The thin-layer rapid-use epicutaneous (T.R.U.E.) test is a valuable first-line screening tool used by many dermatologists and allergists. Although the test focuses on common allergens, frequent questions have arisen from colleagues and patients as to where a specific allergen is derived or what products patients should avoid. With this in mind, this column was developed to provide educational information about the T.R.U.E. test allergens.
This month, the column explores T.R.U.E. test allergen #16: black rubber mix. We will delve into the history of black rubber mix and discuss its origins.
The Contact Dermatides
Irritant contact dermatitis, the most common form, accounts for approximately 80% of environmental-occupational based dermatoses.
Contact urticaria (wheal and flare reaction) represents an IgE and mast cell-mediated immediate-type hypersensitivity reaction that can lead to anaphylaxis, the foremost example of this being latex hypersensitivity. While this is beyond the scope of this section, we acknowledge this form of hypersensitivity due to the severity of the potential reactions and direct the reader to key sources.1,2
Allergic contact dermatitis (ACD) is an important disease with high impact both in terms of patient morbidity and economics. ACD represents a T helper cell Type 1 (Th1) dependent delayed-type (Type IV) hypersensitivity reaction. The instigating exogenous antigens are primarily small lipophilic chemicals (haptens) with a molecular weight less than 500 Da. On direct antigen exposure to the skin or mucosa, an immunologic cascade is initiated, which leads to the clinical picture of ACD.
Affecting more than 70 million Americans each year, ACD has a high impact both in terms of patient morbidity and economics.
The primary focus of this section is to highlight the educational component of this important inflammatory disorder.
Clinical Illustration
A wheelchair-bound patient with an indwelling catheter presented to the University of Miami Contact Dermatitis Clinic with a history of palmar and volar forearm dermatitis and generalized pruritus.
The Oxidative Process
The year 1630 marked a paramount observation by French physician and chemist, Jean Rey. He noted that tin exposed to the elements not only changed in color but also increased in weight. He theorized that air, which was previously considered to be inert, had become incorporated into the metal, accounting for the additional weight.3 Rey shocked the world with his groundbreaking theory because it meant that air must have a weight of its own.
Despite mass skepticism, his theory on elements eventually gained widespread acceptance and, with time, led to several important inventions, most notably the thermometer and the barometer.4
Not all elemental theories, however, proved correct. For example, there were many people who spent their lives in failed attempts in pseudo-alchemy (the science of synthesizing an element, like gold, from an unrelated element).
In One Hundred Years of Solitude, author Gabriel Marquez describes such a character, Colonel Aureliano Buendia. The character’s early failures to synthesize gold led to his obsessive compulsive re-creation of goldfish for the rest of his life.5
In contrast, however, others were able to capitalize on their negative findings. Noted alchemist Robert Boyle may have failed to make gold from iron combustion (burning), but in doing so, he discovered fire matter (a combination of rust ashes and air volume).6 Boyle postulated that a steadfast relationship existed between temperature, volume and pressure, a.k.a. Boyle’s Law (c.1662).
Phlogiston Theory
In a similar vein, Georg Ernst Stahl described the phlogiston theory, stating that through the combustion of metals, a colorless weightless gas substance was released, leaving the true form of the elements — a calx (residual powder of combustion).6 He called the clear, burned-off gas substance phlogiston, from the Greek phlogistos, meaning “flammable”.
The theory was attractive because it helped to explain the formation of rusted metals (a.k.a. “dephlogisticated” metal) and the role of an imperceivable gas in this process.
Of note, the resultant phlogiston theory received strong support throughout the early eighteenth century from alchemists looking for elemental transformation.
That was until Joseph Priestley demonstrated that the theory was erroneous.4 Priestley was an English minister with a remarkable fascination for gases. While observing the fermenting process at the neighborhood brewery, he witnessed the presence of a gas (separate from the air above the grain), which seemed to “spill” down the sides of the barrel. This gas was later determined to be carbon dioxide, marking the first occasion that the possibility of the existence of more than one air was entertained.4
Of interest, Priestley’s further experiments with carbon dioxide led to soda water, a discovery that earned him the Copley Medal from the Royal Society.7
In his later works, Priestley, while using a vacuum chamber to collect the by-products of combustion, noted that the burning of a candle in the presence of mercuric oxide gas led to greater flame intensity. (All of the other gases he produced extinguished the flame.)
He suggested that an element from the salt had become incorporated into the flame, resulting in formation of a calx. He based his conclusion on the phlogiston theory, which explained the calx formation by the irreversible liberation of phlogiston. Since the candle burned until the air in the chamber was consumed, Priestley correctly assumed that the chamber air itself had a purpose. He also postulated that during combustion, it was the air that became “de-phlogisticated,” not the metal.
“Oxygene” Discovered
Priestley shared these observations with friend, French tax collector Antoine Lavoisier. Lavoisier, in turn, compulsively experimented with combustion gas chambers, weighing the substrates, reactants and products throughout the condensation reaction.
Since he knew that the only substance in the closed chamber was water, he discovered that water was composed of two gases: one that was inflammable (hydrogen) and one that was flammable, which together could reform water when cooled.
Furthermore, Lavoisier correctly deduced that it was this other flammable gas that initiated most combustion reactions (being essential to keep a flame burning), and that it also led to combustion products having an acidic taste!
Lavoisier named this gas oxygene (from the Greek words oxys “sour” and genes “I produce”).8
In further combustion experiments, Lavoisier heated liquid mercury and air in his chamber. He demonstrated that as a red mercury calx formed, the volume of air decreased. By doing this he was able to demonstrate what Priestly had postulated — that it was the air that had lost the element (de-phlogisticated), not the metal. Furthermore, at even higher temperatures, the red calx re-released the oxygen back into a gas state, an impossibility under the phlogiston theory.
In doing these experiments, Lavoisier disproved the phlogiston theory and instead proved the Law of Conservation of Matter in chemical reactions (a.k.a. Lavoisier’s Law), and also identified that the element discussed in the phlogiston theory was in fact oxygen. In total, this formed his greatest scientific contribution.
Unfortunately, the scientific community suffered a great loss with the tragic beheading of outspoken liberalist Lavoisier during the French Revolution. Nonetheless, he is credited with fathering the field of elemental chemistry.
Oxidation’s Famous Effects
Oxidation is by far the main cause of age-related deterioration in both organic (skin, internal organs) and inorganic (metals, rubber) systems.
In 1886 the French gave the Statue of Liberty to the United States as a gift for the 100th anniversary of the Declaration of Independence. The 152-foot, shiny, copper-clad, iron Lady Liberty graced the 153-foot pedestal atop Liberty Island (which was then Bedloe’s Island) in New York Harbor.
A century later, Lady Liberty, green with oxidation catalyzed by the salt air, underwent a historic restoration project. Her deteriorating iron interior was replaced with stainless steel (an alloy of different metals that doesn’t oxidize as readily). On her 100th birthday in 1986, she was reopened to the public, with the exception of the staircase in her arm leading to the torch, which is still iron.9
Harnessing Oxidation
Horsedrawn buggies, bicycles, and walking were the main modes of transportation until Thomas Savery introduced the combustion engine in 1698.10
The production and harnessing of steam derived from the combustion (oxidation) of coal and wood set the stage for a multitude of technological advances that would be the hallmark of the Industrial Revolution. By 1896, steam engine repairman Henry Ford was well on his way to designing the first horseless motorized carriage, the quadricycle.
Counteracting Oxidation
The original quadricycle could reach a top speed of 20 mph with its 4-horsepower engine and four bicycle tires made of natural white rubber. Only one was ever made, which Ford sold to a friend for $200. Today it is on display at the Henry Ford museum in Dearborn, MI.12
Over the next 5 years, Ford enjoyed an enormous success with his “horseless carriages”, which led to the founding of the Ford Motor Company in 1903.11
The need for rust-proofing and weather-proofing Ford’s early custom carriages was quickly recognized. Several prototypes (A through S) emerged before the premiere of the classic Ford Model-T in 1908.
Notably, the T was clad in black protective paint to stop the doors from rusting shut in the rain. But one obstacle still to be reckoned with was the white rubber tires, which dried, cracked, and quickly showed dirt and age.11
With the delights of motorized travel becoming widely known came a high demand for this commodity. Ford formed assembly lines to increase production, lower costs, and ultimately take a giant leap toward realizing his dream of making the Model-T affordable to all American families.4
By 1918, half of all carriages on American roads were state-of-the-art motorized Model-Ts, all sporting a most notable innovation: weather-resilient black rubber tires which withstood the forces of oxidation.11
Advances in Manufacturing Rubber
Prior to disproving the phlogiston theory, Joseph Priestley had yet another incidental discovery. He found that dried latex sap could be used to erase pencil marks — he called this pencil eraser a “rubber”, thus coining the term.13 While the sap from the rubber tree plant Hevea brasiliensis had been used since ancient times for waterproofing and sport (bouncing balls), it was not until the 1880s that there was global demand for the wares.14
Sea traders, who had noted that the sun dried and cracked their rubber sheets, were quick to discover that they could protect their wares and retard the oxidation process with the addition of solvents, such as turpentine.15
At the turn of the twentieth century, rubber manufacturing involved mechanically stretching (pulling), molding, and cooling the wares to achieve the desired structure. The word tyre (from French la tire “to pull”) was originally used in reference to the production of toffee candy, which involves the same type of pulling and stretching.16
Like toffee, the original rubber products remained sticky, gummy, and nondurable with changing temperature and humidity conditions.
Pioneering vulcanization
In 1839 Charles Goodyear serendipitously pioneered vulcanization (the chemical acceleration of natural rubber from a liquid to a solid state) with an accidental sulphur spill on a hot stove.
The addition of the sulfur component sped the process of rubber manufacturing, and the rubber accelerator industry (using thiurams, carbamates, and mercaptos) boomed.15,17,18
With the ability to produce large-scale amounts of rubber came the challenge of protecting the rubber against the destructive forces of oxidation.
Interestingly, the first pneumatic (air-filled) tires were invented by Robert Thomson in 1845, and they were not made of rubber, but rather leather-coated canvas. John Dunlap is often called the “Father of the Modern Tire” because in 1888 he improved upon
Thomson’s design by covering the air-filled tires with natural rubber latex, making the first functional pneumatic rubber tires for his son’s tricycle.4 These air-filled tires resulted in a more comfortable ride, and were later used for all automobiles.
Adding antioxidants to the mix
George Oenslager, a chemist for B.F. Goodrich, was first to discover that the addition of rubber antioxidants to the rubber mix increased the life of the tires (c.1910). He noted that the damaging UV radiation was absorbed and transferred to heat before inflicting significant damage on the rubber itself.4 Furthermore, during this process, the additives turned the mixture black, as these ‘sacrificial chemicals’ preferentially submitted to the forces of oxygen (became oxidized), before damaging the rubber molecules.19,20 The very popular 1918 Ford Model T, in fact, sported these long-lasting, antioxidant-added black tires.
One of the first utilized antioxidants was hexamethylenetetramine (HMT), a formaldehyde-releasing antioxidant and vulcanizer. While it is still used today, the carcinogenic and allergenic potential of HMT led to its substitution with less-toxic chemicals, such as the secondary amines of paraphenylenediamine (PPD).
PPD is an oxidative substance that was formulated for hair dye use by Eugene Schueller, a young French chemist and founder of L’Oreal, in 1907. Schueller developed an entire industry based on the principle that PPD, when oxidized, turned hair black.
The possibility of capitalizing upon the oxidation function of PPD led rubber scientists to experiment with PPD derivatives for use in automotive tire industry. The secondary amine mixture of PPD-derivatives were found to offer effective temperature stability, strength and flexibility, and resistance to oxidation over a wide range of physical conditions.18
By 1971, the tire industry had almost unanimously switched to the secondary amines of PPD, which became referred to as the black rubber mix (BRM).
Allergenicity to BRM
Contact dermatitis to the accelerants used in the rubber industry was noted as early as the 1943 by W. E. Obetz, who coined the dermatitis “rubber itch” or “rubber poisoning.”21
Prosser White, an occupational dermatologist of the time, named hexamethylenetetramine (HMT) as the most active culprit in the dermatitis. White noted that during the summer months, the slight increase in acidity of the workers’ perspiration caused the HMT to release formaldehyde. The oxidation of the formaldehyde to formic acid was thought to be the actual perpetrator of the allergic reaction.21
Unfortunately, since the allergy affected only a small occupationally-based population, the dangers of these chemicals were not widely known by the general public.
