I. Characteristics of Exposures

a. Potential External Dose - Exposure can occur from deposition of vapor or aerosol, liquid splash or transfer from a contaminated surface. These exposures can occur in the workplace, outdoors or in the home.

b. Internal Dose - It is the internal dose that is responsible for toxicity.  The external exposure is linked to the internal dose through the flux of chemical that diffuses through the stratum corneum. 

c. Relationship between External Dose and Internal dose – The relationship between external dose and internal dose is described by measurements of permeation:

i. Permeability coefficient (cm/hr)

ii. Flux (mg/cm²/hr)

iii. Diffusivity (cm²/hr)

d. Mixed Exposures – most exposures occur through more than one route and to more than one chemical

i. Many skin exposures have an inhalation or oral component because of chemical volatility and hand to mouth activities.

ii. There are very few “pure” exposures to chemicals in the workplace because most chemicals and products are a mixture of chemicals or in some kind of inert vehicle.

e. Skin versus lung as routes of absorption

i. One function of the skin is as a barrier to absorption.

ii. One function of the lung is to maximize absorption of gasses (oxygen).

iii. Many skin exposures have an inhalation component (vapor or aerosol).

iv. When we compare penetration of a vapor through the skin and through the lung, penetration in the lung is much greater.  Generally in a whole body vapor exposure, less than 10% of the body burden is from the skin route.

II. Determination of systemic toxicity

a. Hazard identification - We have several means of identifying actual or potential systemic toxicity by the dermal route: epidemiology studies, case reports, dermal LD50 studies in animals, ACGIH skin notation and calculations based on permeability.  How do these compare?

i. Epidemiology studies have the advantage of using “realistic” exposures, but large numbers of individuals are required for statistical relevance and the actual exposure parameters are often uncertain and variable between individuals.

ii. Case reports describe accidents or unusual occurrences and therefore by definition are not objective.  They are hard to put into perspective with the rest of the population.

iii. Dermal toxicity studies (i.e. LD₅₀) typically include high exposure levels in lab animals in order to find toxicity.  Because of non-linear biological systems, these exposures may not extrapolate well to humans.  They also don’t provide much information about lower doses.

iv. Skin penetration studies typically use an in vitro model with human or animal skin. They often provide variable results depending on the methods used.

b. Identification of chemicals that may cause systemic toxicity from skin exposures - The American Congress of Governmental Industrial Hygienists (ACGIH) criterion for assigning a skin notation is “potential significant contribution to overall exposures by cutaneous route.”

i. 24% of the chemicals with threshold limit values (TLVs) also have a skin notation.

ii. Primarily, the skin notation is assigned when there is evidence that a hand/forearm exposure during the workday might be significant or when the dermal LD50 from animal toxicity data is less than 1 gram/kg.

iii. The skin notation is considered when repeated dermal application studies in animals have shown effects or when extrapolations of systemic effects from other routes would suggest dermal toxicity.

iv. Alternatives to skin notations have been suggested.

1. Dermal occupational exposure levels would specify maximum acceptable accumulation of chemicals on skin or on workplace surfaces.

2. Another approach would focus on the skin absorption time, which is an estimate of the time during which skin would be exposed to a chemical to attain the same internal dose as an established standard.

3. Both use internal dose, permeability and route-to-route extrapolations. Route-to-route extrapolations consider data on oral or inhalation toxicity, require known skin permeability for the chemicals, and assume no route-of-entry effects.

III. Specific Chemicals causing Mortality

a. Poison Control Data – Non-chemical specific data collected in 1986 from 57 participating poison control centers around the country show that compared to other routes, the incidence of dermal poisonings are very low and fatalities from dermal poisonings are rare (Litovitz et al., 1987).

 

 

b. Pesticides are widely used.  There are hundreds of compounds designed to be toxic to insects.  Worldwide, there are 3 million cases of poisoning annually with about 220,000 deaths worldwide in 1990.  Developing countries experience a 13-fold incidence of poisoning and account for 85% of pesticide use (WHO 1990?).  Although there is not good information about the routes for these fatalities, there is some information about types of exposures for illnesses.  The California Pesticide Illness Surveillance Program (PISP) summarizes illness/injury in 2000 by type of exposure (California Pesticide Illness Surveillance Program, 2002) for definite and probable incidents due to pesticide exposures.

 

Type of exposure for 637 reported incidents
Direct contact with pesticides	40%
Spray, mist or fumes	40%
Residue	20%

 

c. Acids have caused several fatalities and are recognized to be very dangerous with skin contact.

i. Hydrofluoric acid exposures led to OSHA investigations of 4 (skin alone) and 11 mixed exposure deaths in 11 years.  Exposure of more than 2.5% of the body surface area (BSA) may be lethal due to hypocalcemia (Blodgett et al., 2001).  Inhalation can contribute.  HF binds to divalent cat ions and leads to electrolyte imbalance, cardiac arrhythmia and death.

ii. Monochloroacetic acid (MCAA) is a colorless solid.  European Centre for Ecotoxicology and Toxicology of Chemicals reports at least 26 fatalities in 18 years (anonymous, 2001).  More than 10% BSA may be lethal due to lactic acidosis.

d. Phenols are a category of chemicals that can cause burns and lethality.

i. Phenol (hydroxy benzene, carbolic acid) has been used as an antiseptic.  Phenol is a potent CNS stimulant and can cause renal failure by direct damage to the kidney (Cartotto et al., 1996).  Exposure of molten chemical to 64 sq inches of the body (2% BSA, about the size of a woman’s hand) can be lethal (Lewin and Cleary, 1982).  The mechanism is the uncoupling of oxidative phosphorylation.  Inhalation is likely to be a component of phenol exposures.

ii. Foille® was a treatment for burns that contained 2% phenol.  One death has been reported after treating a burn victim by repeatedly soaking a pressure dressing with Foille (Cronin and Brauer, 1949).

iii. 2,4-Dichlorophenol is a feedstock chemical used in the manufacture of insecticides.  Its use has resulted in 5 deaths in the chemical industry in 18 years (anonymous, 2000).  A33-year old male disposing of industrial waste splattered 2,4-dichlorophenol over portions of his arm and thigh, less than 10% of his body surface.  He experienced a seizure within 20 minutes and died (Kintz et al., 1992). 

iv. Resorcinol (dihydroxy phenol) is used to treat acne, eczema and psoriasis among other skin conditions.  A 50-year old housewife died of exogenous ochronosis (inability to complete the degradation of tyrosine and phenylalanine) due to chronic treatment of an ulcer with an ointment containing resorcinol (Thomas and Gisburn, 1961).

e. Mercury compounds fall into the general categories of elemental mercury, mercury salts and organic mercury (Kulig, 1998).  A very toxic organic mercury, dimethylmercury, is used only rarely.  Only 100 labs worldwide use it as an NMR standard.  Lethality is rare with only 4 known cases (Lewis, 1997).  Dimethylmercury penetrates latex and PVC gloves.  It binds to S-containing amino acids and kills nerve cells. 

i. A widely publicized case was that of Dr. Karen Wetterhahn (Nierenberg et al., 1998; Lewis, 1997).  She was the Dartmouth chemistry professor who, in August, 1996, spilled “several drops” of dimethylmercury on her glove.  In January, 1997, she reported feeling tingly and had slurred speech and balance problems.  Three weeks later, she lapsed into coma.  She died in June, 1997.

f. Chemical Warfare Agents can be lethal through the skin. The nerve agents Sarin, Tabun, Soman and VX are all lethal with sufficient skin exposure.

g. Many chemicals are recognized to cause skin cancer, but here we are focusing on systemic cancer.  There are very few documented cases of systemic cancer from skin exposures. Many chemicals cause systemic cancers by other routes and are absorbed through the skin, but we don’t know if enough can penetrate the skin to cause cancer.  The chemicals listed below have definitely been linked to cancer from skin absorption.

i. Over 200 years ago the connection between skin exposure to soot/coal tars with scrotal cancer (Andersen, 1999).

ii. Benzidine induces bladder tumors, primarily by absorption through the skin. It is used as an intermediate in the production of aniline dyes, rubber, plastics and printing inks (Andersen, 1999). 

iii. There are four reported cases of arsenic causing hemangiosarcoma of the liver - three from medicinal use and one from environmental exposure (Suskind, 1983).

h. Hexachlorophene can be lethal from percutaneous absorption.  Children may be specifically susceptible. 

i. Hexachlorophene (6.3%) was added to “baby powder” in France due to a manufacturing error.  It caused encephalopathy and ulcerative skin lesions.  36 of 204 exposed children died within a few days of exposure (Martin-Bouyer et al., 1982). 

ii. pHisoHex® soap contains 3% hexachlorophene.  Repeated bathing of premature children in undiluted pHisoHex has been associated with a vacuolar encephalopathy and lower survival rates.  A study of 248 children autopsied over a 7.5 year period showed encephalopathy in 17 infants (Shuman et al., 1974).  PHisoHex has been restricted to prescription use or as a surgical scrub for health care personnel since 1972 (Freeman and Maibach, 1991).

i. Salicylic acid is a treatment for psoriasis and other skin problems as a 3 or 6% ointment or a keratolytic gel.  One person treated with 12% to trunk and limbs twice daily for 20 days exhibited salicylate poisoning (nausea, confusion and hallucinations).  Encephalopathy and acid base disorders can occur within days.  Thirteen deaths have been recorded.  (Davies et al., 1979, Weiss and Lever, 1964)

IV. Specific Chemicals causing Morbidity.  Many other chemicals have shown that they can cause illness with percutaneous absorption.  Some important ones are listed below.  See previous reviews for details (Freeman and Maibach, 1991; Andersen, 1999; Birmingham, 1980; Loomis, 1980).

a. Selenium (sulfide) shampoo shows nonspecific illness (weakness, dizziness, nausea, perspiration, drowsiness etc.) with improper use 2-3 times weekly for 8 months.

b. Nitroglycerin is used in a transdermal devices for angina. It can cause illness in workers in dynamite manufacturing.

c. Glycol ethers are volatile solvents that cause hematopoetic suppression. They were used to replace xylene in the workplace and caused illnesses.

d. Inorganic mercury causes renal toxicity.

e. Alkyl lead is a gasoline additive that can cause neurotoxicity.

f. Boric acid is absorbed through intact skin and causes gastrointestinal lesions.

g. Diethyl-m-toluamide (DEET) is an insect repellent.  It causes CNS problems.

h. Alcohols are used in alcoholic compresses and cause CNS depression.

i. Benzocaine ointment causes methemoglobinemia.

j. Lindane has caused seizures after only 2 treatments in children.

k. Other topical drugs, like antibiotic sprays, have systemic effects.

l. TCDD is one of the most toxic compounds and penetrates skin.

m. Green tobacco sickness is caused by working in wet tobacco fields.  Migrant workers are typically exposed 8-12 weeks per year.  They may break off flowers at the top of 4-6 ft high plants or harvest leaves by hand picking from the bottom.  Symptoms are headache, nausea and dizziness with illness reported in 9% of workers and hospital treatment required in 1% of workers (McBride et al., 1998; Quandt et al., 2000).  The cause is nicotine poisoning from dermal contact.  Smoking may be protective, and tolerance may occur.

In Summary, there are chemicals that can and do cause systemic toxicity (lethality and morbidity) from skin exposures, but we do not know if the vast majority of chemicals that can be toxic by other routes can be toxic from skin exposures.  Some of the most important research needs in this area are:

      Better characterization of actual dermal exposures,

      Better understanding of inhalation vs dermal exposures and

      Better skin penetration information.

 

Acknowledgements

In preparing this review, significant assistance was provided by Brett Powers of the Fordham Health Sciences Library of the Wright State University School of Medicine and by participants in the OCCSKIN-L listserve.  Thanks to Sid Soderholm for helping convert a PowerPoint presentation to this extended abstract.

 

References

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  2. anonymous (2000). Occupational fatalities associated with 2,4-dichlorophenol (2,4-DCP) Exposure, 1980-1998. MMWR 49, 516-518.

  3. ECETOX (2001) Human Acute Intoxication from Monochloroacetic Acid: Proposals for Therapy. Technical Report 81, European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels.

  4. Birmingham, D. J. (1980). Cutaneous Absorption and Systemic Toxicity. In Cutaneous Toxicity (V. A. Drill, and P. Lazar, Eds.), pp. 53-62. Academic Press Inc., New York.

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