and aflatoxin-contaminated diets

Some of the functions of the kidney

Filter blood and produce urine
• Excretion of metabolic wastes
• Synthesis of renin and erythropoietin
• Regulation of extracellular fluid volume,
electrolyte composition, and acid-base
balance
• Transport, accumulation, and
biotransformation of xenobiotics

Why are kidneys susceptible to toxicity?

Kidneys receive 20-25% of cardiac
output

how does blood flow trough the Glomerulus

• Blood enters via the afferent arteriole
• Blood flows exits via the efferent
arteriole
• Together the afferent and efferent
arterioles control pressure and plasma
flow rate

egulating factors of
the blood flow

Angiotensin II: vasoconstrictor effect on
efferent arteriole
• Prostaglandins: vasodilation of afferent
arteriole

Example of kidney toxicity: NSAIDS

Nonsteroidal Anti-Inflammatory
Drugs (NSAIDS): relieve pain, reduce
inflammation
• NSAIDS block the production of
prostaglandins
• Prostaglandins regulate the pressure
of blood flow through the kidneys
• Prostaglandins: vasodilation of afferent
arteriole

Example of kidney toxicity: ACE-Inhibitors

Angiotensin-converting enzyme (ACE)-inhibitors: medications that
lower blood pressure
• Inhibit the enzyme making angiotensin II
• Angiotensin II: vasoconstrictor effect on efferent arteriole

Taking NSAIDS and ACE-inhibitors at the
same time can lead to

nephrotoxicity
because of significantly decreased
pressure

Toxic responses of the reproductive system include any adverse effects on sexual
function and fertility in adult males and females

Example:

Expose adult animals whatever chemical for 2 weeks prior to breeding:

1) are they ovulating normally

2) is the same amount of sperm being

3) How many embryos implanted

4) How many are giving birth

Toxic responses of the brain: cyanide

• cyanide binds and inhibits
cytochrome c, causing a
disruption in ATP synthesis

cyanide inhibits what in the brain

cytochrome C, and thus ATP synthesis

More than 90% of a dose of ethanol is metabolized in the liver
• Excess NADH leads to steatosis by signaling a down regulation
of fatty acid breakdown and upregulating fatty acid synthesis

liver steatosis → liver fibrosis → liver cirrhosis

neoplasia

new growth or autonomous growth of tissue

Neoplasm

The lesion resulting from neoplasia

Benign

Lesion characterized by expansive growth, frequently exhibiting slow rates of proliferation they do not invade surrounding areas

Malignant

Lesions demonstrating invasive growth, capable of metastasis to other tissues or organs

metastases

Secondary growths derived from a primary malignant neoplasm

Tumor

Lesion characterized by swelling or increasing in size, may or may not be neoplastic

Cancer

Malignant neoplam

Carcinogen

A physical or chemical agent that causes or induces neoplasia

Genotoxic

Carcinogens that interact with DNA resulting in mutation

Non-genotoxic

Carcinogens that modify gene expression but do not damage DNA

Carcinogen

A physical or chemical agent that causes or induces neoplasia

Direct acting carcinogens:

highly reactive
electrophilic molecules which bind to DNA without
biotransformation

Indirect acting carcinogens

: (more common)
chemicals that require biotransformation to be
carcinogenic

The ultimate carcinogenic forms are

frequently strong electrophiles (nucleophiles
are DNA bases and phosphodiester backbone)

Chemicals containing these moieties frequently cause

tumor formation at the site of chemical exposure

Mismatch repair

mechanism to repair point mutations

Excision repair:

mechanism to repair DNA regions containing
chemically modified bases, or DNA chemical adducts

Homologous recombination and nonhomologous end-joining:

mechanism to repair double stranded breaks

oncogene

a gene that is capable of transformation cells in a
culture or inducing cancer in animals.

Proto-oncogenes

are genes that regulate cell proliferation, growth, and differentiation, and control the cell cycle.

Tumor-suppressor genes

are genes that inhibit cell proliferation or cell survival

Examples of non-genotoxic carcinogens

Receptor mediated:

example phenobarbital

Examples of non-genotoxic carcinogens

Hormonal mode of action:

example estrogen

Examples of non-genotoxic carcinogens

Immunosuppression

cancer immune surveillance is
vital, if immune cells are destroyed then that is a
problem

Connect genotoxic carcinogens with the development of cancer

Certainly! Let’s delve into the connection between genotoxic carcinogens and the development of cancer.