Although the components of natural rubber rarely cause Type IV DTH reactions, immediate Type I anaphylaxis reactions to latex are common and represent a significant problem.22,23 We direct the reader to further reading on this important issue.1,2
This being said, there are a large number of additive chemicals used in the rubber manufacturing process that can elicit type IV delayed-type hypersensitivity reactions. Specifically, these fall into the categories of accelerators, activators, antidegradants, vulcanizers, retarders, reinforcing agents, fillers, and pigments, to name a few.22
It is important to note that these chemicals may become an occupational hazard, affecting both the skin and airway, especially if they are aerosolized during heating and pressurizing (see Table I).24
Between 1985 and 1990, the North American Contact Dermatitis Group (NACDG) determined the incidence of synthetic rubber allergy to be approximately 4%, with more than 55% of the exposures being from occupational sources (85% secondary to glove use).25
Among those who had a positive patch test to a rubber mix, thiuram-mix (62%) and BRM (38%) were the most common.26 The contact sensitization prevalence to BRM in the general population is estimated at 2.1% in men and 1.6% in women, representing exposures from a wide range of sources (see Tables II and III).
In the 1990s, recycled tire shreddings were commonly used as fillers for playgrounds. Reports of shredding-associated carcinogens and increasing allergenic sensitization to BRM led to playgrounds being recovered with other substances.27
Another source of BRM exposure, albeit novel, is in the handrails on escalators. The antioxidant materials (used in the rubber mix) remain in the raw final product, which is often not sealed before shoppers come into contact with it. Contact dermatitis to handrails has been causally linked to unilateral palmar dermatitis in at least two cases.28
PPD Reactions
The strong sensitization capacity and rising exposure awareness to PPD led to its designation as the 2006 Allergen of the Year.
Even though 2001 marked the first report of an adverse reaction following the application of a ‘black’ henna tattoo darkened (laced) with PPD-based chemicals, the notoriety of PPD had been previously established.29
In the 1930s, the practice of tinting the eyelashes and eyebrows with PPD dye was common. Many adverse reactions to PPD became apparent, with some women suffering serious blistering reactions, blindness, and even death, most notably to the product “Lash Lure”.30
Since there were no laws in place to regulate these products, cosmetic companies were not liable. By 1938, the Food, Drug, and Cosmetic Act was initiated with the first mandate: to remove “Lash Lure” from the American market and ban the use of PPD on skin.30 Furthermore, it became mandated that all at-home hair dye kits contain instructions for consumers on how to test themselves for allergenicity!
Testing for Black Rubber Mix Sensitivity
The current T.R.U.E test allows the physician to test for rubber accelerator (Carba Mix, site #15), Mercaptobenzothiazole (site #19), Mercapto Mix (site #22), Thiuram Mix (site #24), and antioxidant (BRM, site #16) allergy.31,32 It is not uncommon for patients to be co-sensitized to BRM-PPD and the accelerators as they are commonly used together.33
Menne et al patch tested 43,917 individuals to the components of BRM and PPD and demonstrated that the most allergenic component was N-isopropyl-N-phenyl p-PPD (IPPD).19 Furthermore, Feinman reported that out of 40 patients allergic to IPPD, 15 also reacted to PPD.31
To assure adequate evaluation of the PPD-derived rubber antioxidant allergy, it is recommended that the BRM contain all three paraphenylene diamine-based allergen components. (See Table IV).31 It should also be noted that in patients with disperse textile dye allergies, BRM and PPD show concomitant positivity in 11.2% of patch tested patients.34 This is because these dyes are derived from the same para-aminobenzoic acid (PABA) parent compound, and thus may also cross-react with the other PABA derivatives, such as paraphenylenediamine (PPD), PABA sunscreens, ester anesthetics, hydrochlorothiazide, and sulfonamides.35
The Value of This Patient Case
Our patient was unknowingly coming into daily contact with BRM through contact with the wheels and forearm pads of her wheelchair. Her first step involved covering the pads and wearing gloves for wheeling. Furthermore, she removed any unnecessary rubber products from her daily routine and replaced her indwelling rubber catheter with a silicone one, as patients generally do well on avoidance regimens and by replacing rubber items with PVC, acrylic, silicone, or other plastics.31
On her follow-up visit, her dermatitis had subsided and generalized pruritus had resolved. This case further underscores the importance of appropriate patch testing and subsequent patient education.
The thin-layer rapid-use epicutaneous (T.R.U.E.) test is a valuable first-line screening tool used by many dermatologists and allergists. Although the test focuses on common allergens, frequent questions have arisen from colleagues and patients as to where a specific allergen is derived or what products patients should avoid. With this in mind, this column was developed to provide educational information about the T.R.U.E. test allergens.
This month, the column explores T.R.U.E. test allergen #16: black rubber mix. We will delve into the history of black rubber mix and discuss its origins.
The Contact Dermatides
Irritant contact dermatitis, the most common form, accounts for approximately 80% of environmental-occupational based dermatoses.
Contact urticaria (wheal and flare reaction) represents an IgE and mast cell-mediated immediate-type hypersensitivity reaction that can lead to anaphylaxis, the foremost example of this being latex hypersensitivity. While this is beyond the scope of this section, we acknowledge this form of hypersensitivity due to the severity of the potential reactions and direct the reader to key sources.1,2
Allergic contact dermatitis (ACD) is an important disease with high impact both in terms of patient morbidity and economics. ACD represents a T helper cell Type 1 (Th1) dependent delayed-type (Type IV) hypersensitivity reaction. The instigating exogenous antigens are primarily small lipophilic chemicals (haptens) with a molecular weight less than 500 Da. On direct antigen exposure to the skin or mucosa, an immunologic cascade is initiated, which leads to the clinical picture of ACD.
Affecting more than 70 million Americans each year, ACD has a high impact both in terms of patient morbidity and economics.
The primary focus of this section is to highlight the educational component of this important inflammatory disorder.
Clinical Illustration
A wheelchair-bound patient with an indwelling catheter presented to the University of Miami Contact Dermatitis Clinic with a history of palmar and volar forearm dermatitis and generalized pruritus.
The Oxidative Process
The year 1630 marked a paramount observation by French physician and chemist, Jean Rey. He noted that tin exposed to the elements not only changed in color but also increased in weight. He theorized that air, which was previously considered to be inert, had become incorporated into the metal, accounting for the additional weight.3 Rey shocked the world with his groundbreaking theory because it meant that air must have a weight of its own.
