Friday, October 25, 2013

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Friday, January 25, 2013

Low Homocysteine May Not Be That Great

Homocysteine, a molecule created in the process of what's broadly called "methylation", is believed to be toxic to the endothelial cells that line blood vessels, and an association has been found between cardiovascular disease (CVD) and homocysteine. Some practitioners and researchers even believe that homocysteine is much more important than LDL cholesterol as a risk factor in CVD.

High homocysteine is associated with an extensively researched genetic variant (or polymorphism) named MTHFR C677T, and which if present can often be effectively addressed by eating more foods that contain natural folates such as green leafy vegetables or egg yolks, or by carefully adding a L-5MTHF supplement. (Not "folic acid"which may be toxic in this situation.)

Given the above, low homocysteine levels are typically lauded as a sign of good health. In fact, as with cholesterol, many clinical laboratories have recklessly (or by government decree?) put 0.0 at the low end of their reference interval for homocysteine.

Being no less flattered than most by such follies, I have been proud of my low homocysteine at 5.8, seeing it as a sign of health.

However…

The body detoxifies homocysteine essentially through either recycling the molecule back to methionine (the essential amino acid which it was built from in the first place), or by putting it through a pathway that ultimately converts it into sulfite/sulfate, alpha-ketoglutare, ammonia, and glutathione.

Given these options, if homocysteine is low in the body, it could be for three major reasons:
  1. A high rate of conversion back to methionine. (A good reason in most cases.)
  2. Low production because upstream processes are not working correctly or because a precursor such as methionine doesn't exist in enough quantity. (A bad reason because the ongoing generation and regeneration of homocysteine and methionine from each other drives other crucial processes in the body.)
  3. A high rate of conversion of into sulfite/sulfate etc. (A bad reason if levels of sulfate, alpha-ketoglutarate or ammonia generated this way become toxic - more below.)
Let's look at the pathway in #3 because this is what I have researched when looking into my own issues and biochemistry,

There is an enzyme, CBS, responsible for the first step of conversion through this chain by turning homocysteine into an intermediate called cystathionine. As it happens, the CBS enzyme may be working too fast due to certain rather common variants of genes related to CBS activity. I have several of these variants (e.g., CBS C699T, A360A and BHMT 2,4,8) which make the CBS enzyme work up to ten times faster than normal.

When homocysteine is excessively pulled in this direction by CBS, the following compounds are created at possibly toxic levels:
  • Sulfite and ultimately sulfate - both toxic to the body, but sulfate less so. (When I recently peed on a test strip for sulfate, results came out very high.)
  • Alpha-ketoglutare - high levels can create excess glutamate in the presence of mercury and lead. Glutamate is an excitatory neurotransmitter involved in anxiety, ADHD, and pain sensitivity. (I have mercury fillings, by the way...)
  • Ammonia - high levels act as an irritant and may cause excess cortisol and contribute to the downward spiral of adrenal fatigue and hormone problems that is common in so many (euphemism for "virtually all") people. (Personally, I seem only mildly affected by this as my urinary ammonia is only slightly elevated, and my hormone profile fairly good.)
So what to do? It depends on the person (including which other road blocks are present) and how severe the problems are, but in outline one could, for example, do a ten day trial, reducing sulfur rich foods by say 2/3, while supporting the detoxification and elimination of ammonia and sulfur. (There are some protocols for this that go far beyond what I have room to discuss here.)

Pay attention to how you feel. If you feel worse, obviously stop. If you feel better, know that you shouldn't stay on a low sulfur diet forever (this will cause its own issues), but rather work with a practitioner to investigate how to improve your body's function in sulfur related pathways.

Take away points:
  • One can have low homocysteine and therefore receive a "clean bill of health", yet suffer from mild to severe health issues due to common metabolic pathway problems that result in low homocysteine.
  • If a person has homocysteine, say, below 6 umol/l (some practitioners say 7), it is reasonable to investigate underlying issues.

Saturday, November 24, 2012

The Curse of No Symptoms


A frequent misunderstanding in the world of health is that having no symptoms equals health. This is not so. Symptoms are often the last thing to happen when the is suffering from malfunction. Being symptom free can be a curse, because there are no warning signs until something dramatic happens. [Editor's note. I whipped this up quickly so I'm sorry for grammar/spelling errors.]

24_Lower_Centrals_PA.png
Signs of bone loss

Exhibit A (above):

At the dentist's office.
Dentist: "You look much younger than your age…"
Our Guy: "Well, yes, I take care of myself, and I probably have some good genes". [Delivered with a smirk - he's quite used to hearing this.]
Dentist: "Probably true, but do you see that dark space between the bone and the crowns?"
Guy: "Yes…"
Dentist: "That space is larger than it should be, indicating early bone loss."
Guy: "Oh..."


So why would a person, seemingly healthy for his age, have a problem with bone loss?

Well, on a broad health-philosophical level it boils down to this:

The curse of being relatively free of symptoms or external signs, but with underlying issues that doctors don't look for and that insurance companies will not pay anyone to look for.

Exhibit B:

Notice in his hair trace minerals test result below how all the minerals except copper are below the middle of the reference range. This indicates chronic and severe maldigestion. This guy is probably not absorbing enough nutrients to build and retain bone. (And if that's the case he might not be absorbing enough minerals for his body to fight diseases in the long run either...) Elevated copper also suggests chronic infection.

Screen_Shot_2012-11-24_at_4.08.51_PM.png
Chronic malnutrition 

Exhibit C:

Could an important source of this problem have been discovered years earlier? Yes, if doctors were trained to look at blood tests results over time and if they were trained in their interpretation for what we could call subclinical malfunction (= malfunction without telltale symptoms).

Case in point:

Research suggests that the more the standard blood work marker MCV ("Mean Cell Volume") becomes elevated above 90, B vitamin deficiency and/or H Pylori infection is likely.

H Pylori is a pathogen that primarily lives in the stomach where it  destroys the body's ability to produce stomach acid (HCL) which is needed for the breakdown of proteins and for the stimulation of the pancreas to release enzymes that digest foods and make their nutrients available to the body.

Screen_Shot_2012-11-24_at_4.02.14_PM.png
Elevated MCV = possible H Pylori infection

As you can see in the graph above showing data from several years' worth of blood tests, this 40-something's MCV values have been elevated for at least half a decade, and has also been creeping upwards, almost approaching 100 in 2011.

[Editor's digression: 100 is the point at which his lab results might raise his doctor's eyebrows. The doctor might then ask him to take B-vitamins, which as we will see would do nothing to address the actual underlying issue.]

Exhibit D:

Since our guy, apart from his exceptional youthful good looks, understood that these types of issues are never investigated or addressed by normal healthcare, he sought out a practitioner skilled in functional-nutrititional investigations.

[Editor's note: Excuse the didactic, self-serving tone here, but I'm very passionate about this. If you think that you will stay healthy through "regular medical checkups" alone, you are deluding yourself.]

Our handsