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From: TSS (216-119-132-86.ipset12.wt.net)
Subject: Re: Neuroinvasion by Scrapie following Inoculation via the Skin Is Independent of Migratory Langerhans Cells
Date: January 13, 2005 at 2:11 pm PST

In Reply to: Neuroinvasion by Scrapie following Inoculation via the Skin Is Independent of Migratory Langerhans Cells posted by TSS on January 13, 2005 at 1:38 pm:

WHAT does the fda say, everything is ok, but what about before July 14, 2004 ???

WHAT about all that cream and eye make-up my mother used for decades and she
had the Heidenhain Variant of CJD WHICH is in the brain directly behind the eyes,
causing you to go blind first? she rubbed the stuff on her face and arms for as long as
i can remember, every night...

Similarly, FDA has prohibited the use of the cattle materials that carry the highest risk of BSE in human food, including dietary supplements, and in cosmetics. FDA's rule prohibits use of the following cattle material in human food and cosmetics:

* cattle material from non-ambulatory, disabled cattle,
* cattle material from organs from cattle 30 months of age or older in which infectious prions are most likely to occur, and the tonsils and small intestine of cattle of all ages,
* cattle material from mechanically separated (MS) (beef), and
* cattle material from cattle that are not inspected and passed for human consumption

FDA's rule also requires that food and cosmetics manufacturers and processors make available to FDA any existing records relevant to their compliance with these prohibitions. FDA has also published a proposal requiring manufacturers and processors of food and cosmetics made with cattle material to establish and maintain records demonstrating that their products do not contain prohibited cattle material.
Is the food in the U.S. likely to be a BSE risk to consumers?

FDA and other federal agencies have had preventive measures in place to reduce the U.S. consumer's risk of exposure to any BSE-contaminated meat and food products. Since 1989, USDA has prohibited the importation of live animals and an imal products from BSE-positive countries. Subsequently, USDA expanded the ban to include both countries with BSE and countries at risk for BSE. Since 1997, FDA has prohibited the use of most mammalian protein in the manufacture of ruminant feed. In 2004, FDA issued a rule prohibiting the use of certain cattle materials in human food and cosmetics, and USDA issued a rule prohibiting certain cattle materials from use as human food.

This document was issued in January 2004 and updated in July 2004.
For more recent information on Bovine Spongiform Encephalopathy (BSE)
see http://www.fda.gov/oc/opacom/hottopics/bse.html
This is G o o g l e's cache of http://vm.cfsan.fda.gov/~comm/bsefaq.html as retrieved on Jan 9, 2005 14:48:24 GMT.

July 9, 2004
horizontal rule
FACT SHEET:

I. FDA'S New Interim Final Rule Prohibiting Use of Certain Cattle Materials that May Carry the Risk of Bovine Spongiform Encephalopathy in Human Foods and Cosmetics
and

II. FDA's Proposed Rule on Recordkeeping Requirements for Human Food and Cosmetics Manufactured From, Processed With, or Otherwise Containing Material From Cattle

In response to the finding of an adult cow that tested positive for BSE in the State of Washington, FDA is taking action to minimize human exposure to materials that scientific studies have demonstrated to contain the BSE agent when they come from cattle infected with the disease. This action is consistent with the interim final rule issued by the U.S. Department of Agriculture (USDA) prohibiting certain cattle materials from use as human food. It is widely accepted that consumption of products contaminated with the agent that causes BSE results in the human illness, variant Creutzfeldt-Jakob disease (vCJD). In conjunction with the interim final rule (IFR), FDA is issuing a proposed rule to require that manufacturers and processors of human food and cosmetics that are manufactured from, processed with, or otherwise contain material from cattle, establish and maintain records sufficient to demonstrate that the food and cosmetics are in compliance with the IFR.
I. Interim Final Rule
What action is FDA taking with this interim final rule? FDA is prohibiting the use of certain materials that carry a risk of bovine spongiform encephalopathy (prohibited cattle materials) in food for humans, including dietary supplements, and cosmetics. Prohibited cattle materials include:

* specified risk materials
* small intestine of all cattle
* material from non-ambulatory disabled cattle
* material from cattle not inspected and passed for human consumption
* mechanically separated (MS) beef

The interim final rule also requires that FDA-regulated food and cosmetic manufacturers and processors make available to FDA any existing records that may be relevant to their compliance with the prohibitions in the rule.

What are specified risk materials? Specified risk materials, from cattle 30 months and older, are the:

* brain
* skull
* eyes
* trigeminal ganglia
* spinal cord
* vertebral column (excluding the vertebrae of the tail, the transverse processes of the thoracic and lumbar vertebrae, and the wings of the sacrum)
* dorsal root ganglia.

Specified risk materials from cattle of any age are the

* tonsils and
* distal ileum of the small intestine.

Prohibited cattle materials do not include tallow that contains no more than 0.15 percent hexane-insoluble impurities and tallow derivatives.

What products are covered by the interim final rule? All FDA-regulated human food and cosmetics, including:

* Dietary supplements and dietary ingredients
* Infant formula
* Canned and frozen foods
* Bakery goods, snack food, and candy (including chewing gum)
* Food ingredients, including GRAS substances
* Food additives, including food-contact substances
* Cosmetics and cosmetic ingredients.

How can food manufacturers and processors comply? Manufacturers and processors who currently use prohibited cattle materials will need to switch to alternative ingredients. In addition, the rule requires that manufacturers and processors make existing records related to compliance with the rule available to FDA for inspection and copying.

When does the rule take effect? This rule is in effect as of July 14, 2004, the date of its publication in the Federal Register, however, FDA is providing a 90-day comment period on this interim final rule. The rule applies to human food and cosmetics manufactured from, processed with, or that otherwise contain material, from cattle slaughtered on or after the interim final rule's effective date.

How to comment on this interim final regulation: Comments on this interim final regulation, (Docket Number 2004N-0081), will be accepted until October 12, 2004. Written comments can be sent to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Comments can be sent electronically to www.fda.gov/dockets/ecomments or as an e-mail to fdadockets@oc.fda.gov. Please ensure that you include in your submission the docket number that applies to your comment: Prohibited Cattle Materials--Docket No. 2004N-0081.
II.Proposed Rule

What would be required in the companion recordkeeping proposal? Manufacturers and processors of FDA-regulated human food and cosmetics that use cattle material in their products would be required to keep records demonstrating that these materials do not contain prohibited cattle materials. The proposal also would require that manufacturers and processors make these records available to FDA for inspection and copying.

What types of records would be required? Generally, FDA would expect a manufacturer or processor to have a signed and dated affirmation, including contact information, from the slaughter establishment stating that cattle material supplied by the establishment in a particular shipment does not contain prohibited cattle materials. For human food and cosmetics containing tallow, a manufacturer or processor would need to maintain records (signed, and dated, with contact information) either from the slaughter establishment affirming that the tallow was produced from material containing no prohibited cattle materials, or from the tallow supplier affirming that the tallow contains no more than 0.15 percent insoluble impurities.

How long would the records have to be retained? FDA is proposing that these records be retained for two years.

Where would the records have to be maintained? Records would have to be maintained at the manufacturing or processing establishment or at a reasonably accessible location. Electronic records would be acceptable and are considered to be reasonably accessible if they are accessible from an onsite location.

What about imported human food and cosmetic products containing cattle materials? Importers would be required to electronically affirm their compliance with these recordkeeping requirements at the time the products enter the U.S. and would have to provide the required records to FDA within a reasonable time, if requested.

How to comment on proposed regulations: FDA invites comments on this proposal, e.g., suggestions to make the proposal more effective or less burdensome, questions regarding the agency's data or assumptions, submission of information the agency may not have. The agency is especially interested in comments on other ways in which the proposed recordkeeping requirements might be satisfied, as well as comments on whether existing recordkeeping practices include the required information and, if not, what changes the proposal would necessitate.

Comments on this proposed regulation, Recordkeeping Requirements for Human Food and Cosmetics Manufactured From, Processed With, or Otherwise Containing Material from Cattle, Docket Number 2004N-0257, will be accepted until August 13, 2004. Written comments on the proposal can be sent to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Comments can be sent electronically to www.fda.gov/dockets/ecomments or as an e-mail to fdadockets@oc.fda.gov. Please ensure that you include in your submission the docket number that applies to your comment: Recordkeeping - Docket No. 2004N-0257.
This is G o o g l e's cache of http://vm.cfsan.fda.gov/~comm/bsefact2.html as retrieved on Jan 3, 2005 08:04:11 GMT.

14 July 2004
Source: http://www.access.gpo.gov/su_docs/aces/fr-cont.html

-----------------------------------------------------------------------

[Federal Register: July 14, 2004 (Volume 69, Number 134)]
[Notices]
[Page 42191-42192]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14jy04-96]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2004N-0291]


Risk Assessment for Cosmetics and Potential Contamination With
Bovine Spongiform Encephalopathy Agent; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a risk assessment regarding the potential for variant
Creutzfeldt-Jakob Disease (vCJD) in humans from exposure to cosmetics
containing cattle-derived protein infected with the bovine spongiform
encephalopathy (BSE) agent. FDA is making this document available to
communicate publicly the potential risk to public health from cosmetics
made with cattle materials that may be contaminated with the BSE agent.

ADDRESSES: Submit written requests for single copies of the risk
assessment to the Office of Plant and Dairy Foods (HFS-365), Center for
Food Safety and Applied Nutrition, Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740. Send one self-addressed
adhesive label to assist that office in processing your request, or
include a fax number to which the document may be sent. Alternatively,
you may request a copy of the document by calling 301-436-2367, or you
may fax your request to 301-436-2632. See the SUPPLEMENTARY INFORMATION
section for electronic access to the risk assessment.

FOR FURTHER INFORMATION CONTACT: Morris Potter, Center for Food Safety
and Applied Nutrition (HFS-006), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740, 404-253-1225.

SUPPLEMENTARY INFORMATION:

I. Background

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. Tallow derivatives, particularly fatty acids
and glycerin, are the predominant cattle ingredient used by the
cosmetic industry. Cattle-derived ingredients serve many functions and
may be used as skin conditioning agents, emollients, binders, and hair
and nail conditioning agents.

[[Page 42192]]

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 not
likely; however, cosmetics may be ingested or applied to cut or abraded
skin or to mucosal tissues, particularly in the eye, which could
provide direct routes for infection.

II. Risk Assessment for Cosmetics and Potential Contamination With the
BSE Agent

The risk assessment presents scientific evidence on the risk of
transmission of vCJD to humans from cattle-derived ingredients used in
the manufacture of cosmetics. FDA has prepared a qualitative assessment
that follows the generally accepted framework for risk assessments
endorsed by the Codex Alimentarius Commission. This framework involves
the following steps:
(1) Hazard identification. A review of available information on
vCJD and its link to BSE-infected cattle.
(2) Exposure assessment. An evaluation of the range of possible
cattle-derived ingredients that might be used in the manufacture of
cosmetics and the likelihood that a contaminated cosmetic results in
transmission of the BSE agent to humans.
(3) Hazard characterization. The assessment of the potential for
BSE transmission and development of vCJD in humans.
(4) Risk characterization. The integration of information on
potential hazards with the exposure assessment.
The risk assessment also discusses the quality of information
available for, and the uncertainties associated with, the assessment.
FDA has determined that this risk assessment is appropriate to the
circumstances.

III. Electronic Access

The risk assessment is available electronically at http://www.cfsan.fda.gov
.

Dated: July 9, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-15979 Filed 7-13-04; 8:45 am]

BILLING CODE 4160-01-S

http://cryptome.org/fda071404.txt

July 14, 2004
horizontal rule
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.
References

1.

Will, R.G., J.W. Ironside, M. Zeidler, S.N. Cousens, K. Estibeiro, A. Alperovitch, S. Poser, M. Pocchiari, A. Hofman, and P.G. Smith. 1996. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347: 921-25.
2.

Chazot, G., E. Broussolle, C.I. Lapras, T. Blattler, A. Aguzzi, and N. Kopp. 1996. New variant of Creutzfeldt-Jakob disease in a 26-year-old French man. Lancet 347: 1181.
3.

Prusiner, S.B. 2001. Shattuck Lecture--Neurodegenerative diseases and prions. N Engl J Med 344 (20): 1516-1526.
4.

Collinge, J. 2001. Prion diseases of humans and animals: Their causes and molecular basis. Annu. Rev. Neurosci. 24: 519-50.
5.

Almond, J. and J. Pattison. 1997. Human BSE. Nature 389: 437-38.
6.

Scott, M.R., R. Will, J. Ironside, H-O.B Nguyen, P. Tremblay, S.J. DeArmond, and S.B. Prusiner. 1999. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc. Natl. Acad. Sci. 96 (26): 15137-142.
7.

Hill, A.F., M. Desbruslais, S. Joiner, K.C.L. Sidle, I. Gowland, J. Collinge L.J. Doey, and P. Lantos. 1997. The same prion strain causes vCJD and BSE. Nature 389: 448-450.
8.

Collinge, J. 1999. Variant Creutzfeldt-Jakob disease. Lancet 354: 317-323.
9.

Lasmezas, C.I., J-G. Fournier, V. Nouvel, H. Boe, D. Marce, F. Lamoury, N. Kopp, J-J. Hauw, J. Ironside, M. Bruce, D. Dormont and J-P. Deslys. 2001. Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt-Jakob disease: Implications for human health. Proc. Natl. Acad. Sci. 98 (7): 4142-4147.
10.

Bruce, M.E., R.G. Will, J. W. Ironside, I. McConnell, D. Drummond, A. Suttie, L. McCardle, A. Chree, J. Hope, C. Birkett, S. Cousens, H. Fraser, and C.J. Bostock. 1997. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 389: 498-501.
11.

Brown, P. 1997. The risk of bovine spongiform encephalopathy ('mad cow disease') to human health. J. Am. Med. Assn. 278 (12): 1008-1011.
12.

Brown, P., R.G. Will, R. Bradley, D.M. Asher, and L. Detwiler. 2001. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: Background, evolution, and current concerns. Emerging Infect. Dis. 7 (1): 6-16.
13.

Scientific Steering Committee, European Commission. 1999. Opinion of the Scientific Steering Committee on the Human Exposure Risk (HER) via food with respect to BSE. Accessed online at http://europa.eu.int/comm/food/fs/bse/scientific_advice08_en.html.
14.

Harvard Center for Risk Analysis, Harvard School of Public Health. 2003. Evaluation of the potential for bovine spongiform encephalopathy in the United States. Accessed online at http://www.hcra.harvard.edu/pdf/madcow.pdf.
15.

Fraser, J.R. 1996. Infectivity in extraneural tissues following intraocular scrapie infection. J. Gen. Virol. 77: 2663-68.
16.

Scott, J.R., J. D. Foster and H. Fraser. 1993. Conjunctival instillation of scrapie in mice can produce disease. Vet Microbiol 34 (4): 305-309.
17.

Klitzman R.L., M.P. Alpers, and D.C. Gajdusek. 1984. The natural incubation period of kuru and the episodes of transmission in three clusters of patients. Neuroepidemiology 3 (1): 3-20.
18.

Taylor, D.M., I. McConnell, and H. Fraser. 1996. Scrapie infection can be established readily through skin scarification in immunocompetent but not immunodeficient mice. J. Gen. Virol. 77: 1595-99.
19.

Ingrosso, L., F. Pisani, and M. Pocchiari. 1999. Transmission of the 263K scrapie strain by the dental route. J. Gen. Virol. 80: 3043-47.
20.

Pammer, J., W. Weninger, and E. Tschachler. 1998. Human keratinocytes express cellular prion-related protein in vitro and during inflammatory skin diseases. Am. J. Pathol. 153: 1353-58.
21.

Sugaya, M., K. Nakamura, T. Watanabe, A. Asahina, N. Yasaka, Y. Koyama, M. Kusubata, Y. Ushiki, K. Kimura, A. Morooka, S. Irie, T. Yokoyama, K. Inoue, S. Itohara, and K. Tamaki. 2002. Expression of cellular prion-related protein by murine Langerhans cells and keratinocytes. J. Dermato. Sci. 28: 126-134.
22.

Vossen, P., J. Kreysa, and M. Goll. 2003. Overview of the BSE risk assessment of the European Commission's Scientific Steering Committee (SSC) and it TSE/BSE ad hoc group. Accessed online at http://europa.eu.int/comm/food/fs/sc/ssc/out364_en.pdf.
23.

Scientific Steering Committee, European Commission. 2000. Oral exposure of humans to the BSE agent: Infective dose and species barrier. Accessed online at http://europa.eu.int/comm/food/fs/sc/ssc/out79_en.pdf.

http://www.cfsan.fda.gov/%7Ecomm/bse-ra.html

-------- Original Message --------
Subject:
Docket No. 2004N-0081 and or RIN number RIN-0910-AF47 Use of Materials Derived
From Cattle in Human Food and Cosmetics [comment submission]
Date: Tue, 13 Jul 2004 16:08:38 -0500
From: "Terry S. Singeltary Sr."
To: fdadockets@oc.fda.gov
CC: burt.pritchett@fda.gov, Agriculture@mail.house.gov

COMMENT SUBMISSION
[Docket No. 2004N-O081]
RIN-0910--AF47
Use of Materials Derived From Cattle in Human Food and Cosmetics
http://www.fda.gov/OHRMS/DOCKETS/98fr/04n-0081-nir0001.pdf

Greetings FDA,

I would kindly like to comment on the potential for TSE transmission from
cosmetics to humans and why I think that ALL animal by-products should be
excluded from cosmetics. IF we look at the TSE 'KURU'. Kuru is a
transmissible spongiform encephalopathy that was identified in Papua New
Guinea in the late 1950s. Several thousand cases of the disease occurred
during a period of several decades. Epidemiologic investigations
implicated ritual endocannibalistic funeral feasts as the likely route
through which the infectious agent was spread. The incubation period in
females was estimated to be shorter than that in males. The shortest
incubation periods were estimated in adult women, who may have been
exposed to the largest doses of infectious material.
MY question is, was the woman exposed to larger doses, are was it the
route of the
agent that may have been the factor of shorter incubation in woman, or both?

What is Kuru?
Kuru is a rare and fatal brain disorder that occurred at epidemic levels
during the 1950s-60s among the Fore people in the highlands of New
Guinea. The disease was the result of the practice of ritualistic
cannibalism among the Fore, in which relatives prepared and consumed the
tissues (including brain) of deceased family members. Brain tissue from
individuals with kuru was highly infectious, and the disease was
transmitted either through eating or by contact with open sores or
wounds. Government discouragement of the practice of cannibalism led to
a continuing decline in the disease, which has now mostly disappeared.

snip...

PLEASE NOTE the later ''or by contact with open sores or wounds.''

> and the disease was transmitted either through eating or by contact
> with open sores or wounds.


http://www.ninds.nih.gov/health_and_medical/disorders/kuru.htm

> the Fore women would scoop the brains of their dead relatives out of
> their skulls by hand before cooking. They then wiped the residual
> liquid and cadaver tissue over their paint-daubed bodies, leaving it
> caked in their hair and on their bodies for weeks after a mortuary feast.


Jennifer Cooke: kuru deaths continue in 1999

Sydney Morning Herald, Saturday, August 28, 1999


TSE INFECTION does takes place when the skin surface has been broken by
scarification (Taylor et al, 1996).

The transmission of KURU into animals supported the belief that the
disease had
been transmitted through ceremonial cannibalistic rituals in New Guinea
with a
possible route of spread involving handling fresh tissue and inoculation
through
mucous membranes and wounds including skin abrasions (Gajdusek, 1977)

Masters, C.J., Gajdusek, D.C. and Gibbs, C.J., (1980). The spongiform
encephalopathies: the natural history of CJD and its relationship to
kuru and scrapie.


* Gajdusek D.C. (1996). Kuru: From the New Guinea field journals
1957-1962. Grand Street, 15:6-33


* Gajdusek D.C. (1973). Kuru in the New Guinea Highlands. In
Spillane JD (ed): Tropical Neurology. New York, Oxford University
Press.


* Gajdusek D.C., Gibbs C.J., and M. Alpers (1966). Experimental
transmission of a kuru-like syndrome to chimpanzees. Nature, 209:794.


* Lindenbaum S. (1979). Kuru Sorcery. Mountain View, Ca, Mayfield
Publishing Company.

SCCNFP/0724/03, final
THE SCIENTIFIC COMMITTEE ON COSMETIC PRODUCTS AND NON-FOOD PRODUCTS
INTENDED FOR CONSUMERS
OPINION
CONCERNING
USE OF SPECIFIED RISK MATERIAL IN COSMETICS
CLARIFICATION FOR TALLOW DERIVATIVES
adopted by the SCCNFP on 30 July 2003
by means of the written procedure
SCCNFP/0724/03, final
Opinion on the Use of specified risk material in cosmetics -
Clarification for tallow derivatives
_____________________________________________________________________________________________
2
1. Background

snip...FULL TEXT;

http://www.vegsource.com/talk/madcow/messages/92820.html

THE following was posted the next day by FDA;

July 14, 2004

horizontal rule


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.


References

1.

Will, R.G., J.W. Ironside, M. Zeidler, S.N. Cousens, K. Estibeiro,
A. Alperovitch, S. Poser, M. Pocchiari, A. Hofman, and P.G. Smith.
1996. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet
347: 921-25.

2.

Chazot, G., E. Broussolle, C.I. Lapras, T. Blattler, A. Aguzzi,
and N. Kopp. 1996. New variant of Creutzfeldt-Jakob disease in a
26-year-old French man. Lancet 347: 1181.

3.

Prusiner, S.B. 2001. Shattuck Lecture--Neurodegenerative diseases
and prions. N Engl J Med 344 (20): 1516-1526.

4.

Collinge, J. 2001. Prion diseases of humans and animals: Their
causes and molecular basis. Annu. Rev. Neurosci. 24: 519-50.

5.

Almond, J. and J. Pattison. 1997. Human BSE. Nature 389: 437-38.

6.

Scott, M.R., R. Will, J. Ironside, H-O.B Nguyen, P. Tremblay, S.J.
DeArmond, and S.B. Prusiner. 1999. Compelling transgenetic
evidence for transmission of bovine spongiform encephalopathy
prions to humans. Proc. Natl. Acad. Sci. 96 (26): 15137-142.

7.

Hill, A.F., M. Desbruslais, S. Joiner, K.C.L. Sidle, I. Gowland,
J. Collinge L.J. Doey, and P. Lantos. 1997. The same prion strain
causes vCJD and BSE. Nature 389: 448-450.

8.

Collinge, J. 1999. Variant Creutzfeldt-Jakob disease. Lancet 354:
317-323.

9.

Lasmezas, C.I., J-G. Fournier, V. Nouvel, H. Boe, D. Marce, F.
Lamoury, N. Kopp, J-J. Hauw, J. Ironside, M. Bruce, D. Dormont and
J-P. Deslys. 2001. Adaptation of the bovine spongiform
encephalopathy agent to primates and comparison with
Creutzfeldt-Jakob disease: Implications for human health. Proc.
Natl. Acad. Sci. 98 (7): 4142-4147.

10.

Bruce, M.E., R.G. Will, J. W. Ironside, I. McConnell, D. Drummond,
A. Suttie, L. McCardle, A. Chree, J. Hope, C. Birkett, S. Cousens,
H. Fraser, and C.J. Bostock. 1997. Transmissions to mice indicate
that 'new variant' CJD is caused by the BSE agent. Nature 389:
498-501.

11.

Brown, P. 1997. The risk of bovine spongiform encephalopathy ('mad
cow disease') to human health. J. Am. Med. Assn. 278 (12): 1008-1011.

12.

Brown, P., R.G. Will, R. Bradley, D.M. Asher, and L. Detwiler.
2001. Bovine spongiform encephalopathy and variant
Creutzfeldt-Jakob disease: Background, evolution, and current
concerns. Emerging Infect. Dis. 7 (1): 6-16.

13.

Scientific Steering Committee, European Commission. 1999. Opinion
of the Scientific Steering Committee on the Human Exposure Risk
(HER) via food with respect to BSE. Accessed online at
http://europa.eu.int/comm/food/fs/bse/scientific_advice08_en.html.

14.

Harvard Center for Risk Analysis, Harvard School of Public Health.
2003. Evaluation of the potential for bovine spongiform
encephalopathy in the United States. Accessed online at
http://www.hcra.harvard.edu/pdf/madcow.pdf.

15.

Fraser, J.R. 1996. Infectivity in extraneural tissues following
intraocular scrapie infection. J. Gen. Virol. 77: 2663-68.

16.

Scott, J.R., J. D. Foster and H. Fraser. 1993. Conjunctival
instillation of scrapie in mice can produce disease. Vet Microbiol
34 (4): 305-309.

17.

Klitzman R.L., M.P. Alpers, and D.C. Gajdusek. 1984. The natural
incubation period of kuru and the episodes of transmission in
three clusters of patients. Neuroepidemiology 3 (1): 3-20.

18.

Taylor, D.M., I. McConnell, and H. Fraser. 1996. Scrapie infection
can be established readily through skin scarification in
immunocompetent but not immunodeficient mice. J. Gen. Virol. 77:
1595-99.

19.

Ingrosso, L., F. Pisani, and M. Pocchiari. 1999. Transmission of
the 263K scrapie strain by the dental route. J. Gen. Virol. 80:
3043-47.

20.

Pammer, J., W. Weninger, and E. Tschachler. 1998. Human
keratinocytes express cellular prion-related protein in vitro and
during inflammatory skin diseases. Am. J. Pathol. 153: 1353-58.

21.

Sugaya, M., K. Nakamura, T. Watanabe, A. Asahina, N. Yasaka, Y.
Koyama, M. Kusubata, Y. Ushiki, K. Kimura, A. Morooka, S. Irie, T.
Yokoyama, K. Inoue, S. Itohara, and K. Tamaki. 2002. Expression of
cellular prion-related protein by murine Langerhans cells and
keratinocytes. J. Dermato. Sci. 28: 126-134.

22.

Vossen, P., J. Kreysa, and M. Goll. 2003. Overview of the BSE risk
assessment of the European Commission's Scientific Steering
Committee (SSC) and it TSE/BSE ad hoc group. Accessed online at
http://europa.eu.int/comm/food/fs/sc/ssc/out364_en.pdf.

23.

Scientific Steering Committee, European Commission. 2000. Oral
exposure of humans to the BSE agent: Infective dose and species
barrier. Accessed online at
http://europa.eu.int/comm/food/fs/sc/ssc/out79_en.pdf.


http://www.cfsan.fda.gov/~comm/bse-ra.html

THIS was just published ;

Scrapie transmission following exposure through the skin is
dependent on follicular dendritic cells in lymphoid tissues

Joanne Mohan, Karen L. Brown, Christine F. Farquhar, Moira E. Bruce and
Neil A. MabbottCorresponding Author Contact Information
,

E-mail The Corresponding Author

Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh
EH9 3JF, UK

Received 9 March 2004; Revised 22 April 2004; accepted 12 May 2004.
Available online 8 July 2004.


Abstract

Background: Transmissible spongiform encephalopathies (TSEs) are chronic
infectious neurodegenerative diseases that are characterized by the
accumulation in affected tissues of PrPSc, an abnormal isoform of the
host prion protein (PrPc). Following peripheral exposure, PrPSc usually
accumulates on follicular dendritic cells (FDCS) in lymphoid tissues
before neuroinvasion. Studies in mice have shown that TSE exposure
through scarified skin is an effective means of transmission. Following
inoculation via the skin, a functional immune system is critical for the
transmission of scrapie to the brain as severe combined immunodeficiency
(SCID) mice are refractory to infection. Until now, it was not known
which components of the immune system are required for efficient scrapie
neuroinvasion following skin scarification. Objective: To determine
which cells are critical for the transmission of scrapie to the brain
following inoculation via the skin. Methods: A chimeric mouse model was
used, which had a mismatch in PrPc expression between FDCs and other
bone marrow-derived cells within lymphoid tissues. These chimeric mice
were challenged with scrapie by skin scarification to allow the separate
roles of FDCs and lymphocytes in peripheral scrapie pathogenesis to be
determined. Results: We show that mature FDCs are essential for the
accumulation of scrapie within lymphoid tissues and the subsequent
transmission of infection to the brain following TSE exposure by this
route. Furthermore, we show that the accumulation of PrPSc and
infectivity in the spleen is independent of PrP expression by
lymphocytes or other bone marrow-derived cells. Conclusion: Following
inoculation with scrapie by skin scarification, replication in the
spleen and subsequent neuroinvasion is critically dependent upon mature
FDCs.

Author Keywords: Transmissible spongiform encephalopathy; Scrapie; Skin;
Follicular dendritic cell; Prion protein; Spleen


Corresponding Author Contact Information
Corresponding

author. Tel.: +44 131 667 5204; fax: +44 131 668 3872.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T87-4CTD13F-3&_coverDate=08%2F31%2F2004&_alid=189125137&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=5079&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=8878b345dd3743a8fe239a820e6aea0b


TSS




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