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Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 4:41 pm
by jimmylegs
The effect of toxic doses of cholecalciferol (vitamin D3) on the serum zinc levels in rats.
http://www.ncbi.nlm.nih.gov/pubmed/7682831
Zinc is a trace element important to bone mineralization as well as, in general, nutrition. It is known that cholecalciferol (vitamin D3) affects bone metabolism. In this study, toxic doses of vitamin D3 were injected subcutaneously (25 micrograms/d) to rats for 5 wk. It caused a significant increase in serum zinc levels (p < 0.02). On the other hand, no significant increase was detected in the other groups. Excessive amounts of vitamin D3 caused bone breakdown and increased the levels of zinc in blood.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 5:09 pm
by Squeakycat
jimmylegs wrote:Enhancement of vitamin D3 effect on bone metabolism in weanling rats orally administered zinc sulphate
Abstract
The interaction of vitamin D3 and zinc on bone metabolism [bone, yes. Vitamin D?]was investigated in the femur of weanling rats. Oral administration of vitamin D3 (1.0 μg/100 g body weight) did not cause any increase in the zinc accumulation in the femoral tissue following treatment with zinc sulphate (1.0 mg Zn/100 g). Administration of vitamin D3 or zinc produced significant increases the alkaline phosphatase activity and DNA content of the femoral diaphvsis but not of the epiphysis. The increase in alkaline phosphatase activity was enhanced additionally by simultaneous administration of vitamin D3 and zinc. Moreover, the increase in DNA content was enhanced markedly (about 4 times) by these treatments. At a dose of 0.5 μg of vitamin D3 per 100 g, DNA content was at the control level. This level was increased about 2 times by simultaneous administration of zinc (1.0 mg/100 g).
Not to nitpick, but this is saying that it increases bone metabolism, not the metabolism of vitamin D. I do appreciate that zinc does marvelous things in a tight bond with Vitamin D. Really. I appreciate that.

But my question is whether zinc is necessary to metabolize vitamin D.

I even confess to taking zinc with my calcium and vitamin D. It isn't that I have anything at all against zinc. It is a noble metal. Well, not really, but I think it is. It is not my fault that the creators of the Periodic Table chose to label it an Ignoble Metal. I think that is really unfair.

I see there are additional posts on the next page where you have probably straightened me out. :oops:

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 6:02 pm
by Squeakycat
jimmylegs wrote:The effect of toxic doses of cholecalciferol (vitamin D3) on the serum zinc levels in rats.
http://www.ncbi.nlm.nih.gov/pubmed/7682831
Zinc is a trace element important to bone mineralization as well as, in general, nutrition. It is known that cholecalciferol (vitamin D3) affects bone metabolism. In this study, toxic doses of vitamin D3 were injected subcutaneously (25 micrograms/d) to rats for 5 wk. It caused a significant increase in serum zinc levels (p < 0.02). On the other hand, no significant increase was detected in the other groups. Excessive amounts of vitamin D3 caused bone breakdown and increased the levels of zinc in blood.
Yes. :lol:

We know that hypervitamintosis D will cause hypercalcemia and other effects, likely as this study shows, some effect on serum zinc levels.

But this still doesn't address the question of whether zinc is required to metabolize vitamin D unless I'm missing something.

Vitamin D does a lot with calcium, phosphorous, magnesium and manganese in terms of building bones and intracellular signaling. It wouldn't surprise me at all to find that it interacts with zinc in various ways as it does with these other substances.

But this still doesn't tell me that I need to take zinc to metabolize vitamin D.

If it does, I would really like to know where it plays this role. I am quite familiar with the internal processes which regulate all the various vitamin D forms and how the parathyroid, thyroid, liver and kidneys are intimately involved in vitamin D homeostasis.

I just haven't run across any mention of zinc in any of these and I just reviewed an in-depth presentation on all of this without ever seeing a mention of zinc.

No cigar, yet. :lol:

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 8:23 pm
by NZer1
Ed I see you are enjoying your learning ;)

The question may have unearthed some knowledge going in a different direction.

If Vit D is involved with parathyroid, thyroid, liver and kidneys, then the Thyroid connection to Thalamus, hypothalamus etc may be the link to dysautonomia and the Michael Arata focus on improvement from his 'treatment' approach might be as much about the signal transmission improvement as has been suggested because of the diet and Vit focus (with the wellness package) as well as the manual stimulation of the vagus nerve with PTA.

All together physically and chemically re-booting the autonomic nervous system?

