디테일박스

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

Introduction
The discovery of a cow with bovine spongiform encephalopathy (BSE) in Washington State in December 2003 triggered action to put in place additional safeguards against BSE. Even though the cow was born in Canada, the fact that the cow was discovered in the U.S. and had been sent to slaughter and rendering before 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 ways they are used, provide another route for BSE infectivity to enter the human system. Cosmetics may contain a wide range of cattle-derived ingredients, many of which may carry the BSE agent. FDA prepared this assessment of 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 by the 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 assessment uses scientific evidence to the extent that it exists. The agency has determined that this qualitative risk assessment 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 vCJD had 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 or hallucinations. These symptoms are followed by memory impairment, then dementia in the late stages. The clinical course 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 share characteristics with abnormal prion proteins found in cattle with BSE, scientists have concluded that exposure to the BSE agent is the most plausible explanation for the occurrence of vCJD (Refs. 5 - 8). Monkeys (genetically the closest animal model to humans) inoculated with samples of brain from BSE-infected cattle have been found to develop a 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 to abnormal prion proteins from BSE-infected cattle and different from abnormal prion proteins from patients with CJD and other spongiform encephalopathies (Ref. 4).

Prions are predominantly found in the central nervous system, portions of the intestine, and tonsils of cattle with BSE. Cosmetic ingredients can be derived from some of these tissues. Although large prion doses are known to have a shorter incubation period before the disease develops, even low doses may cause vCJD if infectious prions survive digestion and the host survives long enough to complete a longer incubation period. Although most scientists believe that vCJD in humans is caused by consumption of cattle-derived food products contaminated with the agent that causes BSE (Refs. 11-14), exposure from cosmetics derived from cattle protein is another potential route 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 and tallow derivatives. However, tallow derivatives, particularly fatty acids and glycerin, are the predominant bovine ingredient used by the cosmetic industry and contain very little protein, and are therefore unlikely vehicles for the transmission of prions. Cattle-derived ingredients serve many functions and may be used as skin 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 could transmit disease to humans. Transmission of the BSE agent to humans through intact skin is believed to be unlikely; however, cosmetics may be ingested or applied to cut or abraded skin or to conjunctival tissues that can provide direct routes for infection.

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

Cut or abraded skin also has been proposed as a route for contracting TSE diseases. The transmission of kuru through cut skin has been suggested and was mentioned previously. Taylor et al. (Ref. 18) and Ingrosso et 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 ingestion of 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, dendritic cells, and keratinocytes (the primary cell types found in the epidermis) have been found to contain infectious prion protein, indicating that these cells are potential targets for peripheral infection with a TSE disease.

Use of BSE-contaminated cosmetics could provide a means of human infection via several routes discussed above. 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 via eye rubbing or incorrect application. Any cosmetic product, but particularly shaving creams and gels and lotions, 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 have the same risk as prion-contaminated meat and other food products derived form cattle. Furthermore, the presence of cattle derived ingredients is not generally obvious to the consumer, since the source of the ingredient (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 similar misconformation in normal proteins, which can in turn cause further misconformations. This allows propagation 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 the brain, 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 of the disease, regardless of the size of the initial dose, although incubation periods of 4 or more years appear to be more common (Refs. 11 and 12). The lag period may reflect the fact that transmission from food to brain may be preceded by symptomless amplification of infectious prions in the intestine and lymphoreticular tissues. While cattle at this stage would be clinically normal and may have negative BSE 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 percentage of the exposed population has been diagnosed with vCJD to date. However, ongoing experiments indicate that the infectious dose for cattle is very low. One gram of affected bovine brain homogenate is sufficient to cause BSE in more than 50 percent of calves exposed by mouth. Five years after oral consumption of lower doses of brain material, 2 of 15 calves fed 0.1 gram had onset of BSE, and 1 of 15 fed 0.01 gram had developed the disease. This experiment is ongoing (Ref. 22). There is thought to be a 10- to 10,000-fold increase in the amount of infectious material needed to cause illness in humans as compared with cattle, because of the species barrier (Ref. 23).

Risk Characterization
This is not a quantitative risk assessment. However, it does sketch out the logical structure that a quantitative model could use if one were constructed. Some conclusions can be drawn without a quantitative analysis. Since there is considerable uncertainty associated with the premises outlined in the present analysis, 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 protein used in making cosmetics, the effect of processing on prion concentration, and the transmission rates for dermal and ocular exposure. Particularly large uncertainties associated with the dose response assessment include 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 associated with the risk from food consumption. For example, the number of BSE-affected cattle and the variability in human 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 little exposure, and also little economic consequence from regulating use. Conversely, high use would require substantial 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 ingestion of beef and other food derived from cattle, other routes of exposure may also be important. Although small doses require longer incubation periods for clinical signs to develop, small doses of infectious prions can potentially cause 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 systemic absorption 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 in cosmetics. However, since there are large uncertainties associated with the quantitative estimates of many of the important variables, any quantitative estimate of the risk or rate at which the disease may be expected to occur would be correspondingly imprecise.

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

화장품에 사용된 소 추출 단백질에 노출 되었을 때의 변형 크로이펠트 제이컵 질환(인간광우병)의 (발병)위험에 대한 평가

2004년 7월 14일

 

화장품로부터 프리온의 흡수

BSE를 일으키는 매개체에 감염된 화장품을 통해 질병을 인간에게 옮기는 경로는 여러 가지가 있다. 손상되지 않은 인간 피부를 통한 BSE매개체의 전달은 가능하지 않은 것으로 믿어진다. 하지만 섭취하거나 베거나 벗겨진 피부 혹은 결막 조직에 바른 화장품은 직접적인 감영의 경로를 제공할 수 있다. 

시신경계를 포함한, 중추신경계 조직은 TSE에 감염된 동물과 vCJD (변형CJD)에 감염된 인간에 감염체를 띈다는 사실은 잘 문서화 되어있다. 쥐의 경우 안구에 스크래피(양의 바이러스성 전염병;뇌와 중추 신경계의 질환) 주입은 시신경을 따라 감염을 발생 시켰는데 이는 임파계를 따라 비신경에도 전염이 되었다(Ref. 15).

안구에의 주입에 더하여, 감염성은 눈의 결막을 통하여도 전달될 수 있다. Scott 등(Ref. 16)은 스크래피(양의 바이러스성 전염병;뇌와 중추 신경계의 질환) 가 42%의 설취류에서 결막에 감염체의 높은 농축액을 떨어뜨리는 것만으로 유발 되었다는 사실을 발견하였다.

Klitzman 등(Ref. 17)은 kuru 라는 뉴기니아의 포어 종족 가운데에서만 발병하는 TSE질병은 감염된 인간의 뇌를 장례의식 중 감염된 뇌를 만지거나 먹는 와중에 눈이나 벤 피부에 비벼서 감염되었을지도 모른다는 의견을 제시했다.

베거나 벗겨진 피부는 TSE질병에 걸리는 경로가 될 수도 있다는 의견이 제시되었다. Kuru가 베 피부를 통한 감염이 제안되었고 전에 언급되었다. 

Taylor등(Ref. 18)과 Ingrosso 등(Ref. 19)은 스크래피(양의 바이러스성 전염병;뇌와 중추 신경계의 질환) 는 입의 점막조직을 통하여 좀 더 좀더 잘 전달될 수 있다는 사실을 보여주었다. 한 연구에 의하면 입의 점막에 실험을 위하여 손상을 가한 쥐의 100%에서 스크래피(양의 바이러스성 전염병;뇌와 중추 신경계의 질환) 가 발병하였고 정상적인 점막을 지닌 쥐에서는 71%가 발병했다(Ref. 18).

여기에다가 Pammer 등 (Ref. 20)과 Sugaya등 (Ref. 21)은 상피세포, dendritic cells 그리고 케라티노사이트[(표피에서 발견되는 원시적인 세포형태), 케라틴 생성(합성) 세포] 는 간염성이 있는 프리온 단백질을 포함하고 있는 것이 발견되었는데 이는 이 세포들이 TSE 질병의 2차 감염의 목표가 될 수도 있다는 걸 나타낸다. 

BSE 가 감염된 화장품류의 사용은 위에 기술한 여러 경로를 통하여 인체 감염의 수단을 제공할 수 있다. 많은 화장품류는 정형적으로 눈부위 (마스카라, 눈썹 펜슬, 아이라이너, 아이로션, 아이메이컵 제거제)에 적용되고 샴푸를 포함한 거의 모든 화장품이 비빔을 통하거나 잘못된 사용으로 눈에 들어 갈수 있다. 

어떤 화장품이라도 특히 면도 크림이나 젤 로션 등은 베거나 벗겨진 피부에 사용될 수있다. 섭취 된 화장품류, 립스틱, 치약, 구강 청정제, 귀취제거제 등은 입을 통한 감염 경로일 수 있다.  섭취된 부분은 프리온에 감염된 고기나 소로부터 나온 다른 식 제품과 같은 위험을 지니고 있을 것이다.      

게다가, 소에서 나온 성분의 존재는 고객에게 전반적으로 명백하지 않다. 왜냐면 구성 성분의 원천(즉 소에서 추출된)은 레이블에 부착될 필요가 없기 때문이다.

결론

스폰지 형태 뇌질환의 일종으로 인간에게 발생하는 질환(vCJD)은 소에서 발생하는 BSE와 같은 단백질(프리온)으로부터 초래된다고 판단된다. 비록 소고기의 섭취가 주 노출 원인으로 알려지고 있지만 다른 노출 경로도 또한 중요할 것이다. 

비록 소량 복용은 임상 징후가 나타나는데 더 긴 배양(잠복)기간이 필요하지만 감염성이 있는 프리온의 소량 복용은 잠재적으로 질병을 유발할 수있다.    

소과를 출처로 추출된 단백질이 함유된 화장품류는 잠재적 (질병에 대한)노출 근본 원인이다. 실험적으로 예시된 바와 같이 안구를 통한 단백질 흡수, 그리고 찢겨지거나 벗겨진 피부에 화장품류를 발랐을 때 시스템적인 단백질의 흡수가 일어날 수 있는데 TSE들이 초래 될 수 있다.

결과적으로 소로부터 추출되어 화장품류에 함유된 단백질의 사용으로 어느 정도의 vCJD 발생 위험이 있다고 결론 지을 수 있다. 그러나, 여러 주요 변수들에 대한 정량적인 측정에 대한 큰 규모의 불확정성이 있기 때문에 어떤 (감염)위험 혹은 어느 정도에서 질병이 발생할까 하는 발병 정도는 마찬가지로 정확하지 않다.

화장품류로부터의 BSE (감염)위험은 (감염)노출의 통제를 통하여 제한될 수 있다. 우지에 사용된 추출과정을 이외에도 BSE프리온을 활성화시키지 않는 효율적인 화장품류 제조공정은 아직 알려지지 않았다. 화장품을 통한 BSE 프리온의 전달을 막는 가장 확실한 방법은 화장품류의 제조에 위험성이 높은 소로부터 추출된 단백질의 사용을 피하는 것뿐이다.