Re: Arsenic carcinogenicity: numbers

[Guest guest]

Dear

If you look at the chicken info, it would seem that very little of the Roxarsone is metabolised, the greater amount passing straight through.. The second fact is that inorganic arsenic appears to have a far lower threshold of toxicity than the organic forms (strangely parallelling Selenium). Lots more to be uncovered here. Still haven't found any real links to mechanisms.

R

[infections] Arsenic carcinogenicity: numbers

Thanks . I noticed the very low chronic-exposurecarcinogenicity threshholds the other night, but your document has agood-looking ref for that info, which spurred me to nail down thenumbers. The apparant carcinogenicity threshhold for lifetime exposure indrinking water is disturbingly low at ~3-10 ppb. Ten ppb is only 0.01mg /day, by my claculation, if you drink 1L of water. (I am assumingppb indicates a mass ratio as implied by my second URL below; the termis ambiguous, as wikipedia discusses.) Whereas Tarello'sself-treatment delivered 7 mg /day of arsenic atoms, and theanti-cancer arsenical Trisenox delivers around 5. Of course, the humanlifespan is ~20,000 days, so Tarello's self-treatment at 10 days was1000x briefer than a lifetime exposure via drinking water. Theanti-cancer treatment can be quite a bit longer, sometimes up to 85days in total: http://www.rxlist.com/cgi/generic/arsenic_ids.htmSo that's 75 mg grand total for the Tarello self-treatment, 425 mg(*maximum*) for use of Trisenox against cancer, and 200 mg for a54-year lifetime of 10 ppb in your 1L of water every day. Obviously, aconcentrated exposure could well be much more or less harmful than avery weak exposure spread out over your lifetime. Also, the activitiesof various arsenical compounds may of course vary.While it'd be better to read the actual papers on the cancer risk,here's from the press release from the highly respected Nat'l Academyof Sciences:"The committee found that men and women who daily consume watercontaining 3 parts per billion of arsenic have about a 1 in 1,000increased risk [ie excess risk, I guess] of developing bladder or lungcancer during their lifetime. At 5 parts per billion, the risk isabout 1.5 in 1,000; at 10 parts per billion, it is greater than 3 in1,000; and at 20 parts per billion, it is close to 7 in 1,000." http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=10194Since those cancers are pretty likely to kill you rapidly, that'sbasically an extra 1/1000 to 7/1000 risk of early(er) death. Forscale, I always like to compare these things to one of our largestvoluntary risks, the lifetime risk of dying in a car wreck, which isabout 1/230 in the USA (obviously quite a lot higher or lowerdepending on your driving and whether you drive in trafficky and/ordeer-infested areas). 7/1000 ~= 1/142.>> Dear > You might like to look athttp://www.thepoultrysite.com/articles/567/playing-chicken-avoiding-arsenic-in-your-meat.> Regards> R

[Guest guest]

On Mon, Mar 12, 2007 at 06:18:16AM -0000, wrote:

>While it'd be better to read the actual papers on the cancer risk,

>here's from the press release from the highly respected Nat'l Academy

>of Sciences:

>

> " The committee found that men and women who daily consume water

>containing 3 parts per billion of arsenic have about a 1 in 1,000

>increased risk [ie excess risk, I guess] of developing bladder or lung

>cancer during their lifetime. At 5 parts per billion, the risk is

>about 1.5 in 1,000; at 10 parts per billion, it is greater than 3 in

>1,000; and at 20 parts per billion, it is close to 7 in 1,000. "

>

>http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=10194

You'll notice that those numbers have the risk being proportional to dose

(within rounding error). I'll bet that if you look up the actual papers,

you'd find that this is an assumption, rather than an experimentally

proven fact, and that what they are really doing is extrapolating from

much higher doses (and much higher cancer rates), via the linear

no-threshold model of risk. That model doesn't make any sense -- it's

tantamount to assuming that the body has no detoxification or repair

mechanisms whatsoever -- but it's the usual model that's used in these

situations.

[Guest guest]

> You'll notice that those numbers have the risk being proportional to

dose

> (within rounding error). I'll bet that if you look up the actual

papers,

> you'd find that this is an assumption, rather than an experimentally

> proven fact, and that what they are really doing is extrapolating from

> much higher doses (and much higher cancer rates), via the linear

> no-threshold model of risk. That model doesn't make any sense -- it's

> tantamount to assuming that the body has no detoxification or repair

> mechanisms whatsoever -- but it's the usual model that's used in these

> situations.

Well, the full text NAS report is here. It has a looong table of

borrowed data, several pages long. This URL will land you right in the

middle of the table:

http://books.nap.edu/openbook.php?record_id=10194 & page=42

crane your neck there and take a look at the top line, Chiou et al

2001. For two different tumors, there appear to be raw incidences taken

from Chiou for four different ranges of As exposure. At least that's

how I'm decoding it.

Also, I saw one assertion that there are 7 more or less plausibly

significant avenues for the As carcinogenesis. (So on balance, the

thing is a big tangle.) But one possible mech is inhibition of the DNA

repair enzymes. Such inhibition might actually produce a linear no-

threshhold assumptions, since even in the absence of any exogenous

mutagen, DNA already undergoes significant decay at a constant rate,

which has to be fixed continually.

I'm really kind of stretching here, though. Surely there is somewhat of

a surefeit/buffer of DNA repair activity at baseline, and furthermore I

think that if and when DNA lesions of any kind do start building up,

the SOS response will be triggered and DNA repair will intensify - a

further buffer. Those facts certainly wouldn't be expected to

correspond to a no-threshhold curve. But, assuming that Arsenic-

sponsored oxidative damage and other mechs also contribute, it might

happen to all come out linear-ish when you add it all up. (Not that I

expect you to find that kind of talk very satisfying... but it could

still be true!)

[Guest guest]

> My decoding is the same. But notice that it's really the data for

> patients with exposures >100 ug/L that make that page of the table

> significant. Below that concentration, the number of cases is so

small

> that a single person not getting cancer would change the relative

risk to

> be something very close to one.

Thanks for pointing out my repeated misinterpretations of this

report.

I think you're right about the above. Here's Chiou:

http://171.66.121.65/cgi/reprint/153/5/411.pdf

I'm looking at table 5. I'm using model 3, which sounds best to me -

it takes into account both As concentration and duration of exposure,

corrected for age/sex/smoking. As you can see, you're right: the 95%

CIs of the risk ratios for the 10-50 ug/L and 50-100 ug/L groups each

have lower bounds below unity, so they are not significantly

different from the <10 ug/L group at 95% confidence. Only the 100

ug/L group is.

But they are claiming the dose-dependency *trend* is significant at

95% confidence. I lack the stats to really dig into that. I suppose

it means something like, if you picked the best line for 4 random

points on that x-y rectangle, the sum of squares of the points'

differences from their best line would be larger than the

corresponding value seen here, 95% of the time - ?? I pretty much

made that up. But assuming my guess is pretty close, it doesn't seem

like a terribly fair way to decide between threshhold and no-

threshhold models (not that Chiou asserted so), unless you use

something more like 6 or 8 points. We know the null hypothesis (no

correlation at all) is false at 95% confidence, but quite a bit of

that confidence is deriving from the <10 and >100 points, which would

behave the same whether there is any threshhold (any sub-100

threshhold) or not.

Which is the same thing you already said, if I grasp your meaning. I

guess if you want to exclude existence of a threshhold above X, the

only truly clear way to do that is to simply show that the cancer

incidence at X is significantly different from that at zero - ??

> Oxidative damage would almost certainly have a threshold; and you

can't

> get a no-threshold curve by adding together lots of curves each of

which

> has a threshold. Even if there isn't any threshold per se, just

about

> any kind of repair mechanism works better at low levels of damage

than at

> high levels.

I concede about ox damage. But say As inhibits enzyme XYZ that's

somehow involved in anti-mutagenesis (maybe it functions in the

apoptotic response to major DNA damage). And say that inhibition

levels off around 30 ug/L. Add that to a threshhold curve and the

result might look pretty linear. (Except in the region below the Kd

affinity value between As and X, where inhibition of XYZ is a concave

function of [As], but you might well have no data point in that

region).

> If you look earlier in the report, they explicitly confirm that

they're

> doing as I suspected, and extrapolating high-exposure data to lower

> exposures via the linear no-threshold assumption

What page do they say that on? I am surprised. Especially since the

*press release* makes apparant flat statements about 5 ug/L being

different from zero: " at 5 parts per billion, the risk is [...]. " I

don't think too many reporters would go on to read the full report!

The press release also acknowledges and discusses other contestible

methods used - like comparison to incidences taken from a different

study - making you think you're getting the full story....... no

mention of a no-threshhold assumption. Potentially misleading, I can

personally attest.