1. Genotoxic Carcinogens:
   • Genotoxic carcinogens are substances that can cause damage to an organism’s genetic material (DNA) and potentially lead to cancer.
   • These substances induce mutations, deletions, or rearrangements in the DNA, disrupting its normal structure and function.
   • Examples of genotoxic carcinogens include certain chemicals, radiation (such as UV rays), and some viruses.
2. Cancer Development:
   • The process of cancer development involves two main steps: initiation and promotion.
   • Initiation:
     • Genotoxic carcinogens initiate the process by causing DNA damage in a cell.
     • This damage creates an abnormal cell with altered genetic material.
     • These initiated cells have the potential to become cancerous.
   • Promotion:
     • After initiation, promoters come into play.
     • Promoters stimulate the replication of these neoplastic (abnormal) cells.
     • They facilitate the progression of the tumor.
     • Genotoxic chemicals act as initiators in this context¹.
3. Mechanisms and Implications:
   • Genotoxic effects, such as DNA deletions, breaks, and rearrangements, can lead to cancer if the damage is not immediately repaired or if the cell does not undergo apoptosis (cell death).
   • Regions in the genome that are sensitive to breakage, known as fragile sites, may result from exposure to genotoxic agents.
   • Understanding these mechanisms is crucial for identifying potential markers that drive cancer progression and developing new therapeutic strategies to prevent diseases caused by pathogens^{2 3}.

In summary, genotoxic carcinogens play a pivotal role in cancer development by damaging DNA and initiating abnormal cell growth. Researchers continue to explore these mechanisms to improve cancer prevention and treatment strategies.

Distinguish between direct and indirect acting carcinogens and understand that genotoxic carcinogens are typically electrophiles

Certainly! Let’s explore the differences between direct-acting and indirect-acting carcinogens, as well as the role of genotoxic carcinogens as electrophiles:

1. Direct-Acting Carcinogens:
   • Direct-acting carcinogens are substances that can directly interact with cellular components, including DNA, without requiring metabolic activation.
   • They are typically electrophilic and can form covalent bonds with cellular macromolecules.
   • Examples include certain alkylating agents (such as mustard gas) and some aromatic amines.
   • These carcinogens directly cause DNA damage, leading to mutations and potentially cancer development.
2. Indirect-Acting Carcinogens:
   • Indirect-acting carcinogens are compounds that require metabolic activation within the body to become carcinogenic.
   • They are usually not electrophilic in their native form.
   • Metabolic enzymes (such as cytochrome P450) convert these compounds into reactive intermediates.
   • These intermediates can then react with DNA, proteins, or other cellular components, causing damage.
   • Examples include polycyclic aromatic hydrocarbons (PAHs) found in tobacco smoke and some heterocyclic amines formed during cooking of meat at high temperatures.
3. Genotoxic Carcinogens as Electrophiles:
   • Genotoxic carcinogens are typically electrophiles, meaning they have an affinity for electron-rich sites in cellular molecules.
   • They react with nucleophilic sites in DNA, leading to the formation of DNA adducts.
   • These adducts can disrupt normal DNA replication and repair processes, ultimately contributing to cancer development.
   • Electrophilic genotoxic agents include alkylating agents, aromatic amines, and certain reactive oxygen species.

In summary, direct-acting carcinogens directly interact with cellular components, while indirect-acting carcinogens require metabolic activation. Genotoxic carcinogens, often electrophiles, play a critical role in initiating DNA damage and promoting cancer progression. Understanding these distinctions helps in cancer prevention and risk assessment.

basic understanding of the stages of carcinogenesis

Certainly! Let’s explore the stages of carcinogenesis, which describe the process by which normal cells transform into cancerous cells:

1. Initiation:
   • Initiation is the first step in carcinogenesis.
   • It involves exposure to a carcinogenic agent (such as genotoxic chemicals, radiation, or viruses) that causes DNA damage in a cell.
   • The damaged DNA leads to the formation of an initiated cell with altered genetic material.
   • These initiated cells have the potential to become cancerous.
2. Promotion:
   • After initiation, promotion occurs.
   • Promoters stimulate the growth and replication of initiated cells.
   • These promoters do not cause DNA damage directly but enhance the survival and proliferation of the altered cells.
   • Factors like hormones, inflammation, and growth factors play a role in promotion.
3. Progression:
   • During progression, initiated cells accumulate additional genetic alterations.
   • These alterations lead to the development of a premalignant lesion or dysplasia.
   • Dysplastic cells exhibit abnormal growth patterns and may invade nearby tissues.
   • Further genetic changes can transform dysplastic cells into malignant tumors.
4. Malignant Transformation:
   • Malignant transformation involves the conversion of premalignant cells into cancerous cells.
   • These cells acquire the ability to invade surrounding tissues and spread to distant sites (metastasis).
   • The tumor becomes clinically detectable and poses a threat to health.
5. Metastasis:
   • Metastasis is the final stage.
   • Cancer cells detach from the primary tumor, enter the bloodstream or lymphatic system, and establish secondary tumors in distant organs.
   • Metastatic spread significantly worsens the prognosis.

In summary, carcinogenesis is a complex process involving initiation, promotion, progression, malignant transformation, and metastasis. Understanding these stages helps in cancer prevention, early detection, and targeted therapies.

Routes of administration

oral, IV, inhalation

Common types of target molecules for toxic chemicals

Nucleic acids (DNA)

proteins

membranes

Different types of disrepair

tissue necrosis: tissue cell death, injury overwhelms/ disables repair mechanisms

Fibrosis: extracellular matrix deposition with abnormal composition

Carcinogenesis: failure to repair DNA, Failure to apoptosis failure to terminate cell proliferation

How ionization affects crossing cell membrane

un-ionized form of a drug is usually lipid soluble and can readily cross the cell membrane

ionized = low lipid solubility and cant cross the cell membrane

when pH is = to pKa then un-ionized drug = 50:50 or in other words pKa is the pH where drug is 50% ionized and passes membranes

Genotoxic

carcinogens that interact with DNA resulting in mutation

indirect = require biotransformation; not directly binding to DNA

direct = directly interacting with DNA causing direct damage

non-genotoxic

carcinogens that modify gene expression but don't damage DNA

Stages of carcinogens

1) Initiation: Damage DNA then initiate cell (= potential cancer)

2) promotion: stimulate growth, no DNA damage in this step

3) progression: initiated cells accumulate additional genetic alterations

interesting history fact

Catherin de Medici (1519-1589): tested toxic concentrations on subjects, took note of how rapid they were intoxicated, their degree of response, the effectiveness of the toxin, ect.

Quantal dose curves

all or none. An individual in a population of organisms is classified as either a responder or a non-responder. Shows % of responders at different dosages. CAan show ED50

Individual dose curves

focused on graded response of an individual to varying dosages of a drug. Continues relationships. Represent effect of different doses on individual, measured on a grade scale such as blood pressure, pain relief, enzyme activity. X axis = dose y axis = graded response

How ethanol consumption can lead to liver steatosis

Primary pathway for ethanol breakdown is through ADH (alcohol dehydrogenase) ADH oxidizes NADH to NAD+ while reducing acetaldehyde to ethanol. NADH leads to steatosis by signaling a down regulation of fatty acid breakdown and up regulating fatty acid synthesis.

The route of blood flow through the glomerulus and describe the effect of NSAIDS and ACE-inhibitors on that flow

The blood flow through the glomerulus first goes through afferent arteriole then will get filtered and goes out the efferent arteriole. NSAIDs will cause constriction of afferent arteriole causing increased blood pressure in the glomerulus (stops production of prostaglandins). ACE inhibitors block conversion of angiotensin 1 to angiotensin 2 which inhibits efferent arteriolar vasoconstriction. If taken together no blood flow to the glomerulus will occur going either in or out causes kidneys to die.

How the route of exposure impacts bioavailability (IV and oral)

Route of exposure impacts bioavailability due to the process it has to go through specially the filtration process. When it is ingested orally it must go through the intestinal tract that absorbs and filters before putting things into the blood stream. This bioavailability is much less in comparison to IV because when administered intravenously it goes directly into the blood without a filtering process first which could take some of the medication or toxin out first so essentially the bioavailability in IV is 100% and the oral way of consumption's bioavailability would be less then 100%

Fun fact about batrachotoxin

found in birds, frogs, beetles

binds irreversible to the sodium channels in the body leaving them open

no known antidote at this time

indigenous people have used frogs with poison on darts to hunt

it was discovered in 1963

Takashi T. solved the steroidal structure using x-ray diffraction