Skin absorption is a route by which substances can enter the body through the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

. Along with

inhalation Inhalation (or Inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

ingestion Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in a substance through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms in ...

and injection, dermal absorption is a route of exposure for toxic substances and

route of administration A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

for

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

. Absorption of substances through the skin depends on a number of factors, the most important of which are

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', ''number concentration'', ...

, duration of contact,

solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...

of medication, and physical condition of the skin and part of the body exposed. Skin (percutaneous, dermal) absorption is the transport of chemicals from the outer surface of the skin both into the skin and into circulation. Skin absorption relates to the degree of exposure to and possible effect of a substance which may enter the body through the skin. Human skin comes into contact with many agents intentionally and unintentionally. Skin absorption can occur from occupational, environmental, or consumer skin exposure to chemicals, cosmetics, or pharmaceutical products. Some chemicals can be absorbed in enough quantity to cause detrimental systemic effects. Skin disease (

dermatitis Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved c ...

) is considered one of the most common occupational diseases. In order to assess if a chemical can be a risk of either causing dermatitis or other more systemic effects and how that risk may be reduced, one must know the extent to which it is absorbed. Thus, dermal exposure is a key aspect of human health risk assessment.

Factors influencing absorption

Along with

and injection, dermal absorption is a route of exposure for bioactive substances including medications.Eaton, DL and Klaassen Curtis D. Principles of Toxicology. in Cassarett & Doull's Toxicology, ''The Basic Science of Poisons''. 5th edition. 1996. McGraw-Hill. Absorption of substances through the skin depends on a number of factors: * Concentration * Molecular weight of the molecule * Duration of contact * Solubility of substance * Physical condition of the skin * Part of the body exposed including the amount of hair on the skin In general, the rate of absorption of chemicals through skin follows the following scheme from fastest to slowest: Scrotal > Forehead > Armpit ≥ Scalp > Back = Abdomen > Palm = under surface of the foot.Baynes, RE and Hodgson E. Absorption and Distribution of Toxicants. in Chapter 6 of A Textbook of modern toxicology. 3rd edition. 2004, John Wiley & Sons, Inc.

Structures influencing absorption

To be absorbed through the skin, a chemical must pass through the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rel ...

, glands, or hair follicles. Sweat glands and hair follicles make up about 0.1 to 1.0 percent of the total skin surface. Though small amounts of chemicals may enter the body rapidly through the glands or hair follicles, they are primarily absorbed through the

. Chemicals must pass through the seven cell layers of epidermis before entering the

dermis The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided ...

where they can enter the blood stream or

lymph Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues ...

and circulate to other areas of the body.

Toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

s and

toxicant A toxicant is any toxic substance, whether man-made or naturally occurring. By contrast, a toxin is a poison produced naturally by an organism (e.g. plant, animal, insect). The different types of toxicants can be found in the air, soil, water, or ...

s can move through the layers by

passive diffusion Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to dri ...

. The

stratum corneum The stratum corneum (Latin for 'horny layer') is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the ''stratum disjunctum'' and ''stratum compa ...

is the outermost layer of the epidermis and the rate-limiting barrier in absorption of an agent. Thus, how quickly something passes through this thicker outer layer determines the overall absorption. The stratum corneum is primarily composed of

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

cholesterol, cholesterol

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

s and

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make ...

s. Thus lipid-soluble chemicals make it through the layer and into the circulation faster, however nearly all molecules penetrate it to some minimal degree. Absorption of chemicals in municipal water and dental products such as VOC (Volatile Organic Compounds), TTHM (Total Trihalomethanes), fluoride and disinfectants is a major exposure to environmental health hazards. Skin

Conditions affecting skin absorption

Agents that injure the stratum corneum, such as strong acids, are absorbed faster than chemicals that do not.Rozman, KK and Klaassen CD. Absorption, Distribution and Excretion of Toxicants. in Cassarett & Doull's Toxicology, ''The Basic Science of Poisons''. 5th edition. 1996. McGraw-Hill Skin damage due to burns, abrasions, wounds and skin diseases also increase absorption. Thus populations with skin damage may be more susceptible to adverse effects of agents that are absorbed through the skin. Certain solvents like

dimethyl sulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds a ...

(DMSO) act as carriers and are frequently used to transport medication through the skin. DMSO increases the permeability of the stratum corneum.Baggot JD. Disposition and Fate of Drugs in the Body. Chapter 5 in ''Veterinary Pharmacology and Therapeutics'', 6th edition, 1988 Iowa State Press, Ames. Surfactants like sodium lauryl-sulfate increase the skin penetration of water-soluble substances, possibly by increasing the skin permeability of water.

Medical use of skin absorption

Dermal application of a medication or chemical allows treatment to be localized, unlike ingestion or injection. Some medications seem to be more effective (or are more efficient) using the dermal

. Some ingested drugs are heavily metabolized by the liver and may be inactivated, but using a dermal application bypasses this metabolic step allowing more parent compounds to enter the peripheral circulation. If a drug is absorbed well through the skin it may be used as a means of systemic medication. Dermal dosage forms include:

liniments Liniment (from la, linere, meaning "to anoint"), also called embrocation and heat rub, is a medicated topical preparation for application to the skin. Some liniments have viscosity similar to that of water; others are lotion or balm; still oth ...

, braces,

lotions Lotion is a low-viscosity topical preparation intended for application to the skin. By contrast, Cream (pharmaceutical), creams and gels have higher viscosity, typically due to lower water content. Lotions are applied to external skin with bare ...

ointments A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

, creams, dusting powders,

aerosols An aerosol is a suspension of fine solid particles or liquid droplets in air or another gas. Aerosols can be natural or anthropogenic. Examples of natural aerosols are fog or mist, dust, forest exudates, and geyser steam. Examples of a ...

, and transdermal patches. Specially designed patches are currently used to deliver

fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocain ...

nicotine Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...

and other compounds. Slower skin absorption versus oral or injectable may allow patches to provide medication for 1 to 7 days.Rice, RH and Cohen DE. Toxic Responses of the Skin. in Cassarett & Doull's Toxicology. ''The Basic Science of Poisons''. 5th Edition. 1996. McGraw-Hill For instance

nitroglycerin Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...

given

transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointme ...

ly may provide hours of protection against angina whereas the duration of effect

sublingual Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. The sublingual glands receive their primary ...

ly may only be minutes.

Measurement of skin absorption

The amount of chemical that is absorbed through the skin can be measured directly or indirectly. Studies have shown there are species with differences in the absorption of different chemicals. Measurements in rats, rabbits or pigs may or may not reflect human absorption. Finding the rate at which agents penetrate the skin is important for assessing the risk from exposures.

Direct measurement

In vivo

The transit of chemicals into the skin can be directly measured using non-invasive optical techniques with molecular specificity, such as Confocal

Raman Spectroscopy Raman spectroscopy () (named after Indian physicist C. V. Raman) is a spectroscopic technique typically used to determine vibrational modes of molecules, although rotational and other low-frequency modes of systems may also be observed. Raman ...

. This technique is able to identify unique spectra of molecules and compare to background skin spectra whilst limiting measurement regions using confocal gating, achieving depth-resolved concentration measurement. A single measurement sequence can thereby establish a snapshot profile of chemical concentration against depth inside the skin. By repeating the measurement at multiple timepoints, a dynamic concentration-at-depth profile is determined. Since modern Raman Spectrometers exhibit extremely high SNR, in-vivo absorption testing in human skin is possible on a scale of a few minutes or hours. A chemical may also be directly applied to the skin followed by blood and urine measurements, at set time points after the application, to assess the amount of chemical that entered the body. The concentration in the blood or urine at particular time points can be graphed to show an area under the curve and the extent and duration of absorption and distribution to provide a measure of systemic absorption. This can be done in animals or humans with a dry chemical powder or a chemical in solution. Rats are commonly used for these experiments. An area of skin is shaved before the chemical is applied. Often the area of chemical application is covered to prevent ingestion or rubbing off of the test material. Samples of blood and urine are taken at specific time intervals following application (0.5, 1, 2, 4, 10, and 24 hours) and in some protocols at the chosen end time the animal maybe necropsied. Tissue samples may also be evaluated for the presence of the test chemical.World Health Organization, Environmental Health Criteria 235, Dermal Absorption, 2006. In some test protocols many animals may be tested and necropsies may occur at set intervals after exposure. Biomonitoring, such as taking urine samples at intervals, from workers exposed to chemicals may provide some information but it is difficult to distinguish dermal from inhalation exposure using this method.

Ex vivo

The permeability properties of the stratum corneum are, for the most part, unchanged after its removal from the body. Skin that has been removed carefully from animals may also be used to see the extent of local penetration by putting it in a chamber and applying the chemical on one side and then measuring the amount of chemical that gets into a fluid on the other side. One example of this ex vivo technique is the isolated perfused porcine flap. This method was first described in 1986 as a humane alternative to in vivo animal testing.

In vitro

Techniques such as

static diffusion cell Static may refer to: Places *Static Nunatak, a nunatak in Antarctica United States *Static, Kentucky and Tennessee *Static Peak, a mountain in Wyoming ** Static Peak Divide, a mountain pass near the peak Science and technology Physics *Static el ...

s (Franz cells) and flow-through diffusion cells (Bronaugh cells) have also been used. The Franz Cell apparatus consists of two chambers separated by a membrane of animal or human skin. Human skin is preferred but due to ethical and other considerations is not always available. Human skin often may come from autopsies or plastic surgeries. The test product is applied to the membrane via the top chamber. The bottom chamber contains fluid from which samples are taken at regular intervals for analysis to determine the amount of active cells that has permeated the membrane at set time points. Bronaugh cells are similar to Franz cells but use a flow-through system beneath the membrane layer and samples of the liquid below are taken continuously rather than at set time points. Bronaugh cells have been replaced wit
inline cells
by some manufacturers.

Indirect measurement

It is sometimes impossible for humane reasons to apply a drug to the skin and measure its absorption.

Sarin Sarin (NATO designation GB G-series, "B"">Nerve_agent#G-series.html" ;"title="hort for Nerve agent#G-series">G-series, "B" is an extremely toxic synthetic organophosphorus compound.octanol-water partitioning coefficient (a measurement of the uptake from aqueous solution into powdered stratum corneum). # The weight of the person. Standard weight of an adult 71.8 kg, a 6-year-old child 22 kg and female of child-bearing age 60 kg are generally used. # The nature of the exposure, e.g. a cream applied to the whole body, to just a small area, or a bath in a dilute solution.

Skin contact with dry chemical

:To calculate the dose of chemical a person is exposed to one must multiply the surface area of the skin exposed by the concentration of the chemical in the substance that comes into contact with the skin. Then multiply by the time in contact, by the permeability coefficients, and any unit conversion factors needed, then divide by the weight of the person. :A simple mathematical formula to estimate the dose for a single exposure is: :: concentration of chemical × surface area exposed × permeability coefficient / body weight. :Models for this can be found in the EPA Standard Operating Procedures for Residential Exposure Assessment. These models establish guidelines for estimating pesticide exposure so that one can judge the risk and take appropriate actions if the risk is judged to be too great given the exposure.

Skin contact with chemical in solution (water, etc.)

:This can be modeled similarly to the dry chemical but one has to take into account the amount of solution the skin comes into contact with. Three scenarios for exposure to chemicals in a solution have been proposed and modeled. :a. A person could be exposed partially to a solution for a period of time. For instance if one stood in contaminated flood water for a period of time, or one worked in a situation where the hands and lower arms were immersed in a solution for a period of time. This type of scenario depends on the skin area exposed and the duration of the exposure as well as the concentration of the chemical in the solution. One may have to adjust the absorption coefficients for the different area of the body as the feet are more calloused on the bottom and will allow less chemical through than the lower leg. The rate of absorption of chemicals follows the following general scheme from fastest to slowest: Scrotal > Forehead > Armpit ≥ Scalp > Back = Abdomen > Palm = under the surface of the foot. The dermal absorption of a dilute solution by partial leg or arm exposure has been modeled by Scharf. The EPA also has guidance on calculating the dermally absorbed doses of chemicals from contaminated water. :Mathematical formula: ::''Dermally absorbed dose rate = concentration in water × surface area exposed × exposure time × permeability coefficient × conversion factors''. :b. The second scenario is total body immersion, such as swimming in a pool or lake. Exposure in swimming pools is only partially dermal and a SWIMODEL has been proposed. This model takes into account not only the skin exposure but also considers ocular, ingestion, inhalation, and

mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...

exposure that may occur due to being totally immersed. A second model dealing primarily with skin absorption was created by Scharf to assess the risk of overspray of pesticide from aerial spraying on swimming pools. These models use whole body surface area rather than the surface area of specific parts for the mathematical input. :c. The third scenario is splash, or droplet exposure. This model takes into account that not all water carrying a chemical that comes into contact with skin stays on the skin long enough to allow absorption. Only that portion of a chemical in the solution that ''stays'' in contact with the skin is available for absorption. This may be modeled using water adherence factors as postulated by Gujral 2011.

Skin contact with gas or aerosol

:This is a minor contributor and has been ignored in most risk assessments of chemicals as a route of exposure for gaseous or aerosolized toxicants. More research is needed in this area.

Controlling skin absorption

If skin exposure and absorption are deemed to indicate a risk, various methods to reduce absorption can be undertaken. * Labels of chemicals can be adapted to require the use of gloves or

protective clothing Personal protective equipment (PPE) is protective clothing, helmets, goggles, or other garments or equipment designed to protect the wearer's body from injury or infection. The hazards addressed by protective equipment include physical, ele ...

. * Warnings to wash immediately if the chemical comes into contact with skin can be made. * Close pools or lakes to swimmers. * Limit the exposure time to chemicals, i.e. workers can only work with certain chemicals for a certain length of time per day.

References

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External links

*Skin Exposures & Effects, Centers for Disease Control and Prevention
EDETOX databaseWHO, Environmental Health Criteria 235, Dermal AbsorptionEPA 2012 Standard Operation Procedures (SOPs) for Residential Exposure Assessment
Skin physiology