Apples, Arsenic, and Risk - Part 19: Like Dysentery, Only Sweeter

Ubiquitous = Everywhere

Consumer Reports tells us:

Arsenic is a naturally occurring element that can contaminate groundwater used for drinking and irrigation in areas where it’s abundant, such as parts of New England, the Midwest, and the Southwest. (1)

If we water our apple trees with ground water that is naturally contaminated with arsenic, or groundwater that is contaminated with arsenic from past pesticide and industrial use, that arsenic will be sucked up the trees and end up in the apples they produce.

That's one way, the other way has a bit more of the yuck factor involved.

If you look at the NHAMES data Consumer Reports references, and focus on this statement they make in their report, you will maybe understand why it is "ubiquitous."

Because most ingested arsenic is excreted in urine, the best measure of recent exposure is a urine test. (1)

Perhaps I can make my point using a song from the play "The Book Of Mormon."  That song, "Joseph Smith American Moses" has lyrics that discuss the spread of dysentery.  Now if you are familiar with South Park, the guys who wrote this play are the same ones who write that, so if you have sensitive ears or eyes you may not want to go looking for them.

So with apologies to Stone and Parker, here are my lyrics to illustrate the ubiquitousness of Inorganic Arsenic.

Arsenic goes out in the urine

Urine goes down the sewer

The sewer ends up in the river

The river irrigates the apple tree

The apple tree makes the apple juice

The apple juice goes in the cup

The cup goes to the mouth

The mouth goes to the stomach

Arsenic goes out in the urine

So now that I have that little ditty out of the way, let me put it all together using Vinny Gambini: - from "My Cousine Vinny - as a way to further illustrate what may be happening.

I'll set the scene: Vinny is in court cross examining Russell H. Greenfield, MD who made this statement:

"...the US government put a stop to the use of inorganic arsenical pesticides years ago. The same action, however, has not been taken by other countries, such as China, which just so happens to be the major source of apple juice products found in American stores. Chinese farmers, including apple farmers, still may use pesticides containing arsenic." (1)

The courtroom audience is hush, the air thick...

Vinny Gambini: And where does apple juice come from?
Dr. Greenfield:  China
Vinny Gambini:  Good...but more specifically....
Dr. Greenfield:  From the apples that grow on apple treesVinny Gambini: And those trees...do they require anything other than sunlight and soil to grow?
Dr. Greenfield: They need water.
Vinny Gambini: Water, that's right, don't be afraid just shout 'em right out when you know 'em.  And where does that water come from?
Dr. Greenfield: The rain
Vinny Gambini:  Rain...that's right, is that all?
Dr. Greenfield: Groundwater
Vinny Gambini: Ahh...pumped up from below the surface.  Anywhere else?
Dr. Greenfield: Rivers...
Vinny Gambini: Yes, rivers, streams. pounds, lakes...tanks - as you call them in Texas.  You mean surface water?
Dr. Greenfield: Yeah...surface water
Vinny Gambini: And is the water pumped up from the ground always free of arsenic?
Dr. Greenfield: No
Vinny Gambini: And that urinary arsenic we've been talkin' about.  Anyway that can get into the surface water?
Dr. Greenfield: Yeah, if that's where the treated water is discharged.
Vinny Gambini: So, what do you think? Isn't it possible that the arsenic is naturally coming from the soil or is present in the surface or groundwater used to irrigate the apple trees and not just from pesticides?
Dr. Greenfield: I suppose.
Vinny Gambini: I'm finished with this guy. 

I (almost) rest my case.

Next (and finally the last) Post: Apples, Arsenic, and Risk - Part 20: It is, and always will be, about the dose.


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Apples, Arsenic, and Risk - Part 18: The China Syndrome

Russell H. Greenfield, MD writes:

Dr. Oz and his staff have performed their own investigation into this matter, and they, too, found high levels of arsenic in some apple juice products. The findings raise significant health concerns for us and for our children, and have generated incredulousness that this could happen in our country.

After everything I have read on this topic, a theme began to take shape. A theme that may help answer the question I asked in my last post: Where is the connection being missed by these well educated professionals?

Let's see if you can pick it out:

"...in our country."

"...the US government put a stop to the use of inorganic arsenical pesticides years ago. The same action, however, has not been taken by other countries, such as China, which just so happens to be the major source of apple juice products found in American stores. Chinese farmers, including apple farmers, still may use pesticides containing arsenic." (1)

"More and more food comes into our country from foreign soil each year, but the FDA is able to inspect only a small and woefully inadequate percentage of the products reaching our shores before they reach our store shelves and then our plates. Why? Because funding for the FDA is consistently on the chopping block in Washington, DC. It is this fact that merits our anger." (2)

"Also, request that they apply pressure to improve Chinese agricultural practices, both for our safety and their own population." (3)

"Look for the country of origin on your apple juice label. You’re likely much safer drinking a product that comes only from the United States." (3)

"Go organic when possible. Organic apple juice comes from apples that are, by definition, not treated with harsh pesticides." (3)

"For the past decade, most concentrate has come from China. Concerns have been raised about the possible continuing use of arsenical pesticides there, and several Chinese provinces that are primary apple-growing regions are known to have high arsenic concentrations in groundwater." (4)

"Currently there's an alert for increased surveillance of apple concentrate from China and six other countries "where we have a suspicion there may be high levels of arsenic in their products," says FDA spokeswoman Stephanie Yao. But in fiscal 2010, the agency conducted physical inspections of only 2 percent of imported food shipments." (4)

"The fact is that the U.S. is getting more and more of its fruits and vegetables from other countries, and many of them do not preclude or limit arsenic in their pesticides or even their water supplies as the U.S. does. Oz reported that apple concentrate comes from up to seven countries; 60 percent of it is imported from China alone." (5)

Notice somethin'?

