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Cornish, K. and D.J. Siler. 1996. Hypoallergenic guayule latex: research to commercialization. p. 327-335. In: J. Janick (ed.), Progress in new crops. ASHS Press, Alexandria, VA.

Hypoallergenic Guayule Latex: Research to Commercialization

Katrina Cornish and Deborah J. Siler

  1. BACKGROUND
  2. HISTORY OF GUAYULE COMMERCIALIZATION
  3. THE CHANGING MARKETPLACE
    1. Latex and Latex Products
    2. Latex Allergy (Type I, IgE-Mediated)
    3. Causes of Latex Allergy
    4. The Latex-Hypersensitive Population
    5. Latex Allergy Amelioration
    6. Latex Allergy Circumvention
  4. HYPOALLERGENIC GUAYULE LATEX
    1. Production of Hypoallergenic Guayule Latex
    2. Commercialization Position
  5. CONCLUSIONS
  6. REFERENCES
A fresh look at guayule has led to the discovery and development of hypoallergenic latex to supply a major, new market. Guayule (Parthenium argentatum, Gray, Asteraceae), a new industrial crop candidate, is a desert shrub native to the Chihuahuan desert of Texas and Mexico. It is the only species other than Hevea (the Brazilian rubber tree, Hevea brasiliensis Muell. Arg.) that has been used for rubber production on a commercial scale. Guayule has been known to produce rubber for at least a millennium, but modern commercialization efforts have been unsuccessful. The resurgence of guayule research since the early 1970s has resulted in higher yielding lines and improved agronomic practices, but the low price of imported Hevea natural rubber from tropical countries has continued to bar guayule rubber from the marketplace.

An extraordinary series of events has reversed guayule's dismal prospects, culminating with the emergence of an important natural rubber market in which Hevea cannot be used, i.e. hypoallergenic latex products. This superb opportunity for guayule has arisen because Hevea latex products, due to increased usage and manufacturing short-cuts, are causing serious and widespread health problems. Proteins present in Hevea latex products can trigger immediate (Type I) hypersensitivity, which in its most serious manifestation, leads to life-threatening anaphylaxis. Synthetic alternatives to many Hevea latex products do not have the required range of physical properties that encompass resilience, strength, elasticity, and viral impermeability. The unique properties of natural rubber, together with concerns for public safety, make the development of an alternative, hypoallergenic source of natural rubber imperative. Guayule makes high quality rubber which can be produced as a latex suitable for hypoallergenic product manufacture. Guayule latex products should be safe for use by even those with severe Type I latex allergy. Hypoallergenic latex presents a high margin, rapidly-expanding market for guayule rubber latex products. This market provides a sufficient premium to permit the immediate development of guayule as a major domestic crop. Large scale trials have produced low protein, hypoallergenic guayule latex, which we have shown suitable for product manufacture.

BACKGROUND

Natural rubber is a vital raw material used in enormous quantities by commercial, medical, transportation, and defense industries. The United States is wholly dependent upon imports from developing countries. Although over 2,500 plants are known to produce natural rubber, few synthesize commercial quality or quantities. At present, all commercial natural rubber comes from a single, tropical, plant species, Hevea brasiliensis, largely from plantation-grown, bud-grafted, clonal material. Continuity of the natural rubber supply is endangered by many factors, including diminishing acreage (as growers switch to more profitable crops, such as palm oil), increasing global demand, changing political climes, and crop disease. The recent widespread occurrence of life-threatening "latex allergy" to Hevea rubber products makes development of an alternative source of natural rubber imperative. A domestic natural rubber crop would guarantee sufficient natural rubber to supply existing United States strategic demands as well as the new, major, health-related, hypoallergenic rubber market. A sustainable, domestic rubber industrial crop also would enhance rural economies, utilize semi-arid lands, and bring retired farmlands back into profitable production.

In any development of a new crop, however worthy the underlying rationale, the new crop must have an existing market and be profitable for the grower and the buyer. Approaches to achieving commercial competitiveness may be grouped in two categories, (1) increasing the yield and (2) adding value to the agricultural commodity. Both of these approaches have been attempted with guayule.

HISTORY OF GUAYULE COMMERCIALIZATION

Guayule commercialization has been ventured at several different times during the twentieth century (as reviewed by Bonner 1991), but without lasting success. In the 1900s, the Continental Mexican Rubber Company harvested and processed the native guayule stands. At the height of this endeavor (1910), rubber production was 10,000 t/year and constituted 24% of U.S. rubber imports. From 1906 to 1912, the United States imported 42,000 t of guayule rubber from Mexico. Production ended due to depletion of the native stands and civil unrest. A fresh enterprise began in Texas with the appearance of the Intercontinental Rubber Company and the cultivation of guayule. Rubber production reached 1,400 t/year, with commercial plantings of over 7,500 acres, but ended in 1929 with the onset of the Great Depression. Guayule then had to await the Second World War and the United States inauguration of the Emergency Rubber Project to supply the strategic raw material in light of the war-induced dearth of Hevea natural rubber supplies. This enormous undertaking employed 1,000 scientists and technicians, 9,000 laborers and 13,000 ha of guayule under cultivation in three States. The project had produced its first 1,400 t of rubber when the war ended. The guayule plantings were destroyed due to the reavailability of Hevea rubber, a perhaps over-optimistic view of the utility of synthetic rubber, and international political pressure.

Guayule then waited until the oil shortage of the 1970s. High oil prices caused increased costs of synthetic rubber and led to renewed interest in guayule as an alternative source of natural rubber. Scientific conferences took place which led to extensive lobbying and, in 1978, the Native Latex Commercialization and Economic Development Act (PL 95-592) (Huang 1991). The Gila River Indian Community Guayule Project got underway in 1981, and 1984 saw the act reauthorized as the Critical Agricultural Materials Act (PL 98-284). Considerable progress was made in improving guayule's commercial viability through plant breeding and agronomy. As has been described in detail (Ray 1991), rubber yields were between 220 and 560 kg/ha during the 1950's, and by the Second Guayule Regional Variety Trials (1985-1988) annual yields had been increased to between 600 and 900 kg/ha (Thompson and Ray 1989). Yields of over 1,100 kg/ha have been achieved in breeding plots (Gathman et al. 1989). The advanced lines also have been selected for their ability to regrow after pollarding (trimming the shrubs to about 10 cm above soil level, leaving the trunk and branch stubs). First harvest by pollarding at three years, followed by regrowth and reharvest at two year intervals maximizes the profitability of the current best lines (Thompson and Ray 1989; Estilai and Ray 1991). The affect of cultural practices on rubber yield has been extensively reviewed (Thompson and Ray 1989; Foster and Moore 1991; Nakayama 1991) and suitable agricultural machinery for modern mechanized farming has been successfully developed (Coates 1991). Direct seeding methodologies also have been developed (Foster and Moore 1992; Foster et al. 1993) which greatly reduce the costs involved in the transplanting procedures previously required for good stand establishment. Of course, growing guayule in areas climatically unsuitable for its cold-induced rubber biosynthetic pathway (Appleton and van Staden 1989; Ji et al. 1993; Cornish and Siler 1996) will not give acceptable rubber yields.

During this research and development period, the Gila River Indian Community Guayule Project planted 117 ha of guayule (1981 to 1986) predominantly of line Gila-1 (or AZ101). Unfortunately, this line proved to be a hybrid between P. argentatum and the large, but virtually rubber-free, P. tomentosum. Unsurprisingly, the hybrid proved to be a rapidly-growing but low-yielding line. Nonetheless, a processing plant based on a continuous simultaneous solvent extraction and rubber fractionation process, was built on the Gila River Indian Reservation (Wagner and Schloman 1991). The guayule rubber produced was manufactured into airplane and truck tires. Performance testing has shown that guayule rubber truck tires are of comparable quality to Hevea rubber tires (pers. commun. Wayne Lucas, Automotive Systems Engineering Branch, Yuma Proving Grounds).

This commercialization effort targeted the production of natural rubber in competition with imported Hevea bulk rubber, essentially for the tire market. Thus, guayule was confined to competition with the cheapest end of the natural rubber market. The profitably increases achieved through plant breeding and improved cultural practices were not sufficient to support commercialization. Approximately a doubling of yield or price was still required (Wright et al. 1991).

THE CHANGING MARKETPLACE

The value of an agricultural commodity may be increased through the discovery of a specific new use or market, or through increased demand and/or decreased supply leading to lower competition. The global demand for natural rubber is on the increase (Reisch 1995) even though area has declined, resulting in substantial price rises. Also, latex rubber is more expensive than bulk (solid) rubber, which costs usually about 70% the latex price. Guayule has been extensively investigated (Whitworth and Whitehead 1991) with the hope of its commercialization as a true competitor in natural rubber markets currently occupied by Hevea bulk rubber (d'Auzac et al. 1989). As mentioned earlier, guayule rubber has been used for fabricating automobile tires (Hammond and Polhamus 1965; pers. commun. Wayne Lucas) but has not been used for dipped or extruded goods since their manufacture requires the raw rubber to be in latex form. Unlike laticiferous species, such as Hevea, guayule produces rubber in individual cells, located predominantly in the root and stem bark parenchyma. None of the established extraction methods used to produce bulk rubber from guayule, whether solvent or water-based (Whitworth and Whitehead 1991), have led to competitively-priced product, even from the best bred lines. Guayule, as a source of more valuable latex rubber, has much greater commercial potential than bulk rubber.

Latex and Latex Products

Natural rubber is used in over 40,000 different products, including more than 300 medical applications. High-value dipped and extruded products are manufactured directly from the Hevea latex. A life-threatening "latex allergy" has developed, in recent years, that is triggered by proteins present in latex. Synthetic alternatives to Hevea latex products do not have the required range of physical properties that encompass resilience, strength, elasticity, and viral impermeability. The unique properties of natural rubber, together with concerns for public safety, make the need for an alternative, hypoallergenic source of natural rubber imperative. This special need creates an excellent opportunity for the development of a new, hypoallergenic, natural rubber crop.

In this section, we review the feasibility of ameliorating and circumventing Type I latex allergy caused by the presence of Hevea proteins in latex products. Also, we report on the development of hypoallergenic guayule latex.

Latex Allergy (Type I, IgE-Mediated)

Latex products had been safely used for many decades with only infrequent contact reactions (Type IV) occurring generally in response to chemical additives. However, in the 1980s, life-threatening Type I allergy appeared, which is triggered by proteins present in Hevea latex. A hypersensitive individual must take care to avoid contact with all natural rubber products made from Hevea latex. Allergic reactions to Hevea rubber products include local urticaria, systemic urticaria, rhinitis, conjunctivitis, edema, bronchospasm, tachycardia, anaphylaxis, and death (Slater 1989; Slater et al. 1990; Morales et al. 1989; Tomazic et al. 1992). The Food and Drug Administration responded to this public health problem by issuing a medical alert (March 1991) concerning use of latex products. Most, but not all, severe reactions occur from direct patient contact with latex gloves and other devices during medical and dental procedures.

Causes of Latex Allergy

The surge of Type I latex allergy coincided with sudden world-wide increased demand for latex gloves in response to institution of universal precautions to prevent transmission of the human diseases caused by HIV and Hepatitis B. New and inexperienced glove manufacturers entered the market, and short-cuts in manufacturing became common, in order to supply the increased demand (Bodycoat 1993). Over-production of these gloves led to a drop in price which, combined with the increasing demand, induced some other manufacturers to reduce costs through curtailed processing (Russell-Fell 1993). Altered manufacturing processes included reduction and sometimes elimination of the leaching step normally used to wash the latex products (Bodycoat 1993; Russell-Fell 1993). The washing process removes soluble latex components, as well as chemical additives, and underwashed products contain high levels of Hevea latex proteins.

The use of high protein latex products, especially of single-use latex gloves, as well as their extensive deployment throughout society, led to widespread development of Type I latex allergy. The problem was compounded by requirements for health-care workers to frequently change gloves. Proteins in gloves can bind to glove powder. When gloves are removed, the powder becomes a source of air-borne, respirable, latex allergens (Tarlo et al. 1994; Tomazic et al. 1994).

The Latex-Hypersensitive Population

The first incidents of latex allergy, in the United States, were reported in 1988. Numbers had increased to at least 500,000 by 1992. Published estimates, based on medical testing, indicate that 17,000,000 adults in the general U.S. population are affected by Type I latex allergy, 10%-40% of health care workers, and up to 60% of multiple surgery cases including spina bifida children (Alenius et al. 1993; Hamann 1993; Ownby et al. 1994). Many other countries around the world also have serious problems with latex allergy. The number of latex-hypersensitive people continues to climb due both to increased usage of latex products and to the continued sale of high protein latex gloves and other products. Manufacturing methods known to reduce product protein levels are available, but it is important to realize that even the best processing practices currently available will not produce latex products that are protein-free.

Latex Allergy Amelioration

Since Type I latex allergy arose because of high protein latex products, the manufacture and use of low protein latex products should greatly diminish the incidence of new allergy cases. Various methods for removing protein from latex and latex products are available (Pailhories 1993). However, future latex products will have to be shown to be low protein.

Hevea latex and latex products are difficult materials to assay for protein since latex is a cytoplasm that also contains about 30% rubber in the form of microscopic particles. Latex proteins fall into several groups with some soluble (48%), some associated with organelles (26%), and some bound to the surface of rubber particles (26%) (Kekwick 1993). Allergic patients can react to a large number of different latex protein allergens, which can originate from all of these protein groups. At least 57 different latex proteins and peptides, out of approximately 240, have been shown to be human allergens (Alenius et al. 1994). These range in size from 2 to 100 kD (Hamann 1993; Yeang et al. 1996). Nevertheless, soluble latex proteins, and others not directly associated with rubber particles, should be easier to remove from latex and/or latex products than the rubber particle-bound proteins (Siler and Cornish 1992). Their removal would substantially lower the overall protein level, thus reducing the allergenicity of the final latex product for people who have not yet developed latex allergy.

Latex protein assays must effectively measure all classes of protein allergens in latex, or latex products, and eliminate interference from nonproteinaceous substances in the latex and additives such as ammonia. A suitable method for assaying protein levels in latex has been developed (Siler and Cornish 1995) and an ASTM panel has developed an assay for use with latex products (ASTM 1995).

Latex Allergy Circumvention

As discussed above, it is possible to produce low protein latex products that should moderate the incidence of new allergy cases. However, trace amounts of allergen can induce serious systemic reactions in a hypersensitive person. Thus, production of latex products safe for use by allergic individuals requires the elimination of all latex allergens.

Allergens that are not associated with the rubber particles can be removed from the latex, prior to product manufacture, by repeated purification cycles using centrifugation/flotation (Siler and Cornish 1994a). Certain types of dipped products, such as some surgical gloves, electricians' gloves, and condoms, are made from doubly-centrifuged latex. This is produced by centrifuging standard latex (30%-35% dry rubber), diluting to 20%-25% with water, and centrifuging again. This process can remove about 70% of the non-rubber substances (Pailhories 1993). However, 25% of the proteins are bound to the rubber particles. Even extensive rubber particle purification does not remove them and these proteins would persist in the final product.

We tested the immunogenicity of various latex materials using antibodies, raised in rabbits, against proteins extracted from Hevea latex films. These Hevea latex protein antibodies recognized many of the proteins in complete Hevea latex (Siler and Cornish 1994b). As expected, purified rubber particle preparations, from which the soluble latex proteins were removed, contained far fewer proteins than latex (Siler and Cornish 1992, 1994b). Nevertheless, these highly purified Hevea rubber particle preparations still contained numerous proteins many of which are immunogens (Siler and Cornish 1994b). Also, a report that IgE antibodies from serum of latex-sensitized individuals recognized the 14.6 kD protein "rubber elongation factor" implicates this abundant rubber particle-bound protein as a major allergen in Hevea latex (Czuppon et al. 1993).

Thus, complete removal of both rubber particle-bound and soluble latex protein allergens is required to produce a Hevea latex material safe for use by a latex-hypersensitive person. Removal of the rubber particle-bound proteins would necessitate drastic treatment e.g. with proteases and/or detergents, that would not only probably be prohibitively expensive, but also likely would adversely affect the performance characteristics and quality of the resulting latex products.

Some manufacturers have introduced so-called "hypoallergenic" Hevea latex gloves into the market. Although some of these gloves are low protein, tests demonstrated that many contain substantial amounts of proteins that bind IgE antibodies from sera of Hevea-hypersensitive patients (Yunginger et al. 1994). Low protein hypoallergenic gloves would be unlikely to induce allergies in individuals not already allergic to Hevea latex proteins. However, these gloves would not be safe for use by people who are already Hevea-hypersensitive.

Suggestions have been made to remove the allergens from Hevea latex by breeding or by using genetic engineering techniques (antisense technology) to eliminate the allergenic proteins. These approaches are biologically unsound. This is primarily because many different latex proteins have been shown to be allergens (see above). It is very unlikely that they could be removed from the Hevea tree without dire effects on latex production and plant health. Furthermore, the genetic base of cultivated Hevea is extremely narrow which would likely preclude a plant breeding approach. We confirmed that clonal selection is unlikely to eliminate latex antigens in experiments that demonstrated that Hevea latex protein antibodies recognized many proteins in samples from three different commercial lines of Hevea (Siler and Cornish 1994b). The proteins recognized by the antibodies showed similar patterns in all three clones.

HYPOALLERGENIC GUAYULE LATEX

Different rubber-producing species may contain proteins distinct from those of Hevea and perhaps provide a source of hypoallergenic rubber (Siler and Cornish 1992). Guayule rubber is of high molecular weight and of comparable quality to Hevea rubber. However, guayule had not been seriously considered as a source of latex rubber (this liquid rubber form is essential for the manufacture of dipped and extruded products) since it does not produce its rubber as a tapable latex. Unlike the laticiferous species Hevea, guayule rubber particles are compartmentalized in individual bark parenchyma cells. Nonetheless, methods have been developed to extract guayule rubber in a latex-like form (Jones 1948; Madhavan and Benedict 1984; Cornish and Backhaus 1989; Cornish 1993). It seemed likely that the Hevea protein allergens would be absent from guayule latex since the Hevea and guayule are evolutionarily-divergent species and their rubber particle protein complements are dissimilar. We have proven this to be true. Anti-Hevea latex protein antibodies did not recognize latex proteins from guayule using ELISA (enzyme-linked immunosorbent assay). Proteins extracted from purified rubber particle preparations of guayule showed no reaction, even at concentrations at least 2 or 3 orders of magnitude above the Hevea rubber particle protein concentration that elicited a positive reaction (Siler and Cornish 1994b). Western blot analyses of the rubber particle proteins from guayule with the Hevea antibodies confirmed the lack of cross-reactivity (Siler and Cornish 1994b). These results indicate that Hevea latex allergy can indeed be circumvented using rubber from guayule.

Our results were confirmed in preliminary clinical trials on humans. In one trial, individuals with proven hypersensitivity to Hevea latex were skin-prick tested with latex samples from different sources. All these subjects reacted strongly to Hevea latex (wheals and flare), whereas none responded to guayule latex (Carey et al. 1995). In a second trial, 56 "at risk" people (such as health care workers, spina bifida patients, and multiple surgery cases), ages 16 months to 72 years, and three controls, were tested both by skin prick and by in vitro RAST (radioallergosorbent assay) assays (Ber et al. 1993). The RAST assay detects the presence of human IgE antibodies specific to Hevea latex proteins. 25 reacted to Hevea materials, 25 reacted in the skin prick test, and 30 in the RAST. None reacted to guayule latex, confirming the earlier clinical test results, and our experiments using the rabbit anti-Hevea latex protein antibodies.

Guayule rubber latex should be suitable for the manufacture of high quality, hypoallergenic natural rubber products safe even for the Hevea-hypersensitive individual. Some other rubber-producing plant species also produce high molecular weight rubber but currently none are suitable for commercial cultivation. In contrast, guayule agronomics are well understood (see History of Guayule Commercialization above).

Thus, diverse immunological tests have demonstrated that guayule latex is truly hypoallergenic and that guayule latex products could be used safely by Hevea latex-sensitive people. Of course, it is essential that guayule latex products be maintained as low protein so that allergy problems don't redevelop later. The most difficult proteins to completely remove are those bound to the rubber particles themselves. Guayule rubber particles have less protein than Hevea (Cornish et al. 1993) and, therefore, guayule latex could be produced with lower protein levels than will ever be possible with Hevea latex.

Production of Hypoallergenic Guayule Latex

We have developed processing methods to extract intact guayule rubber particles and generate an artificially-produced purified latex (Cornish 1993). These methods also are suitable for the production of latex from other rubber producing species.

Guayule hypoallergenic latex presents a major new, high value, rapidly expanding market because hypersensitive people cannot safely use Hevea latex products. The U.S. market for latex gloves alone had a retail value of over $3,000,000,000 in 1993. Hypoallergenic natural rubber latex products would provide a sufficient premium to permit the immediate development of guayule as a new crop even at its current rubber yield (about 10% on a dry weight basis).

During the Spring of 1994, a production run was carried out in Arizona, where 2,300 kg of field-grown guayule shrub were processed. A processing system was constructed and used (Coates and Cornish, unpublished results) to generate ammoniated guayule latex for allergy testing, performance testing, and manufacturing trials. This batch of guayule latex was less highly purified than the latex used in the allergy trials described in the last section. Nevertheless, immunological experiments (RAST and Western blot analysis) to investigate the ability of IgE antibodies from Hevea latex allergic patients, and IgG antibodies from hyperimmunized mice, to detect proteins in the guayule latex displayed a total lack of cross-reactivity (Siler et al. 1996). Several additional trials have been completed on this material demonstrating that guayule latex (1) may be compounded using similar procedures to Hevea latex (Schloman et al. 1996), (2) can be used to produce quality latex medical products (H.F. Bader, and K. Cornish, unpublished data), and (3) prototype dipped films provide an impermeable barrier to virus transmission (D. Lytle and K. Cornish, unpublished data).

Commercialization Position

Hypoallergenic latex reflects a technological breakthrough that provides a new impetus to the commercialization of this new crop. However, guayule latex would be years away from successful commercialization but for the diverse and numerous successes of the scientists involved in guayule research in recent years, as described earlier. Their work has led to the advanced guayule lines and refined, mechanized agronomic practices which provide an essential foundation for guayule latex commercialization.

CONCLUSIONS

Large-scale production of guayule latex is feasible and the high quality of guayule natural rubber makes it suitable for hypoallergenic product manufacture. These products should be safe for use by the Hevea-hypersensitive population. Clinical trials on humans showed that even severely Hevea-hypersensitive patients had no reaction to guayule latex. Guayule latex products must be produced with low protein levels so that allergy problems don't develop with the new material. Guayule rubber particles have much less protein than those of Hevea, and guayule latex can be produced with lower protein levels than even highly purified Hevea latex. Upon the generation of sufficient supplies, hypoallergenic guayule latex products first would become available to hypersensitive patients, and the at-risk health-care profession, and then to the general population. Guayule latex provides the first, natural rubber solution to the urgent global need for a reliable hypoallergenic source of natural rubber latex. Concerted and dedicated efforts should make safe guayule latex products a reality and the guayule crop a major feature of the farming landscape of the south-western United States. Continuing research also should lead to the introduction of genetically-engineered guayule lines with enhanced rubber yield and extended growing range.

REFERENCES

Last update June 13, 1997 aw