AH 3175E Module 7 Exam

toxicity is determined by

the chemical and physical properties of the compound

the absorbed dose

the method and duration of exposure

the overall health of the organism exposed

the ability of the organism to dispose of the toxicant

toxicokinetics

the "path" an agent takes in a biological system

toxicodynamics

the adverse effects of the path an agent takes in biological systems

effects of toxicants and their metabolites at the molecular, biochemical, and physiological level

results in localized or systemic effects

toxicity is the result of...

a chemical or its metabolite interacting with a molecular target and interfering with critical cellular function

direct injury

adverse intracellular activities

indirect injury

produced through alteration of extracellular regulatory mechanisms

toxicity

the result of a chemical or its metabolite interacting with a molecular target and interfering with critical cellular function

extracellular interactions

indirect injuries, arise from disruption of overall processes of the organism

energy production and growth

electrolyte and acid/base regulation

waste product removal

cellular and tissue interactions

cellular swelling

a sign of early injury

due to disruption of energy-producing mechanisms

accompanied by disruption of the sodium-potassium pump in the cellular membrane

resultant intracellular change allows the influx of sodium and water

reversible if swelling disappears when the toxicant is removed

severe damage results in cell death

apoptosis: programmed cell death

necrosis: uncontrolled cell death

examples of cellular injury presentations

cellular swelling

fatty changes more serious form of reversible cellular injury

severe damage results in cell death

after cellular injury is incurred, several outcomes are possible...

cells and tissues repair sufficiently to resume normal function

incomplete repair is only sufficient to resume some function

complete death of an organ or the organism occurs

neoplastic growth occurs, which may result in the death of the organism

cell death: apoptosis

a normal part of the cell cycle

destroys cell and recycles contents

can occur within a single cell or noncontiguous cells

programmed cell death, selective destruction

cell death: necrosis

the end-stage response to cellular injury

affects contiguous tissues

triggers an inflammatory response

compensation for necrosis

the body attempts to replace replace the dead tissue

if injury is minimal, function may never be compromised

if damage is extensive, the body may not be able to provide enough cells of the appropriate type to resume normal function

compensation for apoptosis

as the cell dies, one can observe "apoptotic bodies" that in the final stage of apoptosis are digested by phagocytic cells

triggering of apoptosis is complex and involves the cell receiving chemical messengers to "turn on" those genes involved in the self-destruction process

if these genes become mutated and apoptosis is compromised, then the cell is at greater risk of becoming one that may transform into a cancerous cell

manifestations of cellular injury: damage to biomolecules

enzyme inhibition: biochemical pathway interruption

covalent binding: electrophilic metabolites to DNA

receptor inhibition

lethal synthesis

mutagenic

lipid peroxidation

manifestations of cellular injury: damage to biological structures and systems

necrosis: tissue death

inflammation: local or systemic response

cytotoxicity

immune-mediated hypersensitivity reactions

immunosuppression

neoplasia

oxidative stress

state of imbalance between the production of ROS and the body's natural antioxidant defenses

ROS are molecules containing oxygen that are highly reactive and can damage cells

reactive oxygen species

unstable molecules containing oxygen that can damage cells

examples include free radicals like superoxide anions and hydroxyl radicals, as well as non-radical oxidants like hydrogen peroxide

endogenous ROS

internally sourced

mitochondria electron transport, peroxisomes/oxidative enzymes/hydrogen peroxide, endoplasmic reticulum/cytochrome P450, phagocyte/lysosomes/NADPH oxidase/myeloperoxidase

exogenous ROS

exterior influences

cigarette smoke, exposure to sunlight, gamma irradiation, pollutants, drugs, xenobiotics, food/cooking, heavy metals, and alcohol

two primary categories of reactive chemicals

electrophiles and nucleophiles

electrophiles

chemicals that are electron-deficient and accept a pair of electrons to create a covalent bond

ketones, epoxides, aldehydes, quinones

typically contain oxygen

nucleophiles

chemicals that are electron-rich and donate a paire of electrons to create a covalent bond

hydroxide anion, cyanide anion, ammonia

toxicological importance

produced by xenobiotic metabolism and permanently alter biomolecules critical for human health

adducts

formed by BAP-epoxide reacting with DNA

primary molecules targeted by ROS and reactive non-radical compounds:

DNA

Lipids

Proteins

lipid peroxidation

a free radical chain-reaction within lipids leading to structural changes and the addition of oxygen atoms

lipid peroxidation: induces cis-trans isomerization

a change in the orientation of the bonds in the lipid

increasing the membrane rigidity and causing loss of function (including in membrane proteins) potentially destroying the membrane

lipid peroxidation: generates aldehydes

typically reactive compounds

DNA (Deoxyribonucleic acid)

a complex, self-replicating molecule that encodes the genetic instructions for building and maintaining an organism

a base sequence that codes the information necessary for cellular growth, differentiation, and replication

DNA is organized into genes...

of which 30,000 or so encode information that is critical to maintain human life

bases of DNA

purines: adenine (A), guanine (G)

pyrimidines: cytosine (C), thymine (T)

A pairs with T

C pairs with G

DNA utilization: transcription

RNA polymerase gains access to the DNA and then writes a complementary segment of mRNA

the mRNA goes into the cytoplasm and eventually reaches a ribosome

DNA utilization: translation

ribosome "reads" the mRNA and build a series of amino acids into a protein based on the bases contained within the mRNA

as the mRNA is transcribed and translated, specific sequences of nucleotide bases indicate where to start and stop each process, defining the length of the gene

mutations of DNA

correct pairings of bases is A-T and C-G

incorrect base pairing can result in the potential alteration of information that may be important to the normal physiology of the individual

deletion or replacement of a single nucleotide...

can result in an altered protein such as an enzyme

if these changes occur in an informational portion of the DNA, then an abnormal protein may result

damage to DNA occurs...

both spontaneously and as a result of exposures to environmental agents

electrophiles and DNA

capable of reacting with DNA in several ways

electrophiles react with the nucleophilic sites in DNA

phosphate backbone is susceptible to electrophilic attack

radicals

can react with nucleic acids resulting in their damage

redox cycling caused by several drugs that can damage DNA in two ways:

hydroxyl radicals react with sugar-phosphate backbone of nucleic acids resulting in DNA breaks

ROS (reactive oxygen species) can cause oxidative damage

damage by toxicants: UV lights

specifically UVB light (280-320 nm) is capable of inducing the formation of a bond between these two thymine bases forming a thymine dimers in DNA, and nucleotides

ozone

good up high, bad nearby

stratospheric ozone protects the planet from UV-B (causes sunburns and skin cancer) and UV-C (germicidal) light

tropospheric ozone is a potent respiratory irritant

mutation: acquired

some time during the life of an individual

unless these occur in the gametes, they cannot be passed onto offspring

mutation: hereditary

acquired from a parent through the union of the gametes at fertilization and can be present in all the cells of the offspring

apoptosis occurs during

embryological development

normal cellular development

in response to biological, physical, or chemical stressors

one way genetically altered cells are removed from the body if DNA repair does not occur

epigenetics

focuses on the processes that regulate how and when certain genes are turned on and off

epigenetic processes control normal growth and development, deregulated in diseases such as cancer

diet and exposure to environmental chemicals throughout all stages of human development (exposome) among other factors can cause epigenetic changes

epigenetic changes

normally protect against a disease could make people more susceptible to developing that disease later in life

inheritable changes, affecting the health of offspring

epigenome

the set of chemical modifications to DNA and DNA-associated proteins in the cell, which alter gene expression and are heritable

modifications occur as a natural process of development and tissue differentiation

DNA methylation

addition of methyl groups (-CH3) to the bases of DNA molecules in specific places

methyl groups may turn genes on or off

histone modification

DNA in cells is wrapped around histone proteins which form spool-like structures that enable DNA's very long molecules to be wound up neatly into chromosomes inside the cell nucleus

proteins can attach a variety of chemical tags to histones, proteins in cells can detect these tags and determine whether that region of DNA should be used or ignored in that cell

primary routes for ethanol metabolism

alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)

two phase I enzymes

intermediate is acetaldehyde, a toxic metabolite

enzymatic antioxidants

superoxide dismutase: transforms superoxide anion into hydrogen peroxide

catalase: transforms water to hydrogen peroxide

glutathione peroxidase: transforms hydrogen peroxide to water, GSH to GSSH

glutathione reductase: reduces GSSH to GSH

non-enzymatic antioxidants

molecules within the body that can neutralize free radicals and other reactive species without relying on enzymes

act as the body's first line of defense against oxidative stress caused by toxins and other environmental factors

examples of non-enzymatic antioxidants

vitamin E, vitamin C, bilirubin/biliverdin, beta-carotene, uric acid, and glutathione

metal sequestering agents

chelating agents or ligands form a metal complex that reduces their availability/reactivity in their environment

metal ions such as iron...

can form strong reactive oxygen species with hydrogen peroxide

organs are "targeted" for different reasons:

circumstances where target organ would receive a toxic burden

route of exposure: UV light through skin

blood flow: enterohepatic circulation

function: glomerulus of kidney

metabolic enzymes: liver or kidney

unique biochemistry: nerve function

skin feature

five layer of epidermis

top two are dead

primarily keratinocytes

stratum basale

stratum basale

also called stratum germantivum

contains melanocytes and Langerhan's cells

layer is from 0.05mm (eyelid) to 1.5mm (palm)

contains P450s

keratinization of skin

as cells in the stratum granulosum (middle layer) die

cells form cornified (hardened) cell envelope

keratins cross-link into filaments

gives skin its characteristic strength and flexibility

keratinized layers are impermeable to water

factors affecting absorption of xenobiotics through skin

regional variations of skin (thickness)

applied dose, chemical concentration, duration of exposure, surface area involved, physical integrity of stratum corneum, degree of hydration, temperature, presence of other substances, circulatory effects chemical-skin binding

factors that effect the development of skin reactions to chemical exposure

preexisting skin conditions

allergies

age

work experience

temperature

humidity

seasons

skin corrosion

an extreme form of direct skin damage by chemicals is that of skin corrosion

an immediate and irreversible response from a single exposure to an agent that results in epidermal and dermal necrosis

the concentration of the xenobiotic determines

whether skin corrosion or a primary irritant response results from an exposure

skin chloracne

acne induced by contact with chlorinated hydrocarbons is referred to as chloracne

refractory form of acne, that forms persistent yellow cysts on the temples and behind the ears

caused by chloracnegens

examples of chloracnegens causing chloracne

PCBs

PBBs (polybrominated biphenyls)

TCDD, dioxins

byproducts of herbicide production: dioxins

agent orange, potent herbicide sprayed by US military in Vietnam War to clear foliage

contained traces of TCDD

contamination affects Vietnam population to this day

contact dermatitis

the most common occupational dermatosis with more than 90% of reported cases

can be result of direct or indirect contact

both induce inflammatory responses

contact dermatitis: indirect contact

due to allergic sensitization of the individual upon re-exposure to the offending agent

the allergic response is due to the liberation of mediators of inflammation triggered by the immune system

contact dermatitis: direct contact

produces a skin inflammatory response (primary irritant response)

damaging effects of the chemical on the skin, as might occur from an exposure to an organic solvent which dissolves the lipids of the skin

allergic contact dermatitis

represents approximately 20% of the cases of contact dermatitis reported

an allergic immune response upon exposure to a toxicant in individuals who have become sensitized to the specific toxicant

genetic predisposition, sensitizing event, contact after the sensitization

even a small amount of chemical in the sensitized individual can result in a significant dermatitis

prevalent example of allergic contact dermatitis

latex allergy

photodermatitis

chemical exposure in the presence of light induces toxic skin response

certain chemicals result in the production of free radicals that produce effects that are similar to contact dermatitis

phytophotodermatitis

exposure to certain plant products

furocoumarin 8-methoxy psoralen found in limes and PAHs

3 types of skin cancer

basal cell carcinoma (75%)

squamous cell carcinoma (25%)

malignant melanoma (1%)

while melanoma accounts for only 1% of all types of skin cancer...

it has the highest death rate of all types and is more likely to spread (metastasize) in the body

major functions of the liver

carbohydrate metabolism, lipid metabolism, protein metabolism, storage, blood filtering, detoxification, secretion

lobules

functional units of the liver

blood enters lobules through branches of the portal vein and hepatic artery

blood then flows through small channels called sinusoids that are lined with primary liver cells, hepatocytes

blood received by the liver is

80% venous blood (deoxygenated from GI tract and portal vein)

20% arterial blood

hepatocytes

directly receive chemicals from venous return of digestive tract, including toxicants and drugs

comprise approximately 80% of the mass of the liver and are the primary cell that performs liver functions

the portal vein carries blood from the small intestine, spleen, and pancreas

the portal circulation is responsible for the "first pass" effect

the liver is the first organ to receive this blood from the gastrointestinal tract before it enters into the general circulation

main function of hepatocytes

absorb nutrients

store fat-soluble vitamins

produce bile

detoxify xenobiotics and metabolic waste

the liver is often the most vulnerable target for toxicity from...

orally ingested chemicals

the liver is the first organ to be exposed to ingested chemicals following absorption due to its portal blood supply

types of hepatic injury

necrosis

steatosis (lipidosis or fatty liver)

cholestasis

cirrhosis (fibrosis)

vascular injury

neoplasia

steatosis

an increase in hepatic lipid content to greater than 5% of liver weight

steatosis is a common and often reversible response to acute exposures to toxicants

cholestasis

an accumulation of bile pigments and other bile products within the bile canaliculi that restrict the normal flow of bile

liver retains bile salts and bilirubin, which can lead to their elevation in the blood in the production of jaundice

can be reversible or chronic

vascular injury

the sinusoids of the liver are very delicate structures

like capillaries the walls are composed of endothelium

conditions that result in sinusoid blockage can cause the dilatation of these structures, and consequently the liver can become engorged with blood cells

cirrhosis of the liver

a fibrotic disease that is characterized by the loss of significant hepatic function, which can ultimately result in total organ failure

malignant neoplasms

hepatic cancers have been linked to chemical exposures, including Aflatoxin B1, alcohol, and certain viruses

necrosis (hepatocyte death)

can be focal and confined to a few cells, zonal (centrilobular, midzonal, periportal), or massive (panlobular)

kidney functions

elimination of waste products

regulation of acid-base balance

control of blood pressure and volume by formation of renin and its effect on vascular smooth muscle

xenobiotic metabolism (P450 and high glutathione levels)

nephrons

active filtration units of the kidneys

filter 45 gallons of blood daily, entire blood supply filtered every 45 min

99% of water is reabsorbed

glomerulus

a specialized arrangement of capillaries for high-pressure ultrafiltration into the Bowman's capsule

chemical size limitation for filtration is approximately 60,000 g/mole

bowman's capsule

where the glomerular filtrate is collected before its modification as it moves along the renal tubules

proximal convoluted tubule

where approximately 60-80% of glomerular filtrate is reabsorbed

(includes water, Na+, K+, HCO3-, Cl-, PO4^3-, Ca2+, Mg2+, glucose, amino acids, some small organic acids, peptides, proteins)

loop of henle

location where adjustment of salt content and pH of urine occurs

distal convoluted tubule

location where transport of K+, H+, and NH3 into the lumen occurs

collecting duct

location where reabsorption of water and NaCl occurs