What would a nerdy public health blogger do with that theme?  Hmmm, I wonder what was found in the samples collected and analyzed by Consumer Reports?  Let me be clear here, I am writing this BEFORE I have crunched the numbers.  My initial observation is that we will not see any difference in the amount of arsenic from country to country.  I hope so, because I have a really good song to use to make my point!

Okay, back.  Here is what I found (mean value):

Source: Consumer Reports

Interesting....

Looks like the apple juice from China has less inorganic arsenic than that from the USA.  I wonder what that means?  Well, here is what I think, lets look at these two statements:

"The fact is that the U.S. is getting more and more of its fruits and vegetables from other countries, and many of them do not preclude or limit arsenic in their pesticides or even their water supplies as the U.S. does. Oz reported that apple concentrate comes from up to seven countries; 60 percent of it is imported from China alone." (5)

"For the past decade, most concentrate has come from China. Concerns have been raised about the possible continuing use of arsenical pesticides there, and several Chinese provinces that are primary apple-growing regions are known to have high arsenic concentrations in groundwater." (4)

If arsenic pesticides are no longer used in the USA, and apple-growing regions of China have high arsenic concentrations  then we would expect the apple juice from China to have more arsenic than the USA, not less.  In fact, look at the concentrations Consumer Reports found.  I have ranked them from highest to lowest.

Source: Consumer Reports

You know the terrible thing about looking at the data that is reported?  It sometimes makes you have to admit that your assumptions have been wrong.  We assume that foreign apple juice is bad because they don't have our standards.  But when you look at theirs compared to ours, that's not what the data shows.

But the data does show something.  It shows that arsenic is in all apple juice and it looks like the country it comes from plays little into the concentration.  Which makes me wonder what that organic apple juice ol' Chuck Norris wants us to drink contains?

So if it's not arsenic pesticides putting the arsenic in our apple juice (if it is, and we don't use it, that does not bode well for us) where is it coming from?

Enter the word "ubiquitous."


Next Post: Apples, Arsenic, and Risk - Part 18: Like Dysentery, Only Sweeter.


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Apples, Arsenic, and Risk - Part 11: Type 2 diabetes - 80th vs the 20th percentiles

How to make a weak association sound strong:

1. Present the data in a format to disguise the weakness (2% instead of 1.02)
2. Compare percentiles to increase the ORs reported.

Now please don't get me wrong here, there is a perfectly good reason to compare percentiles.  Was this one of them?  I don't think it was done for any other reason than to bolster the paper's claim that there is a positive association between arsenic and type 2 diabetes prevalence.

But let's assume that there is no sneaky reason for presenting this data in her report.

If that's the case, then let me ask this question: Does the OR for the 20%/80% percentile support Consumer Report's claim that there is a link between "low-level arsenic exposure with the prevalence of type 2 diabetes in the United States?" And, if so, will the concentration of arsenic they found in the apple juice they tested be high enough to increase the risk for developing type 2 diabetes?  That is, after all, what is meant by "there is a positive association between arsenic and type 2 diabetes prevalence."

What do we know so far from Dr. Ana Navas-Acien's study on arsenic and type 2 diabetes?  Well we know that for the 93 participants in the study who had type 2 diabetes, their average total arsenic was 6.2 ug/L as you can see in Table 2:

Source

We also know that the third model "was further adjusted for urine arsenobetaine and blood mercury levels" to provide "estimates for the association of inorganic arsenic not derived from seafood and for arsenobetaine."

And we know that the ratio of arsenic concentrations comparing participants with type 2 diabetes for Model 3 was 1.26 (1.02-1.56) as can be seen in Table 2 above.

So...an average of 6.2 ug/L total arsenic generated an OR of 1.26 (1.02-1.56) when it was further adjusted for urine arsenobetaine and blood mercury levels.

What's the average urinary total arsenic they found in the 2003-2004 NHAMES study?

Source

We're going to use this Table again in an upcoming post, it's important here because we need to understand what is meant by the term "low-level arsenic exposure."

There is a weak association when you look at Model 3 because the range is just barely above "1" - (1.02-1.56).  Because that range does not include the number "1", Dr. Ana Navas-Acien can report a "positive" association:

This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence.

and...

These results support our hypothesis that exposure to inorganic arsenic, which in this population was most likely derived from drinking water, is associated with an increased risk of diabetes.

and again...

We found a positive association between total urine arsenic, likely reflecting inorganic arsenic exposure from drinking water and food, with the prevalence of type 2 diabetes in a population with low to moderate arsenic exposure.

Which brings me once again to my question: how much confidence in that number do you have?

Had the paper stopped at:

After adjustment for diabetes risk factors and markers of seafood intake, participants with type 2 diabetes had a 26% higher level of total arsenic...

...we would only have an argument on including the word "weak" to describe the association.  Attach a verb, don't attach a verb, toe-mate-o, toe-maut-o.

Now look at the rest of the "results" paragraph in the abstract at the beginning onf the paper:

After similar adjustment, the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th percentiles were 3.58 for the level of total arsenic (95% CI, 1.18-10.83).

1.26 now jumps to 3.58.  And the 95% CI range is now (1.18-10.83).

Stout! ...or is it robust?

There's one slight problem here.  Are we still talking about "low-level arsenic exposure?"

Look at Table 3....

Source

Notice what the urinary total arsenic concentration is for the 80th percentile?  16.5 ug/L compared to the 20th percentile of 3.0 ug/L.  What's the geometric mean - average - they report?  6.2 ug/L compared to 7.3 ug/L.  Hmmm...interesting.

So let's reword that results statement to reflect what is really going on here.

When Dr. Ana Navas-Acien writes:

After similar adjustment, the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th percentiles were 3.58 for the level of total arsenic (95% CI, 1.18-10.83

What she really is stating is this:

After similar adjustment, the odds ratios for type 2 diabetes comparing participants with a  urinary total arsenic of 16.5 ug/L (almost three times the average) with those without type 2 diabetes and a urinary total arsenic of 3.0 ug/L (less than half the average), were 3.58 (1.18-10.83)

That statement above is factual and accurately describes the results from Table 3.

To get that high of an odds ratio the arsenic has to be almost three times the average level normally found in the population.  And, to top it off, it will only be that high if it is compared to a population that has 2 time less arsenic than the population as a whole.

16.5 ug/L is not a low level of arsenic.  It is above the MCL of 10 ug/L and way above the 4 ug/L Consumer Reports found in the samples of apple juice they tested.

Well Mr. Smarty-Pants, doesn't it also show that increasing the level of arsenic increases the risk of type 2 diabetes!  Explain that you wet blanket!

Yeah, it does show that, but it is based on a sample size which, surprise! surprise! is not referenced (at least I can't find it).

What is the "n" making up the 80th percentile of those with type 2 diabetes and what is the "n" for the 20th percentile for those without?  Remember, we started with 93/695 and then adjusted it once - Model 1, then again, Model 2, then even more, Model 3.  What's the "n" of two populations used in the OR for Model 3?  And then from that population they separated it further into percentiles, what's the "n" of the 80th and the "n" of the 20th?

In statistics, the error - bias - is reduced with more "n"s.

There is, however, another interesting bit of information you can get from Table 3.  Look at the next three columns called "Tertile"

What's a "tertile?":

Any of the two points that divide an ordered distribution into three parts, each containing a third of the population.

You know something you can get from those three tertile columns?  The total "n" of each population that made up that tertile.

So if the 80th percentile is 16.5 ug/L and the highest third of all the data is >10.8 ug/L, how many of the 34 "n" to in the third tertile of Model 3 are in the 80th percentile?

What's also interesting is that when  Dr. Ana Navas-Acien compared the lowest population, the middle, and the highest, there was no statistical significance in any of the pairings.  None.  They all contain the number "1" in the ranges.

I think I'm done looking at this paper.  It has too many issues to accept its claim that:

This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence.

So, low-levels of arsenic - below the MCL and at the levels found in apple juice - do not support a link to cancer, hyperkeratosis, and type 2 diabetes.  Is that it?  Can I move on to something else, you know, like hazardous waste being wacky?

What about Consumer Reports telling its readers about a 2011study in the International Journal of Environmental Research and Public Health that examined the long-term effects of low-level exposure on more than 300 rural Texans whose groundwater?

Consumer Reports claims that these Texans were estimated to have exposure to arsenic at median levels below the MCL and when tested showed poor scores in language, memory, and other brain functions.  What about low levels of arsenic and diminished intelligence?  Isn't that a problem?

Rule number one: Always read the report the findings/recommendations were based on.

Onward...to infinity and..../sigh

Next Post: Apples, Arsenic, and Risk - Part 12: Correlation does not imply causation.


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Apples, Arsenic, and Risk - Part 10: Type 2 diabetes - 1.26 based on what?

In my last post I ended with the question of how much confidence should we have in this Odd Ratio: 1.26 (1.02-1.56)?

The reason for our confidence in it, how solid it is, how much it actually reflects the population it measures, is because it is used to generate the conclusion:

This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence.

And with that conclusion, Consumer Reports was able to tell its readers that there is a link between:

Low-level arsenic exposure with the prevalence of type 2 diabetes in the United States.

Although it may seem like I am beating a dead horse with all of this, I mean c'mon 10 posts?!?, what I am trying to do is take a complicated subject and break it down so one can separate fact from spin.

Step one is being skeptical, even if the work is performed by a respectable organization like Consumer Reports with help from a Johns Hopkins University’s Bloomberg School of Public Health physician - epidemiologist.

Step two is reading the work that is used to support the claim.  Consumer Reports and their scientists claim that low levels of arsenic is harmful.  We know from their 84 samples analyzed for inorganic arsenic the mean level of inorganic arsenic is 4 ug/L or 4 ppb.  We know that the EPA has established an MCL for arsenic in drinking water of 10 ppb based on a 70 kg person consuming 2 liters per day for a lifetime as a "safe" level.  Is 4 ppb arsenic in the apple juice a concern?  Is it a concern for contributing to type 2 diabetes?

Step three is looking at the data.  Looking at it closely to see how it was derived and concurring with the author or disregarding the findings as unsupported.

Here's the thing I want the reader to know.  If her work supported her conclusion I would still write about it and show why.  It doesn't, which is why it takes this direction.  If it did, I would go in that direction. I've got no dog in this hunt as well.

So let's look at how those ORs we derived.  Starting with Table 2:

Source

Here is how they got their "n":

• They randomly selected a one-third random sample of NHANES 2003-2004 study participants aged 6 years and older (n=2673)
• They then selected 1027 participants from those 2673 who had fasted 8 to 24 hours before venipuncture.
• They then excluded 38 pregnant women, 34 participants missing total urine arsenic or urine arsenic species, 24 participants without prior diagnosis of diabetes missing serum glucose, 4 participants missing glycated hemoglobin, 
• They then restricted their analyses to participants who did not report seafood intake in the past 24 hours.

That last bullet was done for this reason:

Our primary assessment of exposure was total urine arsenic concentration adjusted for objective biomarkers of seafood consumption.

So far, so good.  This gave them a total population of 788 (n = 788).

Of that 788, 95 had type 2 diabetes and 695 did not.  All of the OR and percentages they now report will be based on that population.  They are comparing one group to another - those with diabetes to those without.

The hypothesis here is that you will see a higher urinary arsenic level for those with diabetes compared to those without.

Doh!  That's not what they saw when the compared the mean total arsenic in the diabetes group with that of the non-diabetes.  Seems the non-diabetes group had more 7.4 ug/L compared to 6.2.

Now there could be a logical reason for this based on the makeup of the two groups being compared.  We want to compare a similar group with a like similar group.  Instead we are dealing with a random group we pulled from a larger group.  Enter the "Model."

Model 1:

First, we adjusted for sex, age, race and ethnicity (known determinants of diabetes that may be related to arsenic exposure), and urine creatinine.

Okay, even with that adjustment there is still less total arsenic in the diabetes group compared to the non-diabetes group.  0.94 OR, but the range contains a "1" so we can conclude nothing there, although it is consistent with what we see with the raw data.

Model 2:

Second, each model was further adjusted for education, body mass index, serum cotinine, and use of antihypertensive medication.  This model represents the association of total arsenic exposure with diabetes independent of the source but adjusted for traditional diabetes risk factors.

Okay, now there is a shift, based on this model, 1.01, but again, the range contains a "1" so this model statistically shows no association.

Model 3:

Third, each model was further adjusted for urine arsenobetaine and blood mercury levels. This model provides estimates for the association of inorganic arsenic not derived from seafood and for arsenobetaine.

So after adjusting for 1 & 2, they further adjust the population by excluding those who were found to have arsenobetaine and blood mercury levels.  The assumption here is that these folks ate fish and their total arsenic is tainted by organic arsenic from the fish.

Aha!  Now we get a positive association, the 1.26 with a range of 1.02-1.56.  Woot!  Now they can claim a positive association!  There ain't a "1" in that range is there!

Now before we continue, you might be wondering about other risk factors for type 2 diabetes:

Further adjustment for smoking status and alcohol intake, as well as exclusion of participants showing levels below the limit of detection, did not modify the observed associations.

With all that adjusting going on our populations being compared get smaller and smaller allowing the influence of sample error to have a greater role in the accuracy and precision of the number reported.  This is why it is hard for me to accept a positive association where the range is 1.02-1.56.

You'll notice how at the beginning of their paper - the only part 99% of all journal paper readers read - it does not report these ORs, instead it reports a percentage:

The prevalence of type 2 diabetes was 7.7%. After adjustment for diabetes risk factors and markers of seafood intake, participants with type 2 diabetes had a 26% higher level of total arsenic (95% confidence interval [CI], 2.0%-56.0%) and a nonsignificant 10% higher level of dimethylarsinate (95% CI, −8.0% to 33.0%) than participants without type 2 diabetes, and levels of arsenobetaine were similar to those of participants without type 2 diabetes.

I wonder why?

Well for starters, 26% higher sounds much more significant than 1.26.  And 2.0% - 56% sounds more pronounced than 1.02-1.56.  Yeah it means the same thing, but the perception is different, that's why we sell stuff at $9.99 and not $10.00.  Kind of sneaky isn't it?  It's not lying, but it's not being forthright either.  It's spin.  Ahh the games you must play when your results are weak.

But wait...we can make support for our hypothesis even stronger!  Let's compare percentiles!  Now we can report an OR that's got a bit of meat on its bones!

After similar adjustment, the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th percentiles were 3.58 for the level of total arsenic (95% CI, 1.18-10.83), 1.57 for dimethylarsinate (95% CI, 0.89-2.76), and 0.69 for arsenobetaine (95% CI, 0.33-1.48).

Much...much better wouldn't you conclude?  That's brings us back to Figure 2 in my last post, the one with the graphic showing how many "favors association."

Rule number one: Always read the report the findings/recommendations were based on.


Next Post: Apples, Arsenic, and Risk - Part 11: Type 2 diabetes - 80th vs the 20th percentiles


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Apples, Arsenic, and Risk - Part 9: Type 2 diabetes - A very weak link

Ana Navas-Acien, M.D., Ph.D., a physician & epidemiologist at Johns Hopkins University’s Bloomberg School of Public Health, was used by Consumer Reports in their January 2012 article called "Arsenic in your Juice".  According to Consumer Reports:

[Dr. Ana Navas-Acien] was the lead author of a 2008 study in the Journal of the American Medical Association that first linked low-level arsenic exposure with the prevalence of type 2 diabetes in the United States.

If you can remember the "ground rules" I discussed in my last post, we can look at her paper, her data, and her conclusion to see if there is, indeed, a "link" between low-level arsenic exposure and type 2 diabetes.

Let's first look at the paper's claim:

The positive association between total urine arsenic and diabetes after adjustment for markers of seafood intake was consistent for most subgroups examined, with somewhat greater associations in participants who were younger, overweight, and never smokers (FIGURE 2).

Source

We are all taught in our EPI classes, at least I was at Texas A&M's School of Rural Public Health, that if the range of your odds ratio (OR) includes the number one - "1" - there is no statistically significant association.  Period.

Now there is nothing wrong with Dr. Ana Navas-Acien including all her data in her report.  I would have left all the non-associations out, but that's just me.  What's troubling with her work is the graphic she includes in Figure 2.

Source

What can one reasonably conclude from looking at that graphic?  Look how all those black boxes fall on the "favors association" side of the graph.  What is Dr. Ana Navas-Acien trying to convey to her audience?

This is where the "whole truth" comes in.  Her graph makes it look like there is an association between total urine arsenic and diabetes every where she looked.  That's not true.  Look at the ranges.  All but four of them include the number "1."  Look at the P-values reported, all of them are above 0.05 for the interaction.

Remember, we want to reject the null hypothesis that there is ‘no effect of the intervention’ or ‘no differences in the effect of intervention between studies’ (no heterogeneity).  We can only reject the null if the P-Value is less than 0.05 (95%).  The null says there is no association, to reject that notion we need a P-value that is less than 0.05.

Now look at the four Adjusted Ratios in Table 2 that do not include the number "1" in their range:

• 1.71
• 1.35
• 1.55
• 1.54

How large of a difference is that?  They are all less than 2 to 1, so you can't say the association is twice as high.  But there's another factor to consider when looking at those four values.  How many participants - "n" - were in the populations compared?  I'll address that in an upcoming post, because its important.  But let's forget about those four for now and look at the overall "Adjusted Ratio" she reports:

1.26 (1.02-1.56)

How confident should we be in that number?  The range does not include a "1", so we can truthfully state that we see an association here:

After adjustment for biomarkers of seafood intake, total urine arsenic was associated with increased prevalence of type 2 diabetes.

The number spat out, "1.26," does not include the number "1" in its range therefore there is a positive association even though the lower range is only 2/100 higher than "1".

And the whole truth?  Here is what she should have concluded:

Our research shows a weak association between urinary arsenic that has been adjusted for biomarkers of seafood intake and the prevalence of type 2 diabetes.

We have two things working against us here when we calculate ORs and P-values.

1. Statistics looks at the data point as absolute
2. Sample and analytical data points are not absolute numbers - they are a statistical range that we report as a single number.

How much confidence should we have in this Odd Ratio: 1.26 (1.02-1.56)?

Consumer Reports believes there is enough confidence in that number to make the claim that Dr. Ana Navas-Acien "first linked low-level arsenic exposure with the prevalence of type 2 diabetes in the United States."  

That claim was backed up by this journal paper, and in that paper the OR of 1.26 (1.02-1.56) is reported and the conclusion that "This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence." is made.

It all rests on this one bit of data: 1.26 (1.02-1.56).

How much confidence should we have in this Odd Ratio: 1.26 (1.02-1.56)?  It is that number and it's range that allows her to report that:

This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence.

Next Post: Apples, Arsenic, and Risk - Part 10: Type 2 diabetes - 1.26 based on what?

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Apples, Arsenic, and Risk - Part 8: Arsenic and type 2 diabetes

"Mounting scientific evidence...serious health problems..."

Okay...so where are we after seven posts?

"For water with 10 ppb of arsenic, the excess cancer risk is one in 500."  That's been addressed and found to be based on a cancer slope - potency - that is not seen in the real world.  So water or apple juice with less than 10 ppb of arsenic is not a cancer risk.

"Sharyn Duffy of Geneseo, N.Y. having "double the typical levels" of arsenic causing her to develop hyperkeratosis.  "Double the levels" of arsenic would not bring about that disease.  We can ignore that claim of a health problem at low levels - below the MCL.

What else does Consumer Reports claim is the harm associated with low levels of arsenic?

Ana Navas-Acien, M.D., Ph.D., a physician & epidemiologist at Johns Hopkins University’s Bloomberg School of Public Health, also provided guidance. She was the lead author of a 2008 study in the Journal of the American Medical Association (PDF) that first linked low-level arsenic exposure with the prevalence of type 2 diabetes in the United States.

OK, that's probably what lead to Consumer Reports making this statement about arsenic:

It’s a carcinogen known to cause bladder, lung, and skin cancer in people and to increase risks of cardiovascular disease, immunodeficiencies, and type 2 diabetes.

Since EPA has set the reference dose (RfD or MRL) for arsenic based on this:

"This value [0.0008 mg As/kg/day] has been used to calculate a chronic oral MRL for inorganic arsenic of 0.0003 mg/kg/day."

And that value - 0.0008 mg AS/kg/day - was derived from....:

 "a very large study detected no effects in any person at an average total daily intake (from water plus food)."

Where they found "no effects" at that level for....

"Skin lesions." 

What EPA'a ATSDR take on low levels of arsenic is this: A chronic daily intake of 0.0003 mg/kg/day of arsenic will result in no skin lesions.  What it also tells us is that all other diseases associated with arsenic result from concentrations higher than what causes skin lesions.  So if ATSDR sets the protection based on skin lesions it will be protective for all the other diseases at or below that level.  That 0.0003 mg/kg/day is what gives you the 10 ppb MCL for drinking water.

Not so fast, says Dr. Ana Navas-Acien:

After adjustment for biomarkers of seafood intake, total urine arsenic was associated with increased prevalence of type 2 diabetes. This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence.

So this claim bears a bit of scrutiny.  She is one of the scientists Consumer Reports used in their report and they make reference type 2 diabetes as a possible health concern from low levels of arsenic.

This puts us once again back to the question:

1. Is drinking apple juice unsafe because of arsenic?
2. Is drinking water with the 10 ug/L (ppb) of arsenic unsafe?

What does Dr. Ana Navas-Acien mean when she reports "low levels of exposure to inorganic arsenic in drinking water...may play a role in diabetes prevalence."  What "low levels" is she talking about?  Below the MCL?

Confusing. So lets look at what we know.

We know we have apple juice that Consumer Reports found to contain about 4 ppb of arsenic at the 95%CI.  We know we have drinking water that the EPA states will not result in and deleterious effects during a lifetime at 10 ppb.  And now we have a scientist - epidemiologist no less - from Johns Hopkins University’s Bloomberg School of Public Health, telling us there may be link to type 2 diabetes at low levels.

Help me, Obi-Wan Kenobi. You're my only hope.

Well I ain't no Obi-Wan Kenobi, but I can point you in a direction to help make sense of this, at least that's what I am trying to do.

Let's look at what Dr. Ana Navas-Acien concludes in her study:

"We found a positive association between total urine arsenic, likely reflecting inorganic arsenic exposure from drinking water and food, with the prevalence of type 2 diabetes in a population with low to moderate arsenic exposure."

Powerful.  Reading that one would have to conclude that arsenic contributes to type 2 diabetes, and at low levels to boot!  But if you look at her paper closely - and understand what a "positive association" means - you might come away with a much different level of concern about low levels of arsenic and type 2 diabetes.

I've said it before: Always read the journal article, not just the abstract or the conclusion.  This is another example of the truth, whole truth, and nothing but the truth, showing the disingenuous side of scientific research and publication.  I'm not the quickest study, it usually takes me three or or four times to understand what went on and what the data says.

So, first question: Did Dr. Ana Navas-Acien find "a positive association" between inorganic arsenic and type 2 diabetes?  Yes.  Is that "association" the whole truth?  No.  It's all in her "peer reviewed" paper, all you need to do is understand how a positive association works and how to interpret her data.

First, a bit of ground rules for understanding any data presented in a scientific journal article:

When we say" 95% CI" - upper confidence interval - we mean this:

“because of the uncertainty associated with estimating the true average concentration...the 95 percent upper confidence limit (UCL) of the arithmetic mean should be used for this variable.”  That is, we are taking the highest value that statistically would fall within two standard deviations from the mean and not using the average (mean) or median. (1)

When we say "P-value" we mean this:

A P value is the probability of obtaining the observed effect (or larger) under a ‘null hypothesis’, which in the context of Cochrane reviews is either an assumption of ‘no effect of the intervention’ or ‘no differences in the effect of intervention between studies’ (no heterogeneity).

Thus, a P value that is very small indicates that the observed effect is very unlikely to have arisen purely by chance, and therefore provides evidence against the null hypothesis.  

It has been common practice to interpret a P value by examining whether it is smaller than particular threshold values. In particular, P values less than 0.05 are often reported as “statistically significant”, and interpreted as being small enough to justify rejection of the null hypothesis. 

However, the 0.05 threshold is an arbitrary one that became commonly used in medical and psychological research largely because P values were determined by comparing the test statistic against tabulations of specific percentage points of statistical distributions. (2)

That is, when we see a P-value of less than 0.05 we can statistically assume there was an effect or there is an association.  Remember, association does not imply causation!

When we look at an Odds Ratio - OR - we need to adhere to the following when reviewing the range they report with it:

• Conclude that the probability that the outcome is present is higher (in the population) for group 1 if the entire interval is above 1
• Conclude that the probability that the outcome is present is lower (in the population) for group 1 if the entire interval is below 1
• Do not conclude that the probability of the outcome differs for the two groups if the interval contains 1

That last bullet is the important one.  If the range include the number one - "1" - there is no difference between the two groups that is statistically sound - regardless of what Odds Ratio is reported.

Okay, so now that we got that little bit of fun out of the way, lets look at Dr. Ana Navas-Acien's conclusion that there is a positive association between total urine arsenic with the prevalence of type 2 diabetes in a population with low to moderate arsenic exposure.


Apples, Arsenic, and Risk - Part 9: Type 2 diabetes - A very weak link.

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Apples, Arsenic, and Risk - Part 7: Who the heck is Sharyn Duffy of Geneseo, N.Y.?

Okay, so if cancer at these low levels is not the concern the EPA says it is, would there be anything else that would cause Consumer Reports concern regarding the finding of inorganic arsenic in apple juice?  Here is what they report:

• Mounting scientific evidence suggests that chronic exposure to arsenic...even at levels below water standards can result in serious health problems.
• But the many diseases likely to be increased by exposure even at relatively low levels are so common already that its effects are overlooked simply because no one has looked carefully for the connection,” says Joshua Hamilton, Ph.D., a toxicologist specializing in arsenic research and the chief academic and scientific officer at the Marine Biological Laboratory in Woods Hole, Mass.
• It’s a carcinogen known to cause bladder, lung, and skin cancer in people and to increase risks of cardiovascular disease, immunodeficiencies, and type 2 diabetes.
• A 2004 study of children in Bangladesh (PDF) suggested diminished intelligence based on test scores in children exposed to arsenic in drinking water at levels above 5 ppb, says study author Joseph Graziano, Ph.D., a professor of environmental health sciences and pharmacology at Columbia University.
• And a study published in 2011 (PDF) in the International Journal of Environmental Research and Public Health examined the long-term effects of low-level exposure on more than 300 rural Texans whose groundwater was estimated to have arsenic at median levels below the federal drinking-water standard. It found that exposure was related to poor scores in language, memory, and other brain functions.
• Chronic arsenic exposure can initially cause gastrointestinal problems and skin discoloration or lesions. Exposure over time, which the World Health Organization says could be five to 20 years, could increase the risk of various cancers and high blood pressure, diabetes, and reproductive problems.
• Signs of chronic low-level arsenic exposure can be mistaken for other ailments such as chronic fatigue syndrome.
• “Given what we know about the wide range of arsenic exposure sources we have in this country, I suspect there is an awful lot of chronic, low-level arsenic poisoning going on that’s never properly diagnosed.”
• ...but also can cause lasting harm to children’s developing brains and endocrine and immune systems, leading to other diseases, too.
• “Recent studies have shown that early-childhood exposure to arsenic carries the most serious long-term risk,”
• Evidence of arsenic's ability to cause cancer and other life-threatening illnesses has surged because some of the diseases linked to it have latency periods of several decades.

So, what we come away with when reading the Consumer Report's article on Apples and Arsenic is this:

• Mounting scientific evidence...serious health problems
• Many diseases likely to be increased by exposure even at relatively low levels...overlooked
• Increase risks of cardiovascular disease, immunodeficiencies, and type 2 diabetes
• Diminished intelligence based on test scores in children exposed to arsenic in drinking water at levels above 5 ppb.
• Exposure was related to poor scores in language, memory, and other brain functions.
• Increase the risk of various cancers and high blood pressure, diabetes, and reproductive problems.
• Low-level arsenic exposure can be mistaken for other ailments such as chronic fatigue syndrome.
• Low-level arsenic poisoning...that’s never properly diagnosed.
• Lasting harm to children’s developing brains and endocrine and immune systems, leading to other diseases.
• Early-childhood exposure to arsenic carries the most serious long-term risk.
• Ability to cause cancer and other life-threatening illnesses has surged...latency periods of several decades.

Wow!  All that from drinking apple juice?

Not so fast, I'm thinking.  Let's look at it objectively, and ask two questions:

1. Is drinking apple juice unsafe because of arsenic?
2. Is drinking water with the 10 ug/L (ppb) of arsenic unsafe?

Now go back and read the bullets above, what answers to those two questions is being conveyed by Consumer Reports?

Is their report an accurate description of the dangers posed by drinking apple juice that they found had a mean (average) inorganic arsenic concentration of 3.14 ug/L (95%UCL = 3.53) and a median of 2.51 ug/L. (I took all 84 values and ran them using Excel's statistical formulas.  These values exclude three grape juice samples included in their data.)

Some of Consumer Reports' claims of serious health problems they support with a citation link, others are quotes for medical/science professionals, but one in particular is a testimony:

Signs of chronic low-level arsenic exposure can be mistaken for other ailments such as chronic fatigue syndrome. Usually the connection to arsenic exposure is not made immediately, as Sharyn Duffy of Geneseo, N.Y., discovered.

Okay, a real person affected by arsenic...

She visited a doctor in 2007 about pain and skin changes on the sole of her left foot. She was referred to a podiatrist and eventually received a diagnosis of hyperkeratosis, in which lesions develop or thick skin forms on the palms or soles of the feet. It can be among the earliest symptoms of chronic arsenic poisoning. But she says it was roughly two years before she was finally referred to a neurologist, who suggested testing for arsenic. She had double the typical levels.

Okay...she had hyperkeratosis...a skin lesion that's associated with arsenic exposure...she had double the typical levels...  Double?  Typical?

Okay....they named a real person, surely Consumer Reports checked out her story...where did they find her?  What do we know about Sharyn Duffy of Geneseo, N.Y.?  Aha! Google search...nothing.

What support do we have to show that a.) Sharyn Duffy was diagnosed with hyperkeratosis, and b.) she had double the typical levels?  Should we accept the diagnosis and quantification of arsenic presented in the Consumer Reports article as valid?  I tried - as much as I am willing to spend my free time on trying - to find any reference to her case.  Nothing.

I could discount it as "unsubstantiated" but where's the fun in that?

Here is what we know (if you can believe the EPA and ATSDR) about arsenic and skin lesions, such as hyperkeratosis:

[I]n a study with detailed exposure assessment, all confirmed cases of skin lesions ingested water containing >100 μg/L arsenic (approximately 0.0037 mg As/kg/day).

Another large study reported increased incidence of skin lesions associated with estimated doses of 0.0012 mg As/kg/day (0.023 mg As/L drinking water).

Several epidemiological studies of moderately sized populations (20–200 people) exposed to arsenic through drinking water have detected no dermal or other effects at average chronic doses of 0.0004–0.01 mg As/kg/day, and one very large study detected no effects in any person at an average total daily intake (from water plus food) of 0.0008 mg As/kg/day.

Notice how the intake of arsenic is reported in "mg" per liter?  Consumer Reports claims that Sharyn Duffy had "double the typical levels."  The plot thickens (no pun intended...you know...hyperkeratosis...oh, never mind...).

Here is a bit of interesting trivia we also read in the Consumer Reports article:

Because most ingested arsenic is excreted in urine, the best measure of recent exposure is a urine test.

Why's that important?  Because we can measure and get a pretty good estimate of how much total arsenic is being consumed on average - or typical.  And if we know that, we can then double it to find out how much arsenic Sharyn Duffy was exposed to.

In the Consumer Reports article they tell us:

[w]e commissioned an analysis of data from the National Health and Nutrition Examination Survey (NHANES), conducted annually by the National Center for Health Statistics. Information is collected on the health and nutrition of a nationally representative sample of the U.S. population, based on interviews and physical exams that may include a blood or urine test. 

It would have been nice of them to report these values, but nevertheless, we can get a good idea of what they are by looking at NHANES research that has been published.  Here is what I found:

Source Table has been revised since posting)

I am going to assume that Sharyn Duffy of Geneseo, N.Y. is > 20 years of age.  If "most ingested arsenic is excreted in urine" we can assume that the amount of arsenic that Sharyn Duffy was exposed to, if it was "double the typical levels" was approximately 20 ug.  What goes in goes out...

Remember those studies on skin lesions the EPA looked at?  Well here is what they concluded from those studies:

This value [0.0008 mg As/kg/day] has been used to calculate a chronic oral MRL for inorganic arsenic of 0.0003 mg/kg/day.  

EPA considers 0.0003 mg/kg/day "safe" but reports that 0.0008 mg/kg/day "detected no effects in any person at an average total daily intake (from water plus food)."

Let's assume that Sharyn Duffy of Geneseo, N.Y. is a petite woman who weighs 110 pounds or 50 kg.  At 20 ug total intake, she would be consuming 0.4 ug/kg/day or 0.0004 mg/kg/day to get "double the typical levels."

Okay, so she is being exposed to more than the EPA's "safe" dose, but it is way under the 0.0008 mg/kg/day where "no effects in any person at an average total daily intake (from water plus food)" were seen in "one very large study."

So maybe poor Sharyn Duffy of Geneseo, N.Y. is very susceptible to arsenic and the little bit she consumed (if we can trust that it was only enough to "double the typical levels") gave her the disease associated with much higher doses of arsenic.  How does Sharyn Duffy's experience with arsenic affect my answer to the questions I posed earlier:

1. Is drinking apple juice unsafe because of arsenic?
2. Is drinking water with the 10 ug/L (ppb) of arsenic unsafe?

It doesn't.  At worse, Consumer Reports got it wrong, and she was exposed to much more arsenic then "double the typical levels."  At best, Sharyn Duffy of Geneseo, N.Y. is an anomaly...an outlier...and we can ignore her encounter with arsenic because that's not what we would see in the public at large.

Onward....

Next Post: Apples, Arsenic, and Risk - Part 8: Arsenic and type 2 diabetes

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