Long shot, maybe not!
;)
Nigel

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 8:33 pm
by jimmylegs
i wish someone had designed the perfect study but they just don't seem to have done it.. YET.
I'M WAITING, SCIENCE. there should be all sorted out by 2030.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 8:46 pm
by jimmylegs
science says more research is needed too

Nutrition, geoepidemiology, and autoimmunity (2010)
http://www.sciencedirect.com/science/ar ... 7209002006
In general terms, most data that will be discussed herein were obtained in experimental or animal models while human data from real-life clinical settings or randomized clinical trials remain largely unsatisfactory. Our current knowledge on the beneficial impact of nutrition on autoimmunity prompts us to encourage the search for evidence-based nutrition to support the everyday diet choices of patients.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 8:55 pm
by jimmylegs
The immunoregulatory function of vitamin D: implications in chronic kidney disease (2012)
http://www.nature.com/nrneph/journal/v8 ... 12.93.html
"Most of the biological actions of 1,25(OH) 2 D 3 are mediated through the vitamin D receptor (VDR)."

DIETARY REFERENCE INTAKES FOR Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc
http://www.nap.edu/openbook.php?record_ ... 6&page=443
"The structural role of zinc involves proteins that form domains capable of zinc coordination, which facilitates protein folding to produce biologically active molecules. The vast majority of such proteins form a “zinc finger-like” structure created by chelation centers, including cysteine and histidine residues (Klug and Schwabe, 1995). "

Zinc-induced conformational changes in the DNA-binding domain of the vitamin D receptor determined by electrospray ionization mass spectrometry
http://www.sciencedirect.com/science/ar ... 0597002298
"...the binding of the first Zn2+ ion to the protein results in very little conformational change in the protein. The binding of a second Zn2+ ion resulted in a significant alteration in the structure of the protein"

Image

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 9:07 pm
by Squeakycat
NZer1 wrote:If Vit D is involved with parathyroid, thyroid, liver and kidneys, then the Thyroid connection to Thalamus, hypothalamus etc may be the link to dysautonomia and the Michael Arata focus on improvement from his 'treatment' approach might be as much about the signal transmission improvement as has been suggested because of the diet and Vit focus (with the wellness package) as well as the manual stimulation of the vagus nerve with PTA.

All together physically and chemically re-booting the autonomic nervous system?
Vitamin D homeostasis is controlled by a dance between the parathyroid, kidneys, liver and thyroid, but vitamin D is involved in critical processes throughout the body in virtually every cell.

One of its most critical functions is cell replication. It starts the process of getting a cell to kill itself and create a new cell and activates the immune system to clean up the mess that causes.

It directs the building of bone, blood vessels and many other tissues.

I won't go on, but its involvement in the body goes far beyond the organs that regulate it.

What's important is that there is considerable evidence that vitamin D may well be the alpha and omega of MS.

Since it directs the formation of blood vessels, it is likely that it is involved in the venous malformations which are associated with MS and may be the result of the mother's vitamin D deficiency during gestation.

We know further that it is what directs repair of injured and infected blood vessels so a vitamin D deficiency might explain why this damage goes uncontrolled.

What we don't know is whether attaining vitamin D sufficiency, whatever that turns out to be for people with MS, will be able to undo damage that has already happened. There doesn't seem to be much in the literature to say whether vitamin D has any role in repairing damage that follows breaches in the blood brain barrier. We simply don't know. But there are quite a number of clinical trials looking at this question so we may soon have answers.

Whether Dr. Arata is on to something and whether vitamin D might have a role in restoring normal function I think is unknown and maybe even unknowable.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 9:27 pm
by Squeakycat
jimmylegs wrote:The immunoregulatory function of vitamin D: implications in chronic kidney disease (2012)
http://www.nature.com/nrneph/journal/v8 ... 12.93.html
"Most of the biological actions of 1,25(OH) 2 D 3 are mediated through the vitamin D receptor (VDR)."

DIETARY REFERENCE INTAKES FOR Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc
http://www.nap.edu/openbook.php?record_ ... 6&page=443
"The structural role of zinc involves proteins that form domains capable of zinc coordination, which facilitates protein folding to produce biologically active molecules. The vast majority of such proteins form a “zinc finger-like” structure created by chelation centers, including cysteine and histidine residues (Klug and Schwabe, 1995). "

Zinc-induced conformational changes in the DNA-binding domain of the vitamin D receptor determined by electrospray ionization mass spectrometry
http://www.sciencedirect.com/science/ar ... 0597002298
"...the binding of the first Zn2+ ion to the protein results in very little conformational change in the protein. The binding of a second Zn2+ ion resulted in a significant alteration in the structure of the protein"

Image
Yes. I am quite familiar with all of this, but again, it doesn't address the question of whether zinc plays a role in vitamin D metabolism.

I think it is safe to say that any deficiency is going to be problematic, including zinc deficiency.

Look at this another way.

High doses of vitamin D suppress Parathyroid Hormone (PTH) which lessens the uptake of calcium. Calcium is absolutely critical to virtually everything vitamin D does at the sub-cellular level. Most of what it does involves some action on ionized calcium, good old Ca++.

So there is a good case to be made for why you need to ensure adequate levels of calcium when you are taking higher doses of vitamin D. You need to maintain calcium homeostasis and offset the effect vitamin D has on PTH.

Zinc fingers are highly involved in vitamin D receptors (VDR) and things like the creation of bone mass. There is a close link to vitamin D so it stands to reason that zinc needs to be adequate for vitamin D to successfully carry out many of its functions. No dispute about this.

But you are suggesting based on your experience that zinc plays a role in vitamin D metabolism.

I don't see where, but I don't discount your experience. Maybe you have stumbled on something that is not obvious.

I think you are having trouble finding anything to back this because there is nothing to back it. That doesn't mean your experience isn't valid. It may be that you have a unique metabolism, or it might mean that there is some function for zinc in vitamin D metabolism that has been completely overlooked.

Let's organize a clinical trial! :lol:

Maybe we can find that there is a basis for your suggestion that zinc plays a role in vitamin D metabolism.

As you note in another post, I have no evidence to the contrary, except that I am pretty familiar with the details, all the way down to the subcellular level of vitamin D homeostais and I dont' see any zinc, yet.

And with respect to the first article cited here, all my experience with vitamin D is in using high doses in cats with chronic renal failure to maintain calcium homeostasis and control PTH.

I have a lot of experience in this area from initially pioneering the dose levels to figuring out how to avoid hypercalcemia. While all of this had been done for years in humans, when you try to apply things like this to cats or dogs, you have get down and dirty to understand all the details of metabolism and homeostasis

Cat's ain't humans and what works in one may be deadly in another so you have to really get a good understanding at the very lowest, subcellular levels of what is going on to see if this will likely carry over to the other species.

In 12 calendar years and more than 20 cat years, I haven't seen anything to suggest a role for zinc in vitamin D's metabolism. I am completely open to any evidence. I know that the more I know, there is even more I don't know.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Fri Mar 22, 2013 10:26 pm
by NZer1
Ed can you help me understand some thing please.

What is Vit D deficiency?

What is illness created hi use of Vit D?

Do the people with deficiency in Vit D actually have intake but not able to metabolise it?

I'm confused by the terms and head off with thoughts that maybe wrong at the start.

Nigel

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Sat Mar 23, 2013 4:54 am
by jimmylegs
yes looks like we agree more science is needed.

would you agree that circulating levels of 25(OH)d3 from diet and sunshine would rely heavily on all the ingredients needed to effect hydroxylation?

METABOLISM OF VITAMIN D3 BY CYTOCHROMES P450
http://www.bioscience.org/u37153137/gaD ... 4/1514.pdf

A cDNA Encoding a Rat Mitochondrial Cytochrome P450 Catalyzing Both the 26-Hydroxylation of Cholesterol and 25-Hydroxylation of Vitamin D3: Gonadotropic Regulation of the Cognate mRNA in Ovaries
http://online.liebertpub.com/doi/abs/10 ... 1990.9.657

Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (review).
http://europepmc.org/abstract/MED/11172 ... kNtzsbDr.4

Effects of increased microsomal oxygen radicals on the function and stability of cytochrome P450 in dietary zinc deficient rats
http://cat.inist.fr/?aModele=afficheN&cpsidt=5497574

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Sat Mar 23, 2013 4:57 am
by Squeakycat
NZer1 wrote:Ed can you help me understand some thing please.

What is Vit D deficiency?

What is illness created hi use of Vit D?

Do the people with deficiency in Vit D actually have intake but not able to metabolise it?

I'm confused by the terms and head off with thoughts that maybe wrong at the start.

Nigel
I think the broad answer to the question of what is vitamin D deficiency is that it is having less than the body requires. The specific level likely is very individual and depends on the rate at which you make or take vitamin D as well as on the rate that it is used by the body.

The only numbers we know for certain is that levels of less than 30 nmol/l (12 ng/ml) will cause rickets in children or ostemalacia, the adult form of rickets. It is simply too little to build and maintain bone health.

We have a reference in this thread which shows that it appears that vitamin D is being consumed at a high rate by people with MS as they go from having no signs of the disease through CIS and on to frank, clinically definite MS.

Another way of looking at this is to look at the vitamin D levels of people living near the equator who are to some degree, representative of our evolutionary past. Solar exposure below the 32nd parallel where you receive UV-B radiation year around provides on average 10,000 IU - 20,000 IU a day and results in, depending on skin pigmentation, levels that are over 200 nmol/l (80 ng/ml), but generally not much higher than 225 nmol/l (90 ng/ml).

So the definitive answer to the question of what level constitutes deficiency is that it is somewhere between 30 nmol/l (12 ng/ml) and 200 nmol/l (80 ng/ml).

I think your second question is what happens if you have too much vitamin D, high levels. The answer is that you screw up the management of calcium levels in the body. That has very serious effects. It can result in the body taking in too much calcium from the diet and causing calcification of our organs, effectively turning your kidneys into bone, along with the heart and other organs. Paradoxically, it can also cause the body to attempt to sequester calcium to the point that it starts breaking down bone to obtain more and in that process, releases toxic levels of phosphate, one of the other components of bones.

Levels that cause this to happen, again, probably varying individual to individual, but are certainly north of 225 nmol/l (90 ng/ml). It is virtually impossible for this to happen if the source of vitamin D is solar exposure because of mechanism in the skin that limit the production of vitamin D to generally not more than 20,000 IU/day, although if more is needed as we know is the case in pregnancy and during periods of bone growth, the body will allow more than 20,000 IU/day to be made. The mechanism that regulates this isn't so much looking at how much is being made as how much is required based on the rate at which it is being used up.

If you took high levels of vitamin D as a supplement, the answer depends to a large degree on how you take it. Taking high levels daily can trigger hypercalcemia, but taking the same daily amount in pulses once or twice a week will generally avoid it because those much higher pulses cause parathyroid hormone (PTH) levels to drop which lowers the rate of absorption of calcium from the diet as well as blocks attempts to resorp calcium from the bones.

Your third question relates to whether there can be problems with the metabolism of vitamin D that in spite of intake results in a deficiency.

Yes, that can happen and it is a known factor in some diseases, now fairly well documented in the case of children who become diabetic. Genetic findings show that the most common genetic variations in these children are ones related to the processing of vitamin D.

There are a lot of genes involved in vitamin D processing. Ones that convert various forms in the liver. Ones that do the conversions necessary in the kidneys. Ones that transport these various forms to and from the liver and kidneys. Ones that break down or create various forms elsewhere in the body.

Some level of variation in these genes can cause the body to be unable to create or convert various forms of vitamin D so you can certainly have problems in maintaining vitamin D levels in spite of high intake of vitamin D.

So the full answer is that you can have inadequate levels of vitamin D even with relatively high intake or solar production of vitamin D both as a result of high rates of use of vitamin D in conditions which likely are involved in MS or other diseases such as diabetes, Crohn's Disease, Rheumatoid Arthritis and so on as well as from genetic variations that impair the processing of vitamin D.

The answer to all your questions about vitamin D in 150 words, more or less. :lol:

All this is very much more nuanced then I have made it here and it is all subject to continued study that may prove some of this wrong or irrelevant.

The good news is that it seems the whole biomedical field is doing nothing but studying vitamin D these days. I have alerts set up to let me know about new studies on aspects of vitamin D and am getting notices of over 100 a day. Last time I looked at this, there had been over 3,500 new studies uploaded to the US NIH PubMed in the previous 12 months.

The US clinical trials monitoring group, http://www.clinicaltrials.gov reports over 1,200 trials involving vitamin D of which there are 22 looking at the relationship between vitamin D and MS.

These are simply unprecedented levels of research so we will likely soon know much more about this.

One final point. I think it is fair to say that evolutionary history tells us that the body has evolved to make use of abundant resources such as the air we breath, water we drink and the sun light we expose our bodies to. We use iron and zinc which are relatively abundant, rather than gold and platinum.

One additional "final" point. The farther you are away from equator, the less UV-B radiation you get and the lower the amount of vitamin D your body can produce from this source. There are not a lot of dietary sources of vitamin D and few people in the world consume enough of them to maintain adequate levels of vitamin D. Just to get 1,000 IU you would need to eat roughly 1 kg of wild salmon a day. You can of course, get some highly concentrated dietary sources such as cod liver oil, but again, you need to consume an awful lot of it to have high intake levels.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Sat Mar 23, 2013 5:37 am
by Squeakycat
jimmylegs wrote:yes looks like we agree more science is needed.

would you agree that circulating levels of 25(OH)d3 from diet and sunshine would rely heavily on all the ingredients needed to effect hydroxylation?
Oh, yes! I started adult life at a research institute after a few years in the Army, and learned right away that the most important conclusion of any study was that there was a desperate need for more research, the principle currency of those who do research for a living. :lol:

And as a general proposition, the more we know, the more questions we have.