Despite mass skepticism, his theory on elements eventually gained widespread acceptance and, with time, led to several important inventions, most notably the thermometer and the barometer.4
Not all elemental theories, however, proved correct. For example, there were many people who spent their lives in failed attempts in pseudo-alchemy (the science of synthesizing an element, like gold, from an unrelated element).
In One Hundred Years of Solitude, author Gabriel Marquez describes such a character, Colonel Aureliano Buendia. The character’s early failures to synthesize gold led to his obsessive compulsive re-creation of goldfish for the rest of his life.5
In contrast, however, others were able to capitalize on their negative findings. Noted alchemist Robert Boyle may have failed to make gold from iron combustion (burning), but in doing so, he discovered fire matter (a combination of rust ashes and air volume).6 Boyle postulated that a steadfast relationship existed between temperature, volume and pressure, a.k.a. Boyle’s Law (c.1662).
Phlogiston Theory
In a similar vein, Georg Ernst Stahl described the phlogiston theory, stating that through the combustion of metals, a colorless weightless gas substance was released, leaving the true form of the elements — a calx (residual powder of combustion).6 He called the clear, burned-off gas substance phlogiston, from the Greek phlogistos, meaning “flammable”.
The theory was attractive because it helped to explain the formation of rusted metals (a.k.a. “dephlogisticated” metal) and the role of an imperceivable gas in this process.
Of note, the resultant phlogiston theory received strong support throughout the early eighteenth century from alchemists looking for elemental transformation.
That was until Joseph Priestley demonstrated that the theory was erroneous.4 Priestley was an English minister with a remarkable fascination for gases. While observing the fermenting process at the neighborhood brewery, he witnessed the presence of a gas (separate from the air above the grain), which seemed to “spill” down the sides of the barrel. This gas was later determined to be carbon dioxide, marking the first occasion that the possibility of the existence of more than one air was entertained.4
Of interest, Priestley’s further experiments with carbon dioxide led to soda water, a discovery that earned him the Copley Medal from the Royal Society.7
In his later works, Priestley, while using a vacuum chamber to collect the by-products of combustion, noted that the burning of a candle in the presence of mercuric oxide gas led to greater flame intensity. (All of the other gases he produced extinguished the flame.)
He suggested that an element from the salt had become incorporated into the flame, resulting in formation of a calx. He based his conclusion on the phlogiston theory, which explained the calx formation by the irreversible liberation of phlogiston. Since the candle burned until the air in the chamber was consumed, Priestley correctly assumed that the chamber air itself had a purpose. He also postulated that during combustion, it was the air that became “de-phlogisticated,” not the metal.
“Oxygene” Discovered
Priestley shared these observations with friend, French tax collector Antoine Lavoisier. Lavoisier, in turn, compulsively experimented with combustion gas chambers, weighing the substrates, reactants and products throughout the condensation reaction.
Since he knew that the only substance in the closed chamber was water, he discovered that water was composed of two gases: one that was inflammable (hydrogen) and one that was flammable, which together could reform water when cooled.
Furthermore, Lavoisier correctly deduced that it was this other flammable gas that initiated most combustion reactions (being essential to keep a flame burning), and that it also led to combustion products having an acidic taste!
Lavoisier named this gas oxygene (from the Greek words oxys “sour” and genes “I produce”).8
In further combustion experiments, Lavoisier heated liquid mercury and air in his chamber. He demonstrated that as a red mercury calx formed, the volume of air decreased. By doing this he was able to demonstrate what Priestly had postulated — that it was the air that had lost the element (de-phlogisticated), not the metal. Furthermore, at even higher temperatures, the red calx re-released the oxygen back into a gas state, an impossibility under the phlogiston theory.
In doing these experiments, Lavoisier disproved the phlogiston theory and instead proved the Law of Conservation of Matter in chemical reactions (a.k.a. Lavoisier’s Law), and also identified that the element discussed in the phlogiston theory was in fact oxygen. In total, this formed his greatest scientific contribution.
Unfortunately, the scientific community suffered a great loss with the tragic beheading of outspoken liberalist Lavoisier during the French Revolution. Nonetheless, he is credited with fathering the field of elemental chemistry.
Oxidation’s Famous Effects
Oxidation is by far the main cause of age-related deterioration in both organic (skin, internal organs) and inorganic (metals, rubber) systems.
In 1886 the French gave the Statue of Liberty to the United States as a gift for the 100th anniversary of the Declaration of Independence. The 152-foot, shiny, copper-clad, iron Lady Liberty graced the 153-foot pedestal atop Liberty Island (which was then Bedloe’s Island) in New York Harbor.
A century later, Lady Liberty, green with oxidation catalyzed by the salt air, underwent a historic restoration project. Her deteriorating iron interior was replaced with stainless steel (an alloy of different metals that doesn’t oxidize as readily). On her 100th birthday in 1986, she was reopened to the public, with the exception of the staircase in her arm leading to the torch, which is still iron.9
Harnessing Oxidation
Horsedrawn buggies, bicycles, and walking were the main modes of transportation until Thomas Savery introduced the combustion engine in 1698.10
The production and harnessing of steam derived from the combustion (oxidation) of coal and wood set the stage for a multitude of technological advances that would be the hallmark of the Industrial Revolution. By 1896, steam engine repairman Henry Ford was well on his way to designing the first horseless motorized carriage, the quadricycle.
Counteracting Oxidation
The original quadricycle could reach a top speed of 20 mph with its 4-horsepower engine and four bicycle tires made of natural white rubber. Only one was ever made, which Ford sold to a friend for $200. Today it is on display at the Henry Ford museum in Dearborn, MI.12
Over the next 5 years, Ford enjoyed an enormous success with his “horseless carriages”, which led to the founding of the Ford Motor Company in 1903.11
The need for rust-proofing and weather-proofing Ford’s early custom carriages was quickly recognized. Several prototypes (A through S) emerged before the premiere of the classic Ford Model-T in 1908.
Notably, the T was clad in black protective paint to stop the doors from rusting shut in the rain. But one obstacle still to be reckoned with was the white rubber tires, which dried, cracked, and quickly showed dirt and age.11
With the delights of motorized travel becoming widely known came a high demand for this commodity. Ford formed assembly lines to increase production, lower costs, and ultimately take a giant leap toward realizing his dream of making the Model-T affordable to all American families.4
By 1918, half of all carriages on American roads were state-of-the-art motorized Model-Ts, all sporting a most notable innovation: weather-resilient black rubber tires which withstood the forces of oxidation.11
Advances in Manufacturing Rubber
Prior to disproving the phlogiston theory, Joseph Priestley had yet another incidental discovery. He found that dried latex sap could be used to erase pencil marks — he called this pencil eraser a “rubber”, thus coining the term.13 While the sap from the rubber tree plant Hevea brasiliensis had been used since ancient times for waterproofing and sport (bouncing balls), it was not until the 1880s that there was global demand for the wares.14
Sea traders, who had noted that the sun dried and cracked their rubber sheets, were quick to discover that they could protect their wares and retard the oxidation process with the addition of solvents, such as turpentine.15
At the turn of the twentieth century, rubber manufacturing involved mechanically stretching (pulling), molding, and cooling the wares to achieve the desired structure. The word tyre (from French la tire “to pull”) was originally used in reference to the production of toffee candy, which involves the same type of pulling and stretching.16
Like toffee, the original rubber products remained sticky, gummy, and nondurable with changing temperature and humidity conditions.
Pioneering vulcanization
In 1839 Charles Goodyear serendipitously pioneered vulcanization (the chemical acceleration of natural rubber from a liquid to a solid state) with an accidental sulphur spill on a hot stove.
The addition of the sulfur component sped the process of rubber manufacturing, and the rubber accelerator industry (using thiurams, carbamates, and mercaptos) boomed.15,17,18
With the ability to produce large-scale amounts of rubber came the challenge of protecting the rubber against the destructive forces of oxidation.
Interestingly, the first pneumatic (air-filled) tires were invented by Robert Thomson in 1845, and they were not made of rubber, but rather leather-coated canvas. John Dunlap is often called the “Father of the Modern Tire” because in 1888 he improved upon
Thomson’s design by covering the air-filled tires with natural rubber latex, making the first functional pneumatic rubber tires for his son’s tricycle.4 These air-filled tires resulted in a more comfortable ride, and were later used for all automobiles.
Adding antioxidants to the mix
George Oenslager, a chemist for B.F. Goodrich, was first to discover that the addition of rubber antioxidants to the rubber mix increased the life of the tires (c.1910). He noted that the damaging UV radiation was absorbed and transferred to heat before inflicting significant damage on the rubber itself.4 Furthermore, during this process, the additives turned the mixture black, as these ‘sacrificial chemicals’ preferentially submitted to the forces of oxygen (became oxidized), before damaging the rubber molecules.19,20 The very popular 1918 Ford Model T, in fact, sported these long-lasting, antioxidant-added black tires.
One of the first utilized antioxidants was hexamethylenetetramine (HMT), a formaldehyde-releasing antioxidant and vulcanizer. While it is still used today, the carcinogenic and allergenic potential of HMT led to its substitution with less-toxic chemicals, such as the secondary amines of paraphenylenediamine (PPD).
PPD is an oxidative substance that was formulated for hair dye use by Eugene Schueller, a young French chemist and founder of L’Oreal, in 1907. Schueller developed an entire industry based on the principle that PPD, when oxidized, turned hair black.
The possibility of capitalizing upon the oxidation function of PPD led rubber scientists to experiment with PPD derivatives for use in automotive tire industry. The secondary amine mixture of PPD-derivatives were found to offer effective temperature stability, strength and flexibility, and resistance to oxidation over a wide range of physical conditions.18
By 1971, the tire industry had almost unanimously switched to the secondary amines of PPD, which became referred to as the black rubber mix (BRM).
Allergenicity to BRM
Contact dermatitis to the accelerants used in the rubber industry was noted as early as the 1943 by W. E. Obetz, who coined the dermatitis “rubber itch” or “rubber poisoning.”21
Prosser White, an occupational dermatologist of the time, named hexamethylenetetramine (HMT) as the most active culprit in the dermatitis. White noted that during the summer months, the slight increase in acidity of the workers’ perspiration caused the HMT to release formaldehyde. The oxidation of the formaldehyde to formic acid was thought to be the actual perpetrator of the allergic reaction.21
Unfortunately, since the allergy affected only a small occupationally-based population, the dangers of these chemicals were not widely known by the general public.
Although the components of natural rubber rarely cause Type IV DTH reactions, immediate Type I anaphylaxis reactions to latex are common and represent a significant problem.22,23 We direct the reader to further reading on this important issue.1,2
This being said, there are a large number of additive chemicals used in the rubber manufacturing process that can elicit type IV delayed-type hypersensitivity reactions. Specifically, these fall into the categories of accelerators, activators, antidegradants, vulcanizers, retarders, reinforcing agents, fillers, and pigments, to name a few.22
It is important to note that these chemicals may become an occupational hazard, affecting both the skin and airway, especially if they are aerosolized during heating and pressurizing (see Table I).24
Between 1985 and 1990, the North American Contact Dermatitis Group (NACDG) determined the incidence of synthetic rubber allergy to be approximately 4%, with more than 55% of the exposures being from occupational sources (85% secondary to glove use).25
Among those who had a positive patch test to a rubber mix, thiuram-mix (62%) and BRM (38%) were the most common.26 The contact sensitization prevalence to BRM in the general population is estimated at 2.1% in men and 1.6% in women, representing exposures from a wide range of sources (see Tables II and III).
In the 1990s, recycled tire shreddings were commonly used as fillers for playgrounds. Reports of shredding-associated carcinogens and increasing allergenic sensitization to BRM led to playgrounds being recovered with other substances.27
Another source of BRM exposure, albeit novel, is in the handrails on escalators. The antioxidant materials (used in the rubber mix) remain in the raw final product, which is often not sealed before shoppers come into contact with it. Contact dermatitis to handrails has been causally linked to unilateral palmar dermatitis in at least two cases.28
PPD Reactions
The strong sensitization capacity and rising exposure awareness to PPD led to its designation as the 2006 Allergen of the Year.
Even though 2001 marked the first report of an adverse reaction following the application of a ‘black’ henna tattoo darkened (laced) with PPD-based chemicals, the notoriety of PPD had been previously established.29
In the 1930s, the practice of tinting the eyelashes and eyebrows with PPD dye was common. Many adverse reactions to PPD became apparent, with some women suffering serious blistering reactions, blindness, and even death, most notably to the product “Lash Lure”.30
Since there were no laws in place to regulate these products, cosmetic companies were not liable. By 1938, the Food, Drug, and Cosmetic Act was initiated with the first mandate: to remove “Lash Lure” from the American market and ban the use of PPD on skin.30 Furthermore, it became mandated that all at-home hair dye kits contain instructions for consumers on how to test themselves for allergenicity!
Testing for Black Rubber Mix Sensitivity
The current T.R.U.E test allows the physician to test for rubber accelerator (Carba Mix, site #15), Mercaptobenzothiazole (site #19), Mercapto Mix (site #22), Thiuram Mix (site #24), and antioxidant (BRM, site #16) allergy.31,32 It is not uncommon for patients to be co-sensitized to BRM-PPD and the accelerators as they are commonly used together.33
Menne et al patch tested 43,917 individuals to the components of BRM and PPD and demonstrated that the most allergenic component was N-isopropyl-N-phenyl p-PPD (IPPD).19 Furthermore, Feinman reported that out of 40 patients allergic to IPPD, 15 also reacted to PPD.31
To assure adequate evaluation of the PPD-derived rubber antioxidant allergy, it is recommended that the BRM contain all three paraphenylene diamine-based allergen components. (See Table IV).31 It should also be noted that in patients with disperse textile dye allergies, BRM and PPD show concomitant positivity in 11.2% of patch tested patients.34 This is because these dyes are derived from the same para-aminobenzoic acid (PABA) parent compound, and thus may also cross-react with the other PABA derivatives, such as paraphenylenediamine (PPD), PABA sunscreens, ester anesthetics, hydrochlorothiazide, and sulfonamides.35
The Value of This Patient Case
Our patient was unknowingly coming into daily contact with BRM through contact with the wheels and forearm pads of her wheelchair. Her first step involved covering the pads and wearing gloves for wheeling. Furthermore, she removed any unnecessary rubber products from her daily routine and replaced her indwelling rubber catheter with a silicone one, as patients generally do well on avoidance regimens and by replacing rubber items with PVC, acrylic, silicone, or other plastics.31
On her follow-up visit, her dermatitis had subsided and generalized pruritus had resolved. This case further underscores the importance of appropriate patch testing and subsequent patient education.
The thin-layer rapid-use epicutaneous (T.R.U.E.) test is a valuable first-line screening tool used by many dermatologists and allergists. Although the test focuses on common allergens, frequent questions have arisen from colleagues and patients as to where a specific allergen is derived or what products patients should avoid. With this in mind, this column was developed to provide educational information about the T.R.U.E. test allergens.
This month, the column explores T.R.U.E. test allergen #16: black rubber mix. We will delve into the history of black rubber mix and discuss its origins.
The Contact Dermatides
Irritant contact dermatitis, the most common form, accounts for approximately 80% of environmental-occupational based dermatoses.
Contact urticaria (wheal and flare reaction) represents an IgE and mast cell-mediated immediate-type hypersensitivity reaction that can lead to anaphylaxis, the foremost example of this being latex hypersensitivity. While this is beyond the scope of this section, we acknowledge this form of hypersensitivity due to the severity of the potential reactions and direct the reader to key sources.1,2
Allergic contact dermatitis (ACD) is an important disease with high impact both in terms of patient morbidity and economics. ACD represents a T helper cell Type 1 (Th1) dependent delayed-type (Type IV) hypersensitivity reaction. The instigating exogenous antigens are primarily small lipophilic chemicals (haptens) with a molecular weight less than 500 Da. On direct antigen exposure to the skin or mucosa, an immunologic cascade is initiated, which leads to the clinical picture of ACD.
Affecting more than 70 million Americans each year, ACD has a high impact both in terms of patient morbidity and economics.
The primary focus of this section is to highlight the educational component of this important inflammatory disorder.
Clinical Illustration
A wheelchair-bound patient with an indwelling catheter presented to the University of Miami Contact Dermatitis Clinic with a history of palmar and volar forearm dermatitis and generalized pruritus.
The Oxidative Process
The year 1630 marked a paramount observation by French physician and chemist, Jean Rey. He noted that tin exposed to the elements not only changed in color but also increased in weight. He theorized that air, which was previously considered to be inert, had become incorporated into the metal, accounting for the additional weight.3 Rey shocked the world with his groundbreaking theory because it meant that air must have a weight of its own.
Despite mass skepticism, his theory on elements eventually gained widespread acceptance and, with time, led to several important inventions, most notably the thermometer and the barometer.4
Not all elemental theories, however, proved correct. For example, there were many people who spent their lives in failed attempts in pseudo-alchemy (the science of synthesizing an element, like gold, from an unrelated element).
In One Hundred Years of Solitude, author Gabriel Marquez describes such a character, Colonel Aureliano Buendia. The character’s early failures to synthesize gold led to his obsessive compulsive re-creation of goldfish for the rest of his life.5
In contrast, however, others were able to capitalize on their negative findings. Noted alchemist Robert Boyle may have failed to make gold from iron combustion (burning), but in doing so, he discovered fire matter (a combination of rust ashes and air volume).6 Boyle postulated that a steadfast relationship existed between temperature, volume and pressure, a.k.a. Boyle’s Law (c.1662).
Phlogiston Theory
In a similar vein, Georg Ernst Stahl described the phlogiston theory, stating that through the combustion of metals, a colorless weightless gas substance was released, leaving the true form of the elements — a calx (residual powder of combustion).6 He called the clear, burned-off gas substance phlogiston, from the Greek phlogistos, meaning “flammable”.
The theory was attractive because it helped to explain the formation of rusted metals (a.k.a. “dephlogisticated” metal) and the role of an imperceivable gas in this process.
Of note, the resultant phlogiston theory received strong support throughout the early eighteenth century from alchemists looking for elemental transformation.
That was until Joseph Priestley demonstrated that the theory was erroneous.4 Priestley was an English minister with a remarkable fascination for gases. While observing the fermenting process at the neighborhood brewery, he witnessed the presence of a gas (separate from the air above the grain), which seemed to “spill” down the sides of the barrel. This gas was later determined to be carbon dioxide, marking the first occasion that the possibility of the existence of more than one air was entertained.4
Of interest, Priestley’s further experiments with carbon dioxide led to soda water, a discovery that earned him the Copley Medal from the Royal Society.7
In his later works, Priestley, while using a vacuum chamber to collect the by-products of combustion, noted that the burning of a candle in the presence of mercuric oxide gas led to greater flame intensity. (All of the other gases he produced extinguished the flame.)
