Toxicology Unit 1

4 Steps to the Mechanism of Toxicology

1. Delivery

2. Reaction

3. Dysfunction

4. Repair/Disrepair

[all/some] endogenous compounds are potential targets for toxicants

All

all ______ ______ are potential targets for toxicants

endogenous compounds

Most prevalent and toxicologically relevant endogenous compounds are _________ ________ and ________

nucleic acids and membranes

2 types of reactions

covalent and noncovalent

Noncovalent reactions are:

typically reversible

include hydrogen and ionic bonds

covalent reactions are:

typically irreversible (permanent!)

Common with electrophiles and radical cations

Hydrogen abstraction reaction:

What abstracts H atoms? What does it form?

neutral free radicals abstract H atoms from endogenous compounds. Forms cross links with DNA.

Electron transfer reaction:

Exchange of electrons to oxidize or reduce other molecules

Enzymatic Reactions

Toxics act enzymatically on target proteins

Dysfunction of target molecule

toxicant inhibits/blocks functions of the target molecule

Destruction of target molecule

toxicant alters the primary structure of an endogenous molecule by cross-linking or fragmentation

Neoantigen formation

covalent binding to xenobiotics or their metabolites to a protein may invoke an immune response

Dysregulation of gene expression occurs at elements that are responsible for

Transcription

intracellular Signal Transduction components

Synthesis, storage, or release of extracellular signaling molecules

Dysregulation of transcription involves

altering the activation of TFs (No DNA —> RNA)

Dysregulation of signal transduction involves

altering protein phossphorylation or interfering with GTPase activity of G Proteins (GPCR)

Dysregulation of extracellular signal production involves

altering hormone circuits

Dysregulation of ongoing cell function involves

disruption of steps in signal coupling in specialized cells

Dysregulation of excitable cells is an example of

dysregulation of ongoing cell function

An example of ysregulation of excitable cells is

disruption of neutrotransmitters

3 ways cell death is inflicted

1. ATP Depletion

2. Sustained rise in intracellular Ca+2

3. Overproduction of ROS/RNS (Free radicals)

Necrosis

Unorganized cell death caused by MPT (mitochondrial inner membrane permeability) where the cell swells and lyses.

Apoptosis

Organizes cell death where the cell shrinks and breaks into fragments to be phagocytosed.

Key in cell death mechanisms is the release of

cytochrome C

Molecular repair can involve

Chemical alterations being reversed

Removal and reinsertion of new units

Total degradation aod re-synthesis

Chemically altered DNA

Types of molecular repair

Repair of proteins, lipids, and DNA (includes direct repair, excision repair, and recombinational repair)

Molecular repair

1. Proteins

2. Lipids

3. DNA

Tissue Repair involves

regeneration of tissue by proliferation

Types of tissue repair

Replacement of lost cells by mitosis

Replacement of ECM

Side reactions of tissue repair

Inflammation: cytokines secreted and produce free radicals

Altered protein synthesis: cytokines can inc or dec gene transcription

Generalized Reactions: cytokines can trigger fever

If repair fails

Tissue necrosis: happens if repair mechanisms are insufficient or molecular damage is not readily reversible

Fibrosis: Excessive depostion of ECM of abnormal composition (scarring. Dangerous in organs but not skin). ECM production is not turned off.

Carcinogenesis: insufficient function of various repair mechanisms

Failure of DNA repair

1. Mutation, the initiation event

2. Damaged DNA can cause adduct formation

3. Mutation passed to daughter

4. Altered genes produce mutant protein, reprogramming cells for multiplication

5. Creates a rapidly proliferation tumor)

Fill in the Blanks

Exposure site: injection/bite site, skin, GI tract, Respiratory tract, placenta

↑ Absorption

↑ Distribution to target organ

↑ Reabsorption

↑ Toxication

X Presystemic elimination

X Distribuution away from target organ

X Excretion

X Detoxication

Ultimate toxicant

Target molecule

Target location

1. Attributes of Target

2. Reaction types

3. Outcomes

1. Reactivity, Accessibility, Critical function

2. Noncovalent binding, covalent binding, hydrogen abstraction, electron transfer, enzymatic reaction

3. Dysfunction, destruction, neoantigen formation

Fill in the blanks

Role of target molecule: Cell regulation (signalling), Cell maintenance

Cell Regulation: Dysregulation of gene expression, Dysregulation of ongoing function

Cell maintenance: Impaired internal maintenance, impaired external maintenance.

Fill in the blanks

Molecular: Proteins, lipids, DNA

Cellular: Autophagy of damaged cell organelles, Regeneration of damaged axons

Tissue: Apoptosis, cell reproduction, ECM production

Definition of Volatile organics (BP and VP)

BP below 250C at atm

WHO: below 260C

European Union: VP ~ 0.01kPa (~1/11,000atm)

Volatiles may…

be significant contributors to air and groundwater pollution

Definition of Semivolatile organics

USEPA: BP above 240-260C, below 400C

VP range 10^-14 to 10^-4 atm.

PAH stands for

Polycyclic Aromatic Hydrocarbons

PCB

Polychlorinated biphenyls

Varying degrees of solubility, VP, Kow, Toxicity because of varying Cl content

NPL

Carcinogenic

Impacts immune and reproductive sys. and intellectual development

PCDDs

polychlorodibenzodioxins

bioaccumulative

Organophosphorus insecticides

AKA anticholinesterase agents

Neurotoxin

can cause paralytic condition and muscle weakness

Organochlorine pesticide

Low VP and solubility

High Kow (very fat soluble, accumulates in fat)

Bioaccumulates

Associated with suppression of immune system and cancer

Slow biotransformation, does not excrete well (gets stored in fat)

Carbamate insecticide

2ndary amine

Dissapates quickly (shorter half life than OP, but f(x) similarly)

Perfluroinated compounds

PFOS (stain resistant), PFOA (non-stick coating)

Sillanes and Silyl ethers

lubricants and cosmetics

Polybrominated compounds

flame retardants

N-nitro and nitroso compounds

explosives, tobacco smoke, industrial chemicals.

carcinogenic

Heavy metals

Specific gravity exceeds the specific gravity of water by 5+ times

Arsenic

Carcinogenic (bladder, liver, kidney, skin,lung), peripheral vascular disease, cerebrovascular disease, adverse pregnancy.

In pesticides, wood preservatives; byproduct of gold refinement.

Can be ingested or inhaled

Cadmium

Osteroperosis in women, height loss in men, kidney damage, elevated BP, CVD, Itai-Itai

Chromium

III- Essential

VI- Toxic carcinogen

Lead

Naturall occurring toxic metal

Mercury

Bioaccumulates, especiall in water and fish (aquatic invertebrates)

“Dose makes the poison”

Paracelsus

What is a poison

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

Toxicity

Degree to which something is poisonous

Toxicant or Xenobiotic

Toxic substance man-made or resulting from human activity

Toxin

Toxic substance made by living organism

Additive

2+2=4

Synergistic

2 + 4 =10

Potentiation

0+2=4

Antagonism

2+4=3A

Acute

Exposure <24 hours

Subacute

Exposure < 1 month

Subchronic

Exposure 1-3 months

Chronic

Exposure longer than 3 months

In vivo

Alive organism exposed purposefully or accidentally

In vitro

cells derives from organisms

in silico

computer modeling or simulation predictions

Factors affecting disposition

Absorption, distribution, metabolism/biotransformation, excretion

Barriers to absorption

skin or cellular membranes

Passive transport means

no energy is used

Types of passive transport

1. facilitated diffusion (carrier-mediated but not moved against a gradient)

2. simple diffusion

3. filtration

Filtration

Water in bulk flowing across porous membrane. small solute may pass with water. filters by size.

Active transport

Uses energy

Moves against gradient

Can become saturated at high substrate []; exhibits a transport maximum (Tm)

Potentially competitively inhibited

Selective for certain structures

If it says “anion” or “cation” (oat, oct, oatp), it is probably _____ transport

active

Kinds of special tansport

Endocytosis (pino and phago)

Absorption definition

Process by which toxicants cross body membranes and enter the bloodstream

Main sites of absorption

GI tract, lungs, skin

Enteral administration

Oral to rectal system

Parenteral Administration

all routes not enteral. administered other than mouth or alimentary canal

Absorption takes place where in the GI tract?

ANYWHERE. The whole thing, mouth to rectum.

First-Pass effect

Not all of the ingested material is absorbed because the liver extracts some into the bile.

Gas solubility ratio

[] in blood / [] in gas

Gases with low solubility ratio are ____ limited

perfusion. Will exist in gas more than blood.

Depends on blood flow. if there is more flow, the compound will be able to leave.

Gases with high solubility ratio are ____ limited

ventilation. Will exist in blood more than gas.

Depends on how much of the compound is inhaled.

Particles > 5um

deposited in nasophayngeal region. Removed by blowing, sneezing, wiping.

Particles 2-5um

Desposited in tracheo-bonchiolar region. cleared by movement of mucus.

Particles <= 1um

Penetrate alveolar regions of lung and may be absorbed into the blood

Rate-determining layer of skin absorption is the

stratum cornium

Parenteral administration routes

Intraperitoneal, subcutaneous, intramuscular, intravenous

Intraperitoneal

into body cavity

subcutaneous

into layer of skin below dermis and epidermis

intramuscular

into the muscle

intravenous

directly into the bloodstream

Final distribution depends on…

affinity of a xenobiotic for various tissues.

First pass effect, AKA…

Enteropathic circulation

Rate of distribution determined primarily by

1. blood flow

2. Rate of diffusion out of capillary bed and into cells and tissues