PHAR303 Lecture 13 Skin, Eye, Household Hazards

Skin overview

• Largest organ

• Environmental barrier

• Temperature regulation

• Fluid and electrolyte regulation through sweat

• Sensory organ

• Hormone function and alteration of blood flow

• Metabolism of some drugs/toxins through metabolizing enzymes

• Immune function

anatomy of the skin

• 3 layers: epidermis, dermis, hypodermis

• Contains sweat glands, hair follicles, nerves, blood vessels, follicles, and glands

• Toxicants can bypass the stratum corneum through follicles and glands, allowing for faster absorption

epidermis - cell types

• Outermost layer: epidermis

• Langerhans cells: similar to macrophages; take up antigens and function as antigen-presenting cells (APCs)

• Melanocytes: produce pigments that are inserted into keratinocytes

• Merkel cells: act as mechanosensors and respond to touch

epidermis - stratum corneum and cornerocytes

• Stratum corneum: made of flattened, dead keratinocytes (corneocytes)

• Constantly shed every ~4 weeks as new keratinocytes move upward to replace old layers

• Shedding of dead skin occurs from top to bottom, protecting deeper layers

• Corneocytes are connected by lipids and desmosomes

desmosomes

• Desmosomes: strong cell–cell adhesion proteins that hold the stratum corneum together like a brick wall barrier

• Prevent rapid loss of water and entry of xenobiotics into the body

• Fractures can occur between desmosomes, allowing passage of unwanted substances/toxins into the skin for absorption

skin variation

• Thickness of the stratum corneum varies depending on the body region

• Hands and feet (palms and soles) have a thick stratum corneum to resist abrasion and reduce toxin absorption

• Behind the ear has the thinnest stratum corneum, allowing drugs to be more easily absorbed

• Children and elderly individuals have thinner skin, making them more vulnerable to skin-absorbed xenobiotics

• Individuals who lose the stratum corneum layer are also more vulnerable to absorption of xenobiotics

dermis

• Important for thermoregulation and supplies nutrients to the avascular epidermis

• Blood flow to the skin varies up to 100× depending on temperature regulation

• When overheated, connecting veins and capillary networks dilate, leading to heat loss

• Extensive immune system:

  • Macrophages

  • NK

  • Mast cells → release histamine

  • Fibroblasts →

  • T cells → cytokines

  • Keratinocytes → release signaling molecules

absorption of toxins thru skin

• 3 ways toxins can penetrate the skin:

1. Intracellular pathway

• Small or nonpolar toxins can pass through cell junctions between corneocytes

2. Transcellular pathway

• Toxins penetrate through cells

• Lipophilic substances can pass through the plasma membrane

3. sweat glands and hair follciles pathway

• Sweat glands and hair follicles extend from the epidermis into the dermis and may reach the hypodermis

• Serve as a highway for toxin absorption into the skin

toxin absorption promoted by:

• Lipid solubility and low molecular weight: benzene, toluene, CCl₄

• Nicotine patches are slowly and steadily absorbed, reaching the bloodstream

• No first pass through the liver, but there is still first-pass metabolism from skin P450s

• Phase 1: by P450s

• Phase 2: in the epidermis

impaired barrier function of skin

• By disease/abrasion: elevated water content relaxes connections of the stratum corneum

• Occupational exposure: agriculture, cleaning, construction cause local irritation

• Dissolves lipid bilayer systemically absorbed

• Examples: toluene and turpentine

• Found in hardware, paint, and markers

manifestations of exposure to skin toxins

• Disorders caused by exposure:

• Dermatitis (irritant and allergic)

• Photosensitivity

• Hives

• Skin cancer

• Eczema

• Pigment disturbances

contact dermatitis - irritant dermatitis

• Inflammation of the skin through contact with toxins

1. Irritant dermatitis

• Majority of cases

• Primary irritants: cause damage at the site of contact through direct chemical or physical action

• No immunological sensitization required

• Absolute irritants: strong acids, bases, reactive chemical compounds

• Severe inflammation can occur on first exposure

• Direct injury to skin causes an inflammatory reaction

• Does not involve a single mechanism of action; involves many cytokines

• Usually requires initial/excessive exposure to cause damage

- irritant dermatitis continued

• Intensity of dermatitis is proportional to dose

• Great individual variability exists

• Factors affecting susceptibility include:

  • Thickness of the stratum corneum

  • Number of hair follicles

  • Water contact

• Example: a worker with calloused, rough skin will not burn as much as an infant due to differences in skin barrier thickness and protection

irritant dermatitis - acute irritation

• Acute irritation

• Also known as 2nd degree chemical burns

• Substantially disrupts the cornified layer

• Often elicited due to brief exposure to a strong acid, base, oxidizing agent, or reducing agent

• Wet cement causes irritation due to alkalinity

• Danger to dogs and cats

irritant dermatitis - chronic irritation

• Constitutes the majority of irritant dermatitis

• Often elicited due to repeated exposures to a substance that is more neutral in pH

• Causes more gradual damage to the stratum corneum

• soaps, detergents, solvents

allergic dermatitis

• Delayed type IV T cell-mediated hypersensitivity reaction

• Langerhans cells patrol the skin, detect pathogens, consume and process foreign antigens

• Migrate to lymph nodes and present antigens to T cells

• Initiate immune response and maintain tolerance

• T cells become activated and proliferate over a 1–3 week period

• Activated T cells are generated and enter circulation

• Hapten: generates an allergic reaction

• Hapten penetrates the lipid bilayer and becomes attached to a carrier protein

• Hapten–carrier complex forms an antigen

allergic dermatitis continued

• First contact with irritant causes sensitization through the skin

• APCs (Langerhans cells) activate T cells

• Person becomes sensitive after initial exposure

• On next exposure, allergic dermatitis occurs

• Reaction is triggered by activated T cells releasing cytokines, which recruit macrophages and other cells to induce an inflammatory reaction

• Dose is unrelated to effect; a small amount can elicit a large reaction

• Response magnitude depends on the individual person

allergic dermatitis causes

• Examples of allergens:

  • Poison ivy

  • Henna

  • Poison oak

  • Nickel from accessories

  • Rubber latex

  • Glue

  • Drugs and cosmetics

  • Temporary tattoos

• Sensitization test: patch test

• Observes keratinocytes, Langerhans cells, dendritic cells, and cell lines

photoxicology

• Skin exposure to sunlight can lead to toxicity

• Xenobiotics may exhibit toxicity following sunlight exposure

• Sources of light exposure:

  • Sun

  • Ozone depletion leads to increased penetration

  • Indoor tanning

• UVB < UVA < visible light

• Longer wavelengths contain less energy

• Shorter wavelengths contain more energy and are more reactive

• UVA:

  • Less reactive

  • Can penetrate more deeply into the dermis

  • Can lead to cancer and aging

• UVB:

  • More reactive

  • Penetrates less deeply

  • More likely to cause sunburn in the superficial layers of skin

phototoxicity

• Can occur when a compound reacts with sunlight and damages the skin

• Does not involve an immunological response

• Examples:

  • Tattoo ink

  • Antibiotics

  • Chlorpromazine

  • Carrots

  • Citrus

  • Legumes

• Furanocoumarins (e.g., psoralen):

  • Activated by UVA

  • Cause DNA damage

  • Flat molecules that can easily intercalate into DNA

  • Cause permanent hydrogen bond disruption

photocarcinogenicity

• Substances which have their free carcinogenic functions activated by light

• Xenobiotics absorb UV light and produce free radicals

• Xenobiotic + UVA → DNA adducts

• Free radicals attack DNA and proteins, leading to increased cancer risk

• Climate change can enhance skin toxicity

• UV light can create carcinogens from skin creams, etc.

detecting potential phototoxicity

im gay

photoallergy

• Requires sensitization

• Photocontact dermatitis occurs upon exposure to light

• Chemicals that are not problematic usually can cause photocontact dermatitis upon exposure to sunlight

• Xenobiotics absorb UV light and convert into haptens

• Causes allergic contact dermatitis (Type IV hypersensitivity reaction)

• Examples: soaps, drugs, cosmetics

urticaria (hives) type I hypersensitivity

• Direct effect

• Examples:

  • Latex pants

  • Antibiotics

• Anaphylactic symptoms:

  • Hay fever

  • Bronchial asthma

  • Systemic anaphylaxis

• Mechanism:

  • First exposure:

    • IgE antibodies against the allergen source are produced and collected by mast cells

  • Second exposure:

    • Allergen cross-reacts with 2 IgE antibodies

    • Triggers histamine and inflammatory mediator release from mast cells

    • Increases capillary permeability to allow WBC movement

solvents

• Small molecules that can penetrate through the skin barrier easily

• Examples: ethylene glycol, toluene, etc.

• Leaving hands in solvents makes it easy for chemicals to penetrate the skin

• Paint causes local irritation and dermatitis

• Dissolution of the lipid bilayer allows systemic absorption

• Example: turpentine dissolves the skin barrier and causes contact dermatitis

toxicology of the eye

• Anterior part of the eye (cornea, eyelids) is more susceptible to toxin injury

• Some compounds are toxic to the retina, optic nerve, and visual cortex

• Examples: lead, methanol, methyl mercury

• Small molecules can cause eye injury that is usually long-term and/or permanent

defense mechanisms of the eye

• Eyelids and lashes provide a thin protective barrier for the eye

• Cornea has minimal metabolizing enzymes

• The eye can perform Phase I and Phase II metabolism using enzymes present in the eye

toxicology testing in the eye

1. Original test: Draize eye test in rabbits

• No longer used

2. Accepted short-time exposure in vitro test

• Tests if chemicals cause serious eye damage or not

• In vitro test consists of human corneal epithelial cell lines

cataracts

• Clouding of the eye lens

• Usually caused by aging

• Breakdown of proteins causes light scattering, resulting in faded vision

• Causes: UV light, steroids, tobacco

• Impairs properties of the tissue and cells

• Turns the lens white

• Treatment: outpatient surgery with an artificial lens

household hazards: garage, garden

• Examples of environmental skin hazards:

  • Paint thinners

  • Cement

  • Plants

  • UV light

  • Insecticides

  • Herbicides

  • Insects that sting

  • Weeds

• Do not pull out a bee sting:

  • Causes a burst of apamin

  • Mast cell degranulating peptide release

household hazards: bathroom, kitchen, bedroom

• Examples of household/environmental toxins:

  • Drano

  • Ammonium

  • Bleach

  • Toilet cleaner → do not mix with bleach; can produce chlorine gas

  • Medicated antibacterial soaps

  • Band-aids

  • Kitchen latex

  • Oven cleaners with NaOH

  • Bathroom cosmetics

• Carpets can accumulate toxins such as smoke

• Can be harmful for kids and pets