He suggested that an element from the salt had become incorporated into the flame, resulting in formation of a calx. He based his conclusion on the phlogiston theory, which explained the calx formation by the irreversible liberation of phlogiston. Since the candle burned until the air in the chamber was consumed, Priestley correctly assumed that the chamber air itself had a purpose. He also postulated that during combustion, it was the air that became “de-phlogisticated,” not the metal.
“Oxygene” Discovered
Priestley shared these observations with friend, French tax collector Antoine Lavoisier. Lavoisier, in turn, compulsively experimented with combustion gas chambers, weighing the substrates, reactants and products throughout the condensation reaction.
Since he knew that the only substance in the closed chamber was water, he discovered that water was composed of two gases: one that was inflammable (hydrogen) and one that was flammable, which together could reform water when cooled.
Furthermore, Lavoisier correctly deduced that it was this other flammable gas that initiated most combustion reactions (being essential to keep a flame burning), and that it also led to combustion products having an acidic taste!
Lavoisier named this gas oxygene (from the Greek words oxys “sour” and genes “I produce”).8
In further combustion experiments, Lavoisier heated liquid mercury and air in his chamber. He demonstrated that as a red mercury calx formed, the volume of air decreased. By doing this he was able to demonstrate what Priestly had postulated — that it was the air that had lost the element (de-phlogisticated), not the metal. Furthermore, at even higher temperatures, the red calx re-released the oxygen back into a gas state, an impossibility under the phlogiston theory.
In doing these experiments, Lavoisier disproved the phlogiston theory and instead proved the Law of Conservation of Matter in chemical reactions (a.k.a. Lavoisier’s Law), and also identified that the element discussed in the phlogiston theory was in fact oxygen. In total, this formed his greatest scientific contribution.
Unfortunately, the scientific community suffered a great loss with the tragic beheading of outspoken liberalist Lavoisier during the French Revolution. Nonetheless, he is credited with fathering the field of elemental chemistry.
Oxidation’s Famous Effects
Oxidation is by far the main cause of age-related deterioration in both organic (skin, internal organs) and inorganic (metals, rubber) systems.
In 1886 the French gave the Statue of Liberty to the United States as a gift for the 100th anniversary of the Declaration of Independence. The 152-foot, shiny, copper-clad, iron Lady Liberty graced the 153-foot pedestal atop Liberty Island (which was then Bedloe’s Island) in New York Harbor.
A century later, Lady Liberty, green with oxidation catalyzed by the salt air, underwent a historic restoration project. Her deteriorating iron interior was replaced with stainless steel (an alloy of different metals that doesn’t oxidize as readily). On her 100th birthday in 1986, she was reopened to the public, with the exception of the staircase in her arm leading to the torch, which is still iron.9
Harnessing Oxidation
Horsedrawn buggies, bicycles, and walking were the main modes of transportation until Thomas Savery introduced the combustion engine in 1698.10
The production and harnessing of steam derived from the combustion (oxidation) of coal and wood set the stage for a multitude of technological advances that would be the hallmark of the Industrial Revolution. By 1896, steam engine repairman Henry Ford was well on his way to designing the first horseless motorized carriage, the quadricycle.
Counteracting Oxidation
The original quadricycle could reach a top speed of 20 mph with its 4-horsepower engine and four bicycle tires made of natural white rubber. Only one was ever made, which Ford sold to a friend for $200. Today it is on display at the Henry Ford museum in Dearborn, MI.12
Over the next 5 years, Ford enjoyed an enormous success with his “horseless carriages”, which led to the founding of the Ford Motor Company in 1903.11
The need for rust-proofing and weather-proofing Ford’s early custom carriages was quickly recognized. Several prototypes (A through S) emerged before the premiere of the classic Ford Model-T in 1908.
Notably, the T was clad in black protective paint to stop the doors from rusting shut in the rain. But one obstacle still to be reckoned with was the white rubber tires, which dried, cracked, and quickly showed dirt and age.11
With the delights of motorized travel becoming widely known came a high demand for this commodity. Ford formed assembly lines to increase production, lower costs, and ultimately take a giant leap toward realizing his dream of making the Model-T affordable to all American families.4
By 1918, half of all carriages on American roads were state-of-the-art motorized Model-Ts, all sporting a most notable innovation: weather-resilient black rubber tires which withstood the forces of oxidation.11
Advances in Manufacturing Rubber
Prior to disproving the phlogiston theory, Joseph Priestley had yet another incidental discovery. He found that dried latex sap could be used to erase pencil marks — he called this pencil eraser a “rubber”, thus coining the term.13 While the sap from the rubber tree plant Hevea brasiliensis had been used since ancient times for waterproofing and sport (bouncing balls), it was not until the 1880s that there was global demand for the wares.14
Sea traders, who had noted that the sun dried and cracked their rubber sheets, were quick to discover that they could protect their wares and retard the oxidation process with the addition of solvents, such as turpentine.15
At the turn of the twentieth century, rubber manufacturing involved mechanically stretching (pulling), molding, and cooling the wares to achieve the desired structure. The word tyre (from French la tire “to pull”) was originally used in reference to the production of toffee candy, which involves the same type of pulling and stretching.16
Like toffee, the original rubber products remained sticky, gummy, and nondurable with changing temperature and humidity conditions.
Pioneering vulcanization
In 1839 Charles Goodyear serendipitously pioneered vulcanization (the chemical acceleration of natural rubber from a liquid to a solid state) with an accidental sulphur spill on a hot stove.
The addition of the sulfur component sped the process of rubber manufacturing, and the rubber accelerator industry (using thiurams, carbamates, and mercaptos) boomed.15,17,18
With the ability to produce large-scale amounts of rubber came the challenge of protecting the rubber against the destructive forces of oxidation.
Interestingly, the first pneumatic (air-filled) tires were invented by Robert Thomson in 1845, and they were not made of rubber, but rather leather-coated canvas. John Dunlap is often called the “Father of the Modern Tire” because in 1888 he improved upon
Thomson’s design by covering the air-filled tires with natural rubber latex, making the first functional pneumatic rubber tires for his son’s tricycle.4 These air-filled tires resulted in a more comfortable ride, and were later used for all automobiles.