It is certainly true that vitamin D depends on rearranging OH groups to convert it to its various hydroxy forms, ie, its metabolism.

Moreover, it is certainly true that there are at least two critical CYP450 pathways involved and at least 6 that I know have been identified.

But, there isn't a single mention of zinc in the first two studies you cite and nothing in the third one that specifically ties it to the two main CYP450 pathways involved in processing vitamin D, though I don't have access to the full study so I say that based only on looking at the abstract and some other articles which cite the study.

Here is as close as we come to some possible role of zinc at least in rats and a petri dish. There are many CYP450 pathways and nothing here suggests a specific relationship to those involved in the processing of vitamin D. Further, it is fairly explicit in saying that this finding was related to severe Zn deficiency.
It is concluded that severe dietary Zn deficiency in rats caused a functional and structural impairment of liver microsomal P450 via a free radical medicated-like mechanism.
I would hazard a guess that many other critical elements are involved in these pathways and severe deficiencies of any would cause problems if they involved the specific pathways that are needed for a particular reaction to occur.

I think it is entirely plausible that there is a role for zinc in the metabolism of vitamin D and that if there is, it likely is tied up with the CYP450 pathways involved. I just don't think we actually know this with any certainty. That only means we don't know it, not that it isn't involved.

There are lots of targets to explore:
Enzymes involved in the activation and inactivation of vitamin D.
Prosser DE, Jones G.

Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hydroxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1alpha-hydroxylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1alpha,25-dihydroxyvitamin D(3). A five-step inactivation pathway from 1alpha,25-(OH)(2)D(3) to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally induced in vitamin D target cells by the action of 1alpha,25-(OH)(2)D(3). On the basis of alignments and crystal structures of other CYPs, homology models of vitamin-D-related CYPs have been generated. Two human forms of rickets caused by mutations of CYP2R1 and CYP27B1, as well as mouse knockout models of CYP27A1, CYP27B1 and CYP24A1, are helping us to establish the full in vivo physiological roles of the vitamin-D-related hydroxylases.

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Sat Mar 23, 2013 7:13 am
by Anonymoose
Maybe this has something to do with the zinc/vit d dilemna. Activation of renal NMDA receptors decreases vitamin d synthesis. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980358/ Zinc inhibits NMDA receptors. http://www.jneurosci.org/content/18/16/6163.short and http://www.ncbi.nlm.nih.gov/pubmed/21504727 So, zinc supplementation blocks NMDA receptors (I think NMDA is an issue in MS) and allows for greater vitamin d synthesis?

Didn't have time to read through all of that so it might not fit at all. :P

Re: FIRST STEP-Vit D3 min for pwMS=125 nmol/L in blood

Posted: Sat Mar 23, 2013 8:04 am
by Squeakycat
Anonymoose wrote:Maybe this has something to do with the zinc/vit d dilemna. Activation of renal NMDA receptors decreases vitamin d synthesis. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980358/ Zinc inhibits NMDA receptors. http://www.jneurosci.org/content/18/16/6163.short and http://www.ncbi.nlm.nih.gov/pubmed/21504727 So, zinc supplementation blocks NMDA receptors (I think NMDA is an issue in MS) and allows for greater vitamin d synthesis?

Didn't have time to read through all of that so it might not fit at all. :P
I read quickly and if I'm following the threads, they are suggesting opposite effects, though the first is talking about what happens in the kidneys while the latter two studies are focused on NMDA and the role of zinc in the CNS.

As the title of the first suggests, activation of the NMDA receptors has the effect of decreasing vitamin D metabolism, but in the other two studies, they are suggesting that increases in ionic zinc has the effect of decreasing the activity of NMDA receptors which would lead you to suspect that if this happened in the kidneys, it would increase the rate at which vitamin D would be metabolized.

Whether that summation is an accurate reflection of these studies is certainly open to question. I usually have to do drawings of these things with lots of arrows indicating effect to see if I can fit all the pieces in the right places and not have anything left over and wondering where it goes or what it does.

I think we will have to wait for JimmyLegs to do the definitive review of all of this in THE Journal of Endocrinology before we can say, ah, yes, that's it.

While none of this directly addresses the question, it all does point to a series of possible connections that could be important in metabolism of vitamin D.

One of the things we know for sure about things like calcium, magnesium, manganese, zinc and other minerals used in signaling is that there is generally a very small difference between levels that are too little and ones that are too much, measured typically in just a few ng/ml, ie billionths of a gram which is pretty small. :lol: