1 department of health and human services




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7 introduced has to have adequate toxicological evaluation,

8 and the recurring theme is are we switching from devil that

9 we know to the devil that we don't know in terms of DEHP and

10 phthalate plasticizers?

11 [Slide]

12 About the time we were having this workshop, we

13 were fortunate that there were three separate risk

14 assessments being conducted and published. One was done by

15 the American Council on Science and Health. This was an

16 expert panel that was chaired by Dr. Koop. Their conclusion

17 was that benefits of DEHP outweigh the risks to humans. So,

18 they felt that use of DEHP in medical devices was safe.

19 Another group, Health Care Without Harm,

20 commissioned the Lowell Center for Sustainable Production,

21 University of Massachusetts, to look at the issue of DEHP

22 toxicity in medical devices, and this was a report authored

23 by Joel Tichner. Their conclusion was slightly different.

24 They said that DEHP poses a potential risk that should not

25 be ignored, and that alternatives should be sought.


22 1 There is also another risk assessment that is

2 still going on, and this was done by the Center for

3 Evaluation of Risk to Human Reproduction, which is part of

4 the National Toxicology Program, headed by Michael Shelby.

5 They have an expert panel of toxicologists and they have met

6 twice to discuss DEHP toxicity in humans, and they haven't

7 come to a conclusion yet. They have one more meeting coming

8 up in July, 2000. I think this is going to be a very good

9 report, based solely on science, and we are looking forward

10 to that report coming out.

11 [Slide]

12 At the end of the workshop we had a discussion

13 panel, and this discussion panel was clinically oriented.

14 We had transfusion experts, we had pediatricians,

15 epidemiologists, and we were looking for a clinical debate

16 on toxicity and use of DEHP in blood products.

17 These are some of the highlights that the panel

18 was discussing: One of the points that they brought up is

19 that DEHP has an extensive clinical record, 30-40 years of

20 transfusions with DEHP plastic bags, and there is no clear-

21 cut toxicity to humans that has been demonstrated.

22 They pointed out that immediate withdrawal of DEHP

23 is not warranted because it would significantly affect the

24 blood supply and alternatives to DEHP are not well studied.

25 An important point that they brought up is that


23 1 past studies of DEHP toxicity may not have looked at the

2 appropriate endpoints. Most of the studies done in the past

3 have looked at carcinogenicity and recent reports indicate

4 that carcinogenicity in rodents doesn't have the same

5 mechanism as would be found in humans. The more appropriate

6 endpoints now would be reproductive toxicity.

7 They also pointed out that there are

8 subpopulations of patients, such as pediatric patients, that

9 may be more sensitive to DEHP or other plasticizers because

10 of undeveloped metabolic pathways and higher per kilogram

11 exposure. They suggested that new clinical trials should be

12 set up to evaluate levels of DEHP that patients are being

13 exposed to currently and corresponding toxicity in humans.

14 [Slide]

15 Since the workshop, there have been a couple more

16 interesting updates on the risk of DEHP. The International

17 Agency for Research on Cancer has downgraded DEHP from what

18 for many years was labeled as "possibly carcinogenic to

19 humans," to "not classifiable as carcinogenic to humans."

20 This is because it is now felt that the carcinogenicity in

21 rodents is not applicable to humans.

22 The Center for Evaluation of Risk to Human

23 Reproduction has had two out of the three meetings and they

24 have released some preliminary conclusions. It sounds as if

25 they will conclude that doses that cause testicular effects


24 1 in rodents are only about 10-fold higher than what may be

2 reached in some medical procedures, such as dialysis or

3 ECMO. So, they are concerned about this type of toxicity

4 going on with the use of current medical devices.

5 [Slide]

6 From our perspective, this is what we got out of

7 the workshop. It again demonstrated that there are benefits

8 to DEHP in red cell storage, and that to remove DEHP from

9 use currently would significantly affect the supply of red

10 cells.

11 It was also pointed out that human dose and

12 toxicity from DEHP in blood products is not well defined but

13 should be reinvestigated. Some of the things that were

14 suggested in the workshop were studies of multiply

15 transfused individuals such as sickle cell and thalassemia

16 patients, and special subpopulations of patients such as

17 infants exposed to extracorporeal membrane oxygenation.

18 This is an interesting situation were there is IV

19 application of DEHP exposure. Most of the studies that have

20 been done in the past with animals are oral exposure because

21 it is very difficult to do IV exposure in small rodents.

22 So, this is an interesting colleague situation where we can

23 look at effects of DEHP through IV infusion in humans.

24 The reproductive toxicity of DEHP should be an

25 area of active research, and there are a couple of studies


25 1 ongoing right now that are international reproductive

2 toxicity studies. This will show whether offsprings of

3 treated animals do have any type of reproductive effects.

4 We would also encourage development of alternative

5 plasticizers to improve the efficacy in storage, as well as

6 improve the toxicity as compared to DEHP. As with any other

7 complicated issue, this may in the future become a Blood

8 Product Advisory Committee issue. We will be looking for

9 your advice. Thank you very much.

10 DR. HOLLINGER: Any questions for Dr. Vostal?

11 Yes, Dr. Simon?

12 DR. SIMON: I guess the only comment is that, you

13 know, this is such an old issue. When I was with NIH in

14 1972-74 there were several contracts let to look at

15 toxicity, and the conclusion then was that it wasn't

16 significant. I guess it just keeps rearing its head and

17 people continue to be uncomfortable but it seems that with

18 the passage of time it becomes sort of a non-issue.

19 DR. HOLLINGER: Yes, Dr. Mitchell?

20 DR. MITCHELL: I guess I am concerned about the

21 reproductive health aspects of it. Do you know of any

22 ongoing studies? You talked about recommendations for

23 looking at the exposure in humans. Do you know if there are

24 any studies looking at the exposure level in humans?

25 DR. VOSTAL: Right now, I am not aware of any


26 1 studies in humans that are looking at correlating DEHP

2 exposure and reproductive function. There are studies going

3 on in rodents. However, there is always going to be a

4 problem with these types of studies because most of them are

5 oral administration of DEHP and what we are concerned about

6 is IV administration of DEHP, and there may be different

7 metabolic pathways that act on DEHP by different routes.

8 DR. MITCHELL: And, what about epidemiological

9 studies that may be linking DEHP to the decrease in sperm

10 counts that are found in people?

11 DR. VOSTAL: I think those would be great studies

12 to do. Right now there aren't any being conducted. You

13 know, I think there is a lack of funding for that right now.

14 DR. HOLLINGER: Thank you. Our third topic is the

15 report on blood supply monitoring, and Dr. McCurdy is going

16 to give us an update on the monitoring.

17 Report on Blood Supply Monitoring

18 [Slide]

19 DR. MCCURDY: As there were a number of new things

20 that came along leading to increased blood donor deferral

21 and increased loss due to testing, the Surgeon General asked

22 the Public Health Service to determine how the blood supply

23 was responding to these and to do some monitoring. That was

24 a fairly high priority item that was put forth first by an

25 internal advisory committee and accepted by the Surgeon


27 1 General.

2 The National Heart, Lung and Blood Institute

3 arranged to contract with the National Blood Data Resource

4 Center of the American Association of Blood Banks to collect

5 and supply the data, and we made an attempt to overcome some

6 of the problems in the past in selecting how we would

7 collect the data.

8 [Slide]

9 We opted to do a sample of blood centers, and

10 beginning in the next one to three months we will do the

11 same thing for hospital transfusion services. For blood

12 centers, we utilized data from the national surveys that

13 were originally conducted by Dr. Douglas Surgenor and are

14 now being conducted periodically by the AABB blood data

15 center to select, by region of the country, a number of

16 centers that are within one standard deviation of the mean

17 collection for that particular part of the country.

18 There were 27 selected. We had three kinds, as I

19 recall, of samples. One was totally random, which generally

20 is preferred. One was selected, not quite random but

21 selected in slightly different fashion, and we opted to do

22 this one because it was weighted to the cities and our major

23 purpose was to determine whether there was a blood shortage

24 and, if possible, to predict by trend analysis what is going

25 to happen.


28 1 There were 27 selected, 6 were unable to comply

2 with the data requirements and there were 6 substitutes, and

3 there was 1 late dropout so that the final sample was 26

4 centers. The objective was to get data reported by the 10th

5 of the month for the preceding month and have data supplied

6 to the National Heart, Lung and Blood Institute for

7 beginning analysis shortly thereafter. We are doing, I

8 think, as well as might be expected with the timeliness, but

9 we are not getting data from all 26 centers by the 10th of

10 the month.

11 [Slide]

12 The centers that were selected came online at

13 various different times. We began to collect data in

14 February for the month of January but we also asked the

15 centers to go back three months and provide us with

16 retrospective data for October, November and December. You

17 can see that between 15 and 20 of the centers were able to

18 do that, the others came online as time went on, with the

19 last coming on in April, providing data in May.

20 The data is being collected, as you will see, by

21 blood group as well as total because most of us in blood

22 banking have long been aware that the groups O, O positive

23 and negative were much more of a problem than groups A or

24 particularly AB.

25 [Slide]


29 1 Here you see the total number of red cells

2 released for distribution. This is after testing losses.

3 There was a little decrease in December and January and

4 increase in February, March and a little drop-off in April

5 and then a little climb back up in May. These are

6 normalized, if you will, for 26 centers. That is, we are

7 dividing by the number of centers that actually provided

8 data and multiplying by 26. So, these are "independent" of

9 the number of centers reporting. On this slide you see not

10 only the total, in the top line, but also the O positive and

11 O negative in the bottom line. We have data for the others

12 but it is not on this slide.

13 [Slide]

14 This is looking at the monthly amount of blood

15 released as a percent of the total that has been released in

16 this period, here, of 8 months. So, between 12 and 12.5

17 percent of the blood released during this entire period was

18 released for distribution in October, and so forth. The

19 peak here occurs in March; the drop-off in April. Some of

20 these figures, at least at this time, must be looked at with

21 a bit of a jaundiced eye because there were I think between

22 15 and 20 centers involved here and the May data, which I

23 got at the beginning of this week, only represents 10

24 centers of the 26.

25 [Slide]


30 1 We are also asking for inventories taken on the

2 first and third Wednesday of each month. These inventories

3 represent considerably fewer than the 15 to 20 centers that

4 reported at that time because many could not go back and

5 look at inventory, either total or by individual blood

6 group, several months before. Again, you can see that there

7 may be a slight trend upward overall in this but, although I

8 haven't analyzed it, I don't believe it is really

9 particularly significant. These inventories are meant to be

10 taken at a specific time of day on the first and third

11 Wednesday, and ultimately I think we may be able to do some

12 trend analysis on this.

13 [Slide]

14 We are also able to look at inventories by region.
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