Adding antioxidants to the mix
George Oenslager, a chemist for B.F. Goodrich, was first to discover that the addition of rubber antioxidants to the rubber mix increased the life of the tires (c.1910). He noted that the damaging UV radiation was absorbed and transferred to heat before inflicting significant damage on the rubber itself.4 Furthermore, during this process, the additives turned the mixture black, as these ‘sacrificial chemicals’ preferentially submitted to the forces of oxygen (became oxidized), before damaging the rubber molecules.19,20 The very popular 1918 Ford Model T, in fact, sported these long-lasting, antioxidant-added black tires.
One of the first utilized antioxidants was hexamethylenetetramine (HMT), a formaldehyde-releasing antioxidant and vulcanizer. While it is still used today, the carcinogenic and allergenic potential of HMT led to its substitution with less-toxic chemicals, such as the secondary amines of paraphenylenediamine (PPD).
PPD is an oxidative substance that was formulated for hair dye use by Eugene Schueller, a young French chemist and founder of L’Oreal, in 1907. Schueller developed an entire industry based on the principle that PPD, when oxidized, turned hair black.
The possibility of capitalizing upon the oxidation function of PPD led rubber scientists to experiment with PPD derivatives for use in automotive tire industry. The secondary amine mixture of PPD-derivatives were found to offer effective temperature stability, strength and flexibility, and resistance to oxidation over a wide range of physical conditions.18
By 1971, the tire industry had almost unanimously switched to the secondary amines of PPD, which became referred to as the black rubber mix (BRM).
Allergenicity to BRM
Contact dermatitis to the accelerants used in the rubber industry was noted as early as the 1943 by W. E. Obetz, who coined the dermatitis “rubber itch” or “rubber poisoning.”21
Prosser White, an occupational dermatologist of the time, named hexamethylenetetramine (HMT) as the most active culprit in the dermatitis. White noted that during the summer months, the slight increase in acidity of the workers’ perspiration caused the HMT to release formaldehyde. The oxidation of the formaldehyde to formic acid was thought to be the actual perpetrator of the allergic reaction.21
Unfortunately, since the allergy affected only a small occupationally-based population, the dangers of these chemicals were not widely known by the general public.
Although the components of natural rubber rarely cause Type IV DTH reactions, immediate Type I anaphylaxis reactions to latex are common and represent a significant problem.22,23 We direct the reader to further reading on this important issue.1,2
This being said, there are a large number of additive chemicals used in the rubber manufacturing process that can elicit type IV delayed-type hypersensitivity reactions. Specifically, these fall into the categories of accelerators, activators, antidegradants, vulcanizers, retarders, reinforcing agents, fillers, and pigments, to name a few.22
It is important to note that these chemicals may become an occupational hazard, affecting both the skin and airway, especially if they are aerosolized during heating and pressurizing (see Table I).24
Between 1985 and 1990, the North American Contact Dermatitis Group (NACDG) determined the incidence of synthetic rubber allergy to be approximately 4%, with more than 55% of the exposures being from occupational sources (85% secondary to glove use).25
Among those who had a positive patch test to a rubber mix, thiuram-mix (62%) and BRM (38%) were the most common.26 The contact sensitization prevalence to BRM in the general population is estimated at 2.1% in men and 1.6% in women, representing exposures from a wide range of sources (see Tables II and III).
In the 1990s, recycled tire shreddings were commonly used as fillers for playgrounds. Reports of shredding-associated carcinogens and increasing allergenic sensitization to BRM led to playgrounds being recovered with other substances.27
Another source of BRM exposure, albeit novel, is in the handrails on escalators. The antioxidant materials (used in the rubber mix) remain in the raw final product, which is often not sealed before shoppers come into contact with it. Contact dermatitis to handrails has been causally linked to unilateral palmar dermatitis in at least two cases.28
PPD Reactions
The strong sensitization capacity and rising exposure awareness to PPD led to its designation as the 2006 Allergen of the Year.
Even though 2001 marked the first report of an adverse reaction following the application of a ‘black’ henna tattoo darkened (laced) with PPD-based chemicals, the notoriety of PPD had been previously established.29
In the 1930s, the practice of tinting the eyelashes and eyebrows with PPD dye was common. Many adverse reactions to PPD became apparent, with some women suffering serious blistering reactions, blindness, and even death, most notably to the product “Lash Lure”.30
Since there were no laws in place to regulate these products, cosmetic companies were not liable. By 1938, the Food, Drug, and Cosmetic Act was initiated with the first mandate: to remove “Lash Lure” from the American market and ban the use of PPD on skin.30 Furthermore, it became mandated that all at-home hair dye kits contain instructions for consumers on how to test themselves for allergenicity!
Testing for Black Rubber Mix Sensitivity
The current T.R.U.E test allows the physician to test for rubber accelerator (Carba Mix, site #15), Mercaptobenzothiazole (site #19), Mercapto Mix (site #22), Thiuram Mix (site #24), and antioxidant (BRM, site #16) allergy.31,32 It is not uncommon for patients to be co-sensitized to BRM-PPD and the accelerators as they are commonly used together.33
Menne et al patch tested 43,917 individuals to the components of BRM and PPD and demonstrated that the most allergenic component was N-isopropyl-N-phenyl p-PPD (IPPD).19 Furthermore, Feinman reported that out of 40 patients allergic to IPPD, 15 also reacted to PPD.31
To assure adequate evaluation of the PPD-derived rubber antioxidant allergy, it is recommended that the BRM contain all three paraphenylene diamine-based allergen components. (See Table IV).31 It should also be noted that in patients with disperse textile dye allergies, BRM and PPD show concomitant positivity in 11.2% of patch tested patients.34 This is because these dyes are derived from the same para-aminobenzoic acid (PABA) parent compound, and thus may also cross-react with the other PABA derivatives, such as paraphenylenediamine (PPD), PABA sunscreens, ester anesthetics, hydrochlorothiazide, and sulfonamides.35
The Value of This Patient Case
Our patient was unknowingly coming into daily contact with BRM through contact with the wheels and forearm pads of her wheelchair. Her first step involved covering the pads and wearing gloves for wheeling. Furthermore, she removed any unnecessary rubber products from her daily routine and replaced her indwelling rubber catheter with a silicone one, as patients generally do well on avoidance regimens and by replacing rubber items with PVC, acrylic, silicone, or other plastics.31
On her follow-up visit, her dermatitis had subsided and generalized pruritus had resolved. This case further underscores the importance of appropriate patch testing and subsequent patient education.
