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July 14, 2004

# An Evaluation of the Risk of Variant Creutzfeldt-Jakob Disease from Exposure to Cattle-DerivedProtein Used in Cosmetics

## Introduction

The discovery of a cow with bovine spongiform encephalopathy (BSE) in Washington State in December2003 triggered action to put in place additional safeguards against BSE. Even though the cow was bornin Canada, the fact that the cow was discovered in the U.S. and had been sent to slaughter and renderingbefore it was identified as positive indicates a vulnerability in the U.S. BSE protective net.

While BSE is usually identified with either food safety or animal health, cosmetics, because of the waysthey are used, provide another route for BSE infectivity to enter the human system. Cosmetics may contain awide range of cattle-derived ingredients, many of which may carry the BSE agent. FDA prepared this assessmentof the risks to public health if cattle-derived ingredients are used in cosmetics.

This qualitative risk assessment follows the generally accepted framework for risk assessments endorsed bythe Codex Alimentarious Commission, the U.S. National Academy of Sciences, and other authoritative bodies.The framework divides risk assessment into four components: (1) hazard identification, (2) exposure assessment,(3) hazard characterization (or dose-response assessment), and (4) risk characterization. The risk assessmentuses scientific evidence to the extent that it exists. The agency has determined that this qualitative riskassessment is appropriate to the circumstances.

## Risk Assessment

### Hazard Identification

In April 1996, British scientists reported a previously undetected new variant of Creutzfeldt-Jakob disease(vCJD) in young patients, with symptoms somewhat different from sporadic CJD (Refs. 1 and 2). All cases of vCJDhad histopathologic evidence of spongiform changes in the brain, but also showed formation of "florid" plaques(a core of amyloid protein with surrounding halos of vacuoles) not typically seen in other forms of CJD (Ref. 3).Clinically, vCJD usually begins with a psychiatric presentation, such as depression, anxiety, nightmares orhallucinations. These symptoms are followed by memory impairment, then dementia in the late stages. The clinicalcourse may last up to two years before death occurs (Ref. 4).Because scientific evidence suggests that the presence and infectivity of abnormal prion proteins in vCJD sharecharacteristics with abnormal prion proteins found in cattle with BSE, scientists have concluded that exposure tothe BSE agent is the most plausible explanation for the occurrence of vCJD (Refs. 5 - 8). Monkeys (genetically theclosest animal model to humans) inoculated with samples of brain from BSE-infected cattle have been found to developa TSE that is histopathologically similar to vCJD (Ref. 9), as have mice inoculated or fed with BSE-infected tissue(Ref. 10). In addition, studies have shown that abnormal prion proteins from vCJD patients are molecularly similar toabnormal prion proteins from BSE-infected cattle and different from abnormal prion proteins from patients with CJD andother spongiform encephalopathies (Ref. 4).

Prions are predominantly found in the central nervous system, portions of the intestine, and tonsils of cattlewith BSE. Cosmetic ingredients can be derived from some of these tissues. Although large prion doses are knownto have a shorter incubation period before the disease develops, even low doses may cause vCJD if infectiousprions survive digestion and the host survives long enough to complete a longer incubation period. Although mostscientists believe that vCJD in humans is caused by consumption of cattle-derived food products contaminated withthe agent that causes BSE (Refs. 11-14), exposure from cosmetics derived from cattle protein is another potentialroute of exposure.

### Exposure Assessment

**BSE in the United States**On December 23, 2003, USDA diagnosed a positive case of BSE in an adult Holstein cow in the State of Washington.

**Use of Cattle Protein in Cosmetics**Cosmetics may be made from a variety of cattle-derived ingredients. These ingredients include albumin,brain extract, brain lipid, cholesterol, fibronectin, sphingolipids, collagen, keratin, and tallow andtallow derivatives. However, tallow derivatives, particularly fatty acids and glycerin, are the predominantbovine ingredient used by the cosmetic industry and contain very little protein, and are therefore unlikelyvehicles for the transmission of prions. Cattle-derived ingredients serve many functions and may be used asskin conditioning agents, emollients, binders, and hair and nail conditioning agents.

**Absorption of Prions from Cosmetics**There are several routes through which cosmetics contaminated with the agent that causes BSE couldtransmit disease to humans. Transmission of the BSE agent to humans through intact skin is believedto be unlikely; however, cosmetics may be ingested or applied to cut or abraded skin or to conjunctivaltissues that can provide direct routes for infection.

It is well-documented that central nervous system tissue, including the optic nerve, carries infectivityin animals with TSEs and humans with vCJD, and serves as an efficient route of transmission. In mice, intraocularinjection of scrapie caused infection along the optic nerve, which eventually spread into non-neural tissue viathe lymphatic system (Ref. 15). In addition to intraocular injection, infectivity has been transmitted to animalsvia the conjunctiva of the eye (mucosal tissue). Scott et al. (Ref. 16) found that scrapie was induced in 42 percentof rodents by dropping a high concentration of infectivity onto the conjunctiva. Klitzman et al. (Ref. 17) suggestedthat kuru, a human TSE disease found only among the Fore people of New Guinea, might have been transmitted byrubbing infected human brain into eyes or cut skin, while handling and consuming infected brain during funeralrituals.

Cut or abraded skin also has been proposed as a route for contracting TSE diseases. The transmission ofkuru through cut skin has been suggested and was mentioned previously. Taylor et al. (Ref. 18) and Ingrossoet al. (Ref. 19) demonstrated increased transmission of scrapie via oral mucosal tissue. In one study,100 percent of mice with experimentally damaged oral mucosal tissue developed scrapie through ingestionof infected material, while only 71 percent of mice with intact mucosa developed the disease (Ref. 18).In addition, Pammer et al. (Ref. 20) and Sugaya et al. (Ref. 21) noted that epithelial cells, dendriticcells, and keratinocytes (the primary cell types found in the epidermis) have been found to containinfectious prion protein, indicating that these cells are potential targets for peripheral infectionwith a TSE disease.

Use of BSE-contaminated cosmetics could provide a means of human infection via several routes discussedabove. Many cosmetics are typically applied in the area of the eye (mascara, eye brow pencil, eyeliner,eye lotion, and eye makeup remover) and almost any cosmetic, including shampoo, can get into the eye viaeye rubbing or incorrect application. Any cosmetic product, but particularly shaving creams and gels andlotions, may be applied to cut or abraded skin. Cosmetics that are ingested, such as lipstick, dentifrices,mouthwash, and breath fresheners, would have an oral route of infection, and the ingested fraction would havethe same risk as prion-contaminated meat and other food products derived form cattle. Furthermore, thepresence of cattle derived ingredients is not generally obvious to the consumer, since the source of theingredient (i.e. cattle derived) does not need to be placed on the label.

### Hazard Characterization

Prions with a particular abnormal tertiary structure are apparently able to generate a similarmisconformation in normal proteins, which can in turn cause further misconformations. This allowspropagation of the disease and is also important for understanding the relationship between dose,response, and the incubation required for the disease to develop. Once the prions have entered thebrain, the prion concentration grows with a relationship that has been described as exponential (Ref. 14).

In cattle, there is a minimal incubation period of six months to a year required for the development ofthe disease, regardless of the size of the initial dose, although incubation periods of 4 or more yearsappear to be more common (Refs. 11 and 12). The lag period may reflect the fact that transmission fromfood to brain may be preceded by symptomless amplification of infectious prions in the intestine andlymphoreticular tissues. While cattle at this stage would be clinically normal and may have negativeBSE test results, various tissues could be infectious (Refs. 11 and 12).

Despite widespread exposure in the U.K. to BSE-contaminated meat products, only a very small percentageof the exposed population has been diagnosed with vCJD to date. However, ongoing experiments indicatethat the infectious dose for cattle is very low. One gram of affected bovine brain homogenate is sufficientto cause BSE in more than 50 percent of calves exposed by mouth. Five years after oral consumption of lowerdoses of brain material, 2 of 15 calves fed 0.1 gram had onset of BSE, and 1 of 15 fed 0.01 gram had developedthe disease. This experiment is ongoing (Ref. 22). There is thought to be a 10- to 10,000-fold increase in theamount of infectious material needed to cause illness in humans as compared with cattle, because of the speciesbarrier (Ref. 23).

### Risk Characterization

This is not a quantitative risk assessment. However, it does sketch out the logical structure that aquantitative model could use if one were constructed. Some conclusions can be drawn without a quantitativeanalysis. Since there is considerable uncertainty associated with the premises outlined in the presentanalysis, it follows that there will also be considerable uncertainty associated with the risk estimate.In the exposure assessment, there are considerable uncertainties associated with the origin of proteinused in making cosmetics, the effect of processing on prion concentration, and the transmission rates fordermal and ocular exposure. Particularly large uncertainties associated with the dose response assessmentinclude the magnitude of the species barrier and the length of the incubation period.

With exception of the uncertainty associated with estimates of the dermal and ocular transmission rates,most of the uncertainties associated with a risk assessment of BSE prions in cosmetics are also associatedwith the risk from food consumption. For example, the number of BSE-affected cattle and the variability inhuman susceptibility will impact the risk of both food- and cosmetic-associated vCJD.

Some of these uncertainties may concomitantly affect both sides of a cost-benefit analysis. In particular,if there is not substantial use of cattle-derived protein in making cosmetics, then there will be littleexposure, and also little economic consequence from regulating use. Conversely, high use would requiresubstantial substitution and alternative means of animal-by-product disposal.

## Conclusions

A form of spongiform encephalopathy that occurs in humans (vCJD) is thought to result from the same protein(a prion) that causes BSE in cattle. Although the primary source of exposure is likely to be due to the ingestionof beef and other food derived from cattle, other routes of exposure may also be important. Although small dosesrequire longer incubation periods for clinical signs to develop, small doses of infectious prions can potentiallycause disease. Cosmetics that contain protein derived from bovine sources are a potential source of exposure.It has been demonstrated experimentally that TSEs may result from ocular absorption of protein, and systemicabsorption of protein may also occur when cosmetics are applied to lacerated or abraded skin. As a result,it may be concluded that there is some risk of occurrence of vCJD from the use of cattle-derived protein incosmetics. However, since there are large uncertainties associated with the quantitative estimates of manyof the important variables, any quantitative estimate of the risk or rate at which the disease may be expectedto occur would be correspondingly imprecise.

The risk of BSE from cosmetics may be reduced through the control of exposure. Aside from the derivationprocesses used on tallow, the effectiveness of cosmetic manufacturing processes for inactivating BSE prionsis unknown. The surest way to prevent transmission of BSE-prion through cosmetics is to avoid the use ofhigh-risk cattle-derived protein in the manufacture of cosmetics.

## References

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Foodborne Illness

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