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