Toxicology Exam 6 Flashcards
(194 cards)
1
Q
What is the function of pesticides?
A
Substances that kill or control (prevent, repel or mitigate) pests: Ideally specific to the targeted pest
2
Q
What are the types of pesticides?
A
- Insecticides
- Herbicides
Other less common:
- Fungicides, Rodenticides, etc…
- Fumigants
3
Q
What factors drive the use of pesticides?
A
Absorption
Occupational exposures
Environmental exposures
4
Q
How does absorption drive the use of pesticides?
A
- Respiratory Track
- Dermal absorption
- Small amounts via GI
- Accidental child or animal ingestion
- Pesticide residues in food and populations at risk
5
Q
How do occupational exposures drive the use of pesticides?
A
- Manufacturing
- Formulating
- Manipulation and Application
- Harvesting of crops
6
Q
How do environmental exposures drive the use of pesticides?
A
Contaminated soil and water → Food and drinking water
7
Q
What are the factors modulating environmental exposure impact?
A
- Persistence
- Biomagnification
8
Q
What is the EPA?
A
Environmental Protection Agency (EPA)
9
Q
What is the role of the EPA?
A
- Registers pesticides for use
- Establishes maximum allowable levels of residues to be enforced by federal agencies
- Assess risks and cumulative effects of exposures of at-risk populations
10
Q
How many pesticides are registered through the EPA, and what is the cost?
A
> 140 pesticides registered
~$50-$100 million
11
Q
What information is required for the EPA to register pesticides for use?
A
- Chemistry - Biotransformation/degradation
- Environmental fate
- Drift
- Impact on non-targeted species
- Persistence and Bioaccumulation - Occupational Exposure
- Toxicology
- Performance and Efficiency
12
Q
What are the primary targets of Insecticides?
A
Primary Target: Nervous System
Impairment of neuromuscular and peripheral CNS communication
Inhibitors of Acetylcholinesterases
13
Q
What are examples of insecticides?
A
Organophosphates (OP)
Carbamates
Neonicotinoids
Axonic excitotoxins
Avermectins
Rotenoids
14
Q
What insecticides impair AChE function?
A
OPs and carbamates
15
Q
What insecticides impair AChR function?
A
Neonicotinoids
16
Q
What insecticides impair voltage-gated Na+ channel function?
A
- Chlorinated ethanes
- Pyrethroids
17
Q
What insecticides impair Inhibitory post-synaptic Cl- channels (GABA or glutamate-activated) function?
A
- Hexachlorocyclohexanes
- Cyclodienes
- Pyrethorids II
- Avermectins
18
Q
What is the pesticidal function of Organophosphates (OP)?
A
- CarbEs provide resistance in insects, while PTEs detoxify more efficiently OP in the liver
- Irreversible inhibition of acetylcholinesterase (AChE)
19
Q
What is the pesticidal function of Carbamates?
A
- Esters of N-methyl carbamic acid
- Inhibit AChE
- Reversible
20
Q
Where is the use of Organophosphates (OP) permitted?
A
- Most OPs were banned from residential use since 2001.
- Used as agricultural pesticides and mosquito abatement in public spaces is permitted.
21
Q
What is the pesticidal function of Organochlorine (OC)?
A
- Successfully used in the control of malaria and typhus.
- Banned for the most part, but due to their low-cost DDT, hexachlorocyclohexane (HCH), aldrin, and dieldrin are still used in developing countries
22
Q
What is the pesticidal function of Neonicotinoids?
A
Bind strongly overstimulating and blocking ACh receptors in insects, causing paralysis and death
23
Q
How do neonicotinoids harm pollinators?
A
Strong experimental evidence that they harm pollinators (bees)
- Ability to reproduce
- Ability to fly
- Contribute to extinction
24
Q
What is the pesticidal function of Axonic excitotoxins?
A
They prevent the closure of voltage-gated Na+-channels or inhibition of postsynaptic Cl–channels
25
What are the differences between Organochlorine and OPs?
Less soluble than OPs and carbamates but more persistent
26
What is the pesticidal function of pyrethroids?
Pyrethroids = synthetic compounds that duplicate pyrethrins
High potency, low mammalian toxicity, low persistence.
27
What is the pesticidal function of Avermectins?
Insecticides and Parasite control
28
How does Ivermectin work?
Ivermectin binds with high affinity to Glutamate-gated Cl- channels in invertebrate nerve and muscle cells, causing an increase in the permeability of the cell membrane to Cl- with hyperpolarization of the nerve or muscle cell. Hyperpolarization results in paralysis and death of the parasite either directly or by causing the worms to starve.
29
What is the pesticidal function of Rotenoids?
Organic farming
Inhibitor of the mitochondrial electron transport chain
- ROS formation
- Impaired bioenergetics
30
What disease can Rotenoids cause?
Parkinson’s disease
31
What are the two types of herbicide classification?
Selective and non-selective
32
How are herbicides classified based on their mode of application?
- Contact
- Translocated
33
How are herbicides classified based on where they are applied?
- Pre-planted
- Pre- and Post-emergent
34
How do herbicides effect (plants, weeds, vegetation)?
- Growth retardation
- Kill or severely injure
35
What are the mechanisms of herbicides?
- Cell membrane disruptors: Paraquat
- Inhibition of photosynthesis or respiration: Atrazine
- Inhibition of cell division
- Inhibition of protein and lipid synthesis
- Inhibition of specific enzymes: Glyphosate
- Regulators of growth
36
What are examples of Bipyridyl herbicides?
Paraquat, Diquat
37
What is the mechanism of Bipyridyl herbicides?
Redox cycling and Oxidative Damage
1. Formation of free radicals and other reactive oxygen species (ROS)
2. Depletion of the redox cofactor NADPH
37
What is the difference between Paraquat and Diquat?
- Paraquat accumulates in the lung and kidney
- Diquat accumulates in the GI tract, kidney, and the eye
38
How does the herbicide class Atrazine affect the environment?
- Inhibits Photosystem II
- Pre-emergent control of broad-leaved weeds.
Contamination of ground and drinking water is very common.
- Feminization of leopard frogs.
Endocrine disruptor
39
What is the mechanism of Phosphonomethyl aminoacids herbicides?
Inhibits 5-enolpyruvylshikimate-3-phosphate synthase that generates an amino acid intermediate (EPSP)
40
What is the mechanism of Glufosinate herbicides?
- Glutamine synthetase
NH4
- Mammals can cope to a certain limit via other metabolic pathways
41
What are the classes of fungicides?
Dicarboximides or Dithiocarbamates
Inorganic
42
Where do Dicarboximides or Dithiocarbamates come from, and what is the method of their fungicidal mechanism?
- Associated with metal ions
- Inactivate –SH groups in amino acids, proteins, and enzymes.
43
How do Dicarboximides or Dithiocarbamates affect humans?
Affect Thyroid function
44
What is the mechanism of organic fungicides?
Cu sulfate--> Nonspecific denaturation of proteins and enzymes
45
What are examples Rodenticides?
1. Phosphides (Mitochondrial ETC)
2. Fluoroacetic acid
3. Coumarin or Warfarin (anticoagulant)
4. Bromethalin (Uncouples mitochondrial oxidative phosphorylation)
5. Thioureas (reductant)
46
What is the mechanism of Fluoroacetic acid?
- Mitochondrial Aconitase
- Citrate cannot be dehydrated to cis-aconitate by aconitase and therefore blocks the TCA cycle
47
What is the mechanism of Coumarin or Warfarin?
(Anticoagulant)
- Antimetabolite of vitamin K, inhibits the formation of prothrombin
- Hemorrhage
48
What do Thioureas (reductant) cause?
Pulmonary edema and pleural effusion
49
What is the mechanism of Bromethalin?
Uncouples mitochondrial oxidative phosphorylation
50
What is metal?
- Most elements in the periodic table are metals
- Propensity to lose electrons and react with oxygen (O2) to form oxides.
51
What are the physical properties of metals?
High reflectivity, electrical and thermal conductivity, mechanical ductility, and strength
52
Where are metals found?
- Distributed naturally by biological or geological activity or by anthropogenic activity
- Their levels increase due to
Geological events
Anthropogenic activities
- Uses: Industry (technology), agriculture and medicine
53
What are anthropogenic sources of metal?
- Lifestyle
Smoking
Urban areas
- Accidental
- Diet
- Occupational
Mining, Smelting
54
What are the Natural / Endemic Metal Intoxications sources?
- Arsenic
- Selenium
- Thallium
- Animals can be used as sentinels of environmental contamination
55
What are the 4 classifications of metals?
- Alkali and alkaline-earth metals (essential)
- Essential transition metals
- Xenobiotic heavy metals
- Metalloids
56
What are examples of Alkali and alkaline-earth metals (essential)?
Sodium (Na), potassium (K), magnesium (Mg) and calcium (Ca)
57
What are examples of Essential transition metals?
Copper (Cu), manganese (Mn), iron (Fe) and zinc (Zn)
58
What are examples of Xenobiotic heavy metals?
Mercury (Hg), lead (Pb) and cadmium (Cd).
59
What is an example of metalloids?
Arsenic (As) are considered to have chemical and physical properties of both metals and non-metal elements.
60
What are the Functions of Homeostasis of essential metals?
- Cofactors of many enzymatic processes
Cells and organisms have evolved complex homeostatic mechanisms to handle essential metals
Transport
Compartmentalization
Protein binding
61
What is the mechanism of toxicity for iron (Fe)?
- Fe is a redox-active metal that catalyzes the formation of ROS.
- Fe is required as a cofactor of several enzymes, including those of mitochondrial respiration and heme enzymes (Fe-S clusters).
62
What disease can iron (Fe) cause?
Hereditary hemochromatosis
Mutations in the Human homeostatic iron regulator (HFE) gene (interacts with transferrin) excessive intestinal absorption of dietary iron, resulting
63
How is iron (Fe) normally transported through the body?
Iron import can occur via endocytosis of Fe3+-bound transferrin receptor 1 or via Fe2+ importers DMT1
Intracellular Fe is stored in ferritin.
Export occurs through ferroportin
64
What is the function of copper (Cu) under normal conditions?
Cofactor of many enzymes involved in cellular respiration ( cytochrome C oxidase, CCO), radical detoxification (superoxide dismutase, SOD1), and biosynthesis of macromolecules.
65
What is the mechanism of copper (Cu) transport?
- CTR1 transporters accept Cu+ from carriers
1) CCS distributes Cu to SOD1 (antioxidant), while 2) Atox1 transfers Cu to the secretory pathway and nucleus.
- Cu is also delivered to cytochrome C oxidase (CCO) in mitochondria by Cox17, Cox11 and Sco1. Cu-ATPases (ATP7A and ATP7B) transport Cu to the secretory pathway
66
What diseases can copper toxicosis cause?
Wilson Disease and Menkes Disease
67
What is Wilson Disease?
What causes it?
How is it treated?
- Autosomal recessive genetic disorder (ATP7B)
- Accumulation of Cu in the brain, liver, kidneys, and cornea as a result of impaired biliary excretion
- Liver transplantation or chelation therapy
68
What is Menkes Disease?
What is it caused by?
How does Menkes Disease affect different breeds of dogs?
- X-linked recessive disorder (ATP7A)
- Abnormal intestinal Cu absorption with a secondary deficiency in Cu-dependent mitochondrial enzymes.
- Dogs:
Bedlington Terriers: COMMD1 (unclear function [traffic of ATP7A and B?]) and ABCA12 (a gene close related to ATP7B) mutations
Labradors ATP7A and ATP7B mutations lead to copper toxicosis and liver failure.
69
What is Manganese (Mn) intoxication?
Mn2+ intoxication in humans is commonly described as manganism, a neurological condition that shares several overlapping features with Parkinson's disease.
70
What is the function of Manganese (Mn) under normal conditions?
Mn2+ is a key constituent of some metalloenzymes (MnSOD, mitochondrial superoxide dismutase) and is a required cofactor for the function of other enzymes (glutamine synthetase), as well as for the synthesis of proteins and vitamins.
Mn2+ modulates oxidative stress, which is crucial for normal brain activity.
71
How does Manganese (Mn) intoxication affect someone?
-Mn2+ exposure affects the neurotransmission of dopamine
-Mn2+ affects normal neurotransmission of glutamate and GABA
-Mn2+ exposure activates microglial cells with the production of proinflammatory cytokines
-Mn2+ exposure impairs the proteasome system, autophagy, and endosomal trafficking leading to abnormal protein aggregation.
-Mn2+ induces mitochondrial dysfunction, inducing the production of ROS
72
What is the function of zinc (Zn) under normal conditions?
- Zn has a structural role in proteins and activates substrates for nucleophilic attack
73
Why do essential metals become toxic?
Toxicity linked to either:
- An increased exposure and accumulation (very rarely)
- An impairment in the proper intracellular homeostasis
74
What is the function of xenobiotic heavy metals?
Xenobiotic (heavy) metals have no physiological functions.
75
What are some examples of xenobiotic heavy metals?
Lead (Pb)
Mercury (Hg)
Cadmium (Cd)
76
What are the sources of lead (Pb)?
How is it absorbed?
What are its negative effects?
- Sources: gasoline, industrial processes, paint, water pipes, solder in canned food
- Absorption: Inhalation and ingestion of Pb and Pb-containing particles or products
- Neurotoxic and alterations during neurodevelopment
- Anemia
77
What is the main disease that mercury (Hg) causes?
Minamata Disease
78
What is Minamata Disease?
What are its symptoms?
What was it caused by?
- Is a neurological syndrome caused by severe mercury poisoning.
- Ataxia, numb hands and feet, muscle weakness, peripheral vision loss, and hearing and speech damage.
- Insanity, paralysis, coma, and death. A congenital form can also affect fetuses in the womb.
- It was caused by the release of MeHg in the industrial (Chisso Corporation) wastewater from 1932 to 1968 that bioaccumulated in shellfish and fish
79
What are the sources of mercury (Hg)?
- Hg is found in the environment as sulfide compounds generated from volcanic activity and erosion
- Higher in fish and in the water near ore deposits
Predators (Biomagnification)
Hg is released by anthropogenic sources such as fuel combustion, waste disposal, and industrial activities.
80
What are the forms of mercury (Hg), and how are they absorbed?
- Elemental Hg0 used in thermometers and amalgams is primarily absorbed via inhalation and mucosa
- Inorganic Hg2+ used in medicine and everyday life products is partially absorbed through the gut.
- Organic Hg (ethyl [EtHg] and methylmercury [MeHg]) originate from biomethylatilation. MeHg is absorbed by the GI tract.
81
What are the sources of Cadmium (Cd)?
Cd(II) is the only reduction state that seems to be accessible for biological systems.
- Sources:
Cd occurrence is mainly associated with Zn and, to a lesser extent, Pb and Cu minerals.
Industry: Metal-coating, alloys, batteries (manufacturing and disposing of)
82
What is the mechanism of Cadmium (Cd) transport?
What is its toxicity linked to?'
What is the mechanism of its detoxification?
- Cd transport across membranes is through molecular mimicry via several transporters such as Cu/Zn transporters, DMT1, and Ca2+ channels.
- Cd toxicity is linked to its ability to bind thiol-containing molecules such as GSH and protein-Cys, as well as the displacement of redox-active metals such as Fe.
- Cd detoxification of cells is facilitated by the activity of GST and the detoxification of GSH-Cd adducts via MRPs (multidrug transporters).
83
What are the sources of xenobiotic heavy metals?
They are present in measurable concentrations in living organisms due to their environmental presence.
84
What are the sources of arsenic?
Arsenic toxicity is a worldwide health concern affecting several millions of people, mainly by groundwater contamination.
Is present naturally in air, water and soil.
85
What are the general mechanisms of xenobiotic heavy metal toxicity?
Xenobiotic metal toxicity is largely attributable to the interference with cellular biochemical systems, including redox-related processes
86
What are the main effects of xenobiotic heavy metal toxicity?
Effects:
Carcinogen
GI alterations and axonopathy
Brain
87
What xenobiotic heavy metals create DNA adducts?
Thiol groups?
Redox reactions?
DNA-adducts
Cr, Pt
Thiol groups
As, Cd
Redox reactions
ROS and Oxidative Stress
Cu, Fe
88
Why is the Mad Hatter mad?
The Hatter’s erratic, agitated behavior in the classic story refers to a real industrial hazard in Lewis Carroll’s Britain of 1865. Hatters or hat-makers commonly exhibited slurred speech, tremors, irritability, shyness, depression, and other neurological symptoms, hence the expression “mad as a hatter.” The symptoms were associated with chronic occupational exposure to mercury. Hatters toiled in poorly ventilated rooms, using hot solutions of mercuric nitrate to shape wool felt hats.
89
What are the components of gas exchange?
1. Nasal (and oral) passages
2. Conducting Airways: Ciliated epithelium
3. Gas-exchange region (Pulmonary acini)
90
What are the components/function of the Nasal (and oral) passages?
- Nostrils to pharynx (Nasopharynx)
- Air entrance
91
What are the components of Conducting Airways?
- Trachea
- Bronchi
92
What does gas exchange in the lung consists of?
1. Ventilation
2. Perfusion
3. Diffusion
93
What is ventilation?
What is vital capacity pertaining to this?
What is the total volume concerning this?
The influx of O2-rich air, efflux of CO2-rich air
Vital capacity = maximum inspiratory and expiratory movement
Tidal volume = resting conditions
94
What is Perfusion in regard to gas exchange?
- Entire circulation output of the right heart ventricle
-Xenobiotics from the peripheral venous system reach the pulmonary capillaries immediately
95
What does Diffusion of gas exchange result in?
O2 --> erythrocytes
96
What are the determinants of lung injury by pollutants?
1. Solubility inversely correlates with gas penetrance
2. Particle size
3. Deposition
4. Clearance of deposited particles lessens the damage
97
What gases are relatively insoluble?
What gases are completely insoluble?
- Relatively insoluble: Ozone (O3) and nitric dioxide (NO2)
- Insoluble carbon monoxide (CO) and hydrogen sulfide (H2S)
98
What does gas deposition increase with?
- Larger volumes and higher velocities (Exercise)
- Air holdings
99
What are the mechanisms of gas deposition?
- Interception
- Inertial Impaction
- Gravitational Sedimentation
- Electrostatic deposition
- Brownian Diffusion
100
What is gas deposition interception?
When it contacts the surface of an airway wall
101
What is gas deposition Inertial Impaction?
Air velocity and particle mass
102
What is gas deposition Gravitational Sedimentation?
Weight and gravity
103
What is gas deposition Brownian Diffusion?
Random motion and deposition
104
How are deposited particles cleared to lessen damage?
1. Mechanical
2. Mucociliary escalator
- Nasal and Tracheobranchial
- Conductive airways
105
What are the Antioxidant properties that help with the clearance of gas particles?
1. Lymphatics and lymph nodes
Dissolved and enter the venous system
Pulmonary vasculature
2. Phagocytosis
106
What are the two categories of responses to lung injury?
Acute and Chronic
107
What are the mechanisms of Acute lung injury?
- Injury
- Inflammation and Oxidative Burden
- Bronchoconstriction
- Pulmonary Edema
- Cell proliferation
108
What are the types of INJURY in acute lung injury?
- Cell death
- Oxidative damage
- Bioactivation
109
What is the mechanism of Inflammation and Oxidative Burden in acute cell injury?
Active production or ROS by immune cell activation
110
What is Bronchoconstriction?
- Decrease in airway diameter
- Allergic response
111
What is pulmonary edema?
- Accumulation of fluid
- Alteration of ventilation and perfusion
112
What are the results of chronic lung injury?
- Emphysema
- Fibrosis (stiffness)
- Asthma
- Lung Cancer
- Developmental effects (post natal development)
113
What is emphysema?
Destruction of gas-exchanging area
114
What is Fibrosis?
(stiffness)
- Increase collagen
115
What is asthma?
Narrowing of the bronchi
116
What disease is a cause of lung inflammation?
What is the mechanism that results in lung inflammation?
Asbestos
- Engulfed and retained by macrophages
- Release of cytokines
- Inflammation
- Cancer (mesothelioma)
117
What is Chronic Obstructive Pulmonary Disease (COPD)?
COPD is a complex pathological process involving a variety of inflammatory cells, inflammatory mediators and related cell signaling pathways (ROS, and proteases)
118
What are the two diseases of COPD?
1. Emphysema (air sacs are damaged)
2. Chronic Bronchitis (the lining of the airways stays constantly irritated and inflamed)
119
What is the leading cause of COPD?
- Cigarette smoking is the leading cause of COPD. Fewer than 50% of heavy smokers develop COPD
- However, up to 25% of people with COPD never smoked. Long-term exposure to other irritants—air pollution, chemical fumes, or dust—also may contribute. Asthma
120
What are the results of Air pollutants?
- Long-term exposure to air pollution increases mortality
- Cardiovascular, neurodegeneration, and cancer
121
What is the topic of Inhalation Toxicology about?
Adverse effect of Indoor and Outdoor exposures
122
Where do aldehydes come from?
Reaction products of photo-oxidation of hydrocarbons
123
Where does Formaldehyde have toxic effects?
- Absorbed in the upper respiratory tract mucus
- Sensory nerve fibers
124
What is particulate matter?
Mix of organic, inorganic and biological materials in the atmosphere
125
What are examples of particulate matter?
Metals
Gas-particle interactions
Ultrafine carbonaceous matter
126
How is ozone toxic?
- Activated by UV
- UV splits O2 to O* (radical) which recombines with O2 to generate ozone (O3)
127
What is the troposphere?
Nitric oxides from combustion absorb UV generating O*, which reacts with hydrocarbons as well as generating free radicals
128
What is radon?
How does it form?
Where is it from?
- Colorless, odorless, radioactive gas (DNA damage)
- Forms naturally from the decay of radioactive elements (uranium) found in different amounts in soil and rock worldwide.
- Radon gas in the soil and rock can move into the air, underground, and surface water.
129
What is the safe level of radon?
There is there is no known safe level of exposure
130
What is the relationship between radon and cancer?
- The estimated second leading cause of cancer in the US. Evidence:
- Studies of people working in underground mines with high levels of radon exposure
- Studies comparing radon levels in the homes of people with lung cancer with the levels in the homes of similar people without lung cancer
- Studies comparing lung cancer cases or deaths in areas with differing levels of radon exposure
131
What are two sources of Reductive air pollution?
Sulfur dioxide SO2
Sulfuric acid
132
What are the sources of sulfur dioxide SO2?
What are the effects of sulfur dioxide?
- Smelting and related combustion-based industries
- Incomplete combustion of coal
- Water soluble irritant absorbed in the upper airways
- Bronchoconstriction (sulfite interaction with sensory receptors) and increased mucus secretion
133
What are the sources of sulfuric acid?
- Sulfated fly ash from the reaction of sulfates with metals and water vapor
- Photochemical reactions in the troposphere (metal-dependent or independent)
134
How do meteorological inversions increase air pollution?
- Metereological inversions might lead to toxic levels of SO2
- Impairs macrophage function
Surface temperature inversions play a major role in air quality, especially during the winter when these inversions are the strongest. Pollutants from vehicles, wood burning, area sources, and industry become trapped near the ground during inversions, leading to poor air quality.
135
What are the functions of the skin epidermis?
1. Protects the body from external insults
2. Participates in thermal, electrolyte, hormonal, metabolic, and immune regulation
136
What is the cellular composition of the epidermis?
What do cells of the epidermis express?
- Keratinocytes
- Melanocytes (melanin granules)
- Langerhans cells (macrophages) and lymphocytes
- Cells of the epidermis and pilosebaceous units express biotransformation enzymes
137
What is the Striatum corneum of the skin?
What is its function in terms of xenobiotic absorption?
- Primary barrier
- Percutaneous absorption depends on the hydrophobicity of the xenobiotic
138
What are the two types of contact dermatitis?
- Irritant contact dermatitis
- Allergic contact dermatitis
139
What is irritant contact dermatitis?
What causes it?
What are the effects?
- Non-immune response to the direct action of xenobiotics
- Strong acids, bases, solvents, and unstable or reactive chemicals
- Disruption of macromolecules or injury of cellular components
- Chemical Burns
140
What is Allergic contact dermatitis?
What type of allergic reaction is it?
What is the mechanism?
- Delayed hypersensitivity reaction
- (Type IV)
1. Initial sensitization
2. Minute quantities elicit subsequent overt reactions
3. Inflammation induced by T- lymphocytes
141
What type of sensitivity reaction is Contact urticaria?
What is its mechanism?
What causes it?
- Type I hypersensitivity reaction
- Histamine and vasoactive peptide release from Mast cells
- Latex
142
What skin agents cause cancer?
Arsenic and Polycyclic aromatic hydrocarbons
143
How are we exposed to Phototoxicology (Ultraviolet radiation)?
We are exposed to radiation that spans the electromagnetic spectrum
144
What are the different UV wavelengths?
What are the two types of UV exposure?
UVC (100–280 nm) that does not reach the skin, as it is filtered by atmospheric ozone
UVB (280–315 nm)
UVA (315–400 nm)
Visible
Infrared
145
What is solar radiation?
Solar radiation that primarily reaches the earth (290-700 nm) is at the visible and UV spectra
146
What are the sources of UV radiation?
Sources:
Natural (Sun)
Artificial heat and light sources
147
Why is UV light needed for vitamin D?
Ultraviolet radiation is critical for the conversion of 7-dihydro cholesterol to pre-vitamin D (precursor of Vitamin D)
148
Explain the metabolism of vitamin D
- 7-dehydrocholesterol is converted to pre-vitamin D3 (pre-D3) in response to UVB.
- Isomerization (catalyzed by heat) of pre-vitamin D3 forms Vitamin D3 in the epidermal basal layer
- D3 is hydroxylated by liver hydroxylases ), which are then hydroxylated in the kidney to yield calcitriol
- Synthesis of calcitriol is stimulated by parathyroid hormone (PTH)
149
What is a Chromophore?
A chromophore is the section of a molecule that causes us to see color.
150
What is the mechanism of Electromagnetic radiation?
What is this toxicity affected by?
Electromagnetic radiation must be absorbed to exert toxicity.
Toxicity is affected by:
1. Epidermal thickness
2. Water content
3. Chromophores (UVB)
151
What is the mechanism of toxicity of chromophores?
UV-photon is absorbed by a chromophore and can either convert the energy into harmless heat very quickly or have a long-lived excited state
Melanin
Amino acids
DNA
152
What are the effects of different types of UV radiation?
- Erythema (“Reddening” of the skin)
- Skin thickening
- Premature aging (senescence)
- Cancer (melanomas)
153
What is skin aging caused by?
In general, an individual’s skin reflects several stages of extrinsic aging superimposed on the level of intrinsic aging.
Exposure to sun, pollution and tobacco are now well known to trigger molecular processes that damage the skin structure, leading to the aged skin appearance
154
What is melanoma?
Melanoma, the most serious type of skin cancer, develops in the cells (melanocytes) that produce melanin — the pigment that gives your skin its color.
155
What are the risk factors of melanoma?
- The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma.
- Immunosuppression, sun sensitivity, and exposure to UV radiation are additional risk factors.
25 to 40 percent of the members of melanoma-prone families have mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A)
156
What are the two classifications of pigment darkening of the skin?
Increased pigmentation (Melanin) – 3 days – UVB
Photo-oxidation – Immediately – UVA
157
What does skin pigment darkening result in?
The cutaneous immune function increases the local production of growth factors and induces the formation of DNA-damaging reactive oxygen species that affect keratinocytes and melanocytes.
158
What is the tanning response?
The tanning response is a defensive measure in which melanocytes synthesize melanin and transfer it to keratinocytes, where it absorbs and dissipates ultraviolet energy.
159
What does UV light increase skin pigmentation through?
In part through the action of α-melanocyte–stimulating hormone (α-MSH) on its receptor, the melanocortin receptor 1 (MC1R), whose signaling increases the expression of enzymes involved in the production of melanin.
160
When does melanoma most frequently occur?
Melanoma occurs most frequently after intermittent exposure to the sun and in people with frequent sunburns.
161
What Epidemiologic observations have been made about UV exposure and melanoma?
Epidemiologic observations suggest that chronic or low-grade exposures to ultraviolet light induce protection against DNA damage, whereas intense, intermittent exposures cause genetic damage.
162
What is Genetic Photosensitivity?
What disease can it cause?
Impaired ability of skin cells to repair UV-induced damage
Xeroderma pigmentosum: Patients have 2,000- and 10,000-fold increased incidence of melanoma and nonmelanoma skin cancers
163
What are different Autoimmune diseases that result from reactions of the skin?
- Lupus erythematosus
- Cutaneous Porphyrias (Sun exposed areas)
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What is Lupus erythematosus?
- UV-induced apoptotic keratinocytes are not cleared and stimulate the immune system
- Infiltration of immune cells or immune complexes in the skin
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What is Cutaneous Porphyrias?
- Accumulating porphyrin precursors or derivatives via disruption in heme synthesis in erythropoietic cells.
- Fluoresce (400-410 nm) and generate free radicals. Burning sensation after sun exposure
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What is Phototoxicity mediated by?
Mediated by exogenous chemicals that absorb UV light and produce free radicals (photodynamic)
Primarily mediated by UVA
St John’s Wort
Non-photodynamic
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What is the mechanism of phototoxicity?
The unbound furocoumarin (F) is excited by UVA, forming a radical singlet state (F*) and the triplet state (FT), which triggers singlet oxygen formation.
Complexed with DNA in the dark, DNA: F are converted to covalent mono adducts (DNA-F) by UVA, a fraction of which may be converted to cross-links (DNA=F) in a subsequent photochemical step.
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What type of hypersensitivity reaction is Photoallergy?
Type IV delayed hypersensitivity reaction
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What results from photoallergy?
What is the mechanism of photoallergy?
- Eczema
- UV light converts a photosensitizing chemical to a hapten that elicits the allergic response
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What is Risk Assessment?
The systematic scientific characterization of potential adverse health effects resulting from human exposures to hazardous agents or situations.
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What is risk?
The probability of an adverse outcome to occur under specified conditions of exposure
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What is risk management?
The process by which policy actions are chosen to control hazards identified in risk assessments
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What are the objectives of Risk Assessment?
1. Balance risks and benefits
2. Set target levels of risk (exposures)
3. Set priorities for program activities
4. Estimate residual risks and the extent of risk reduction after steps are taken to reduce risks
5. Hazard
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Risk Assessment/Management Framework
Research:
- Laboratory and field measurements
- New mechanistic understandings of toxicology
- New genomic research
Risk assessment:
- Hazard identification
- Dose-response assessment
- Exposure assessment
- Risk characterization
Risk management:
- Development of regulatory options
- Evaluation of public health
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What are the 4 Elements of Risk Assessment?
1. Hazard identification
2. Dose-response assessment
3. Exposure assessment
4. Risk characterization
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What is Hazard identification?
The examination of all relevant toxicological and related data to identify the hazard associated with a chemical
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What is a Dose-response assessment?
Determining the relationship between the magnitude of the exposure and the probability of adverse health effects.
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What is Hormesis?
A phenomenon in which exposure to a harmful substance gives beneficial effects to living organisms when the dose of the harmful substance is small
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What is Exposure assessment?
Determining the extent of human exposure
Accident (consequences), Occupation (prevention)
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What is Risk characterization?
It involves integrating information from the previous 3 steps to develop a qualitative or quantitative estimate of the nature and magnitude of human risk and the uncertainty associated.
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What is a HAZARD?
A potentially harmful agent
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What are the steps to Assessing the Toxicity of Chemicals?
1. Structure/Activity Relationships
2. In vitro and short-term tests
3. Animal bioassays
4. Epidemiological data
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What are the types of Epidemiological Studies?
- Cross-sectional
- Longitudinal:
Case-control
- Cohort
Prospective
Retrospective
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What is a Cross-sectional study
Survey groups of individuals to identify risk factors and disease prevalence (at one specific point in time). The most important problem is differentiating cause and effect from the simple association.
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What is a longitudinal study?
Studying a population over an extended period.
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What is a case-control study?
People with the outcome of interest are matched with a control group who do not. Retrospectively the researcher determines which individuals were exposed to the agent or treatment
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What is a cohort study useful for?
Best method for determining the incidence and natural history of a condition
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What is a prospective study?
A group of people who do not have the outcome of interest (disease or toxicosis) are chosen. A variety of variables that might be relevant to the development of the condition are measured and followed over a period of time to see whether they develop the outcome of interest.
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What is a retrospective study?
These use data already collected for other purposes. The methodology is the same but the study is performed posthoc. The cohort is “followed up” retrospectively. The study period may be many years but the time to complete the study is only as long as it takes to collate and analyze the data.
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What are Epidemiological findings judged by?
- Strength of association
- Consistency or reproducibility
- Specificity
- Temporal relationship
- Dose-response relationship
- Plausibility (probability) and coherence (logical)
- Verification and analogy
- Design
Power of detection
Confounding factors
Approach
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What is the “critical adverse effect” to be assessed?
A critical adverse effect is defined as the significant adverse biological effect that occurs at the lowest exposure level
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What are the different Thresholds of Dose-Response Assessment?
- No or Lower adverse effect levels
NOAEL
LOAEL
LD50: dose that produces 50% lethality
LC50: concentration that produces 50% lethality
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What are uncertainty factors?
Uncertainty factors are used to compensate for a deficiency in knowledge concerning the accuracy of test results and the difficulty in estimating the health effects in a different species and/or in different exposure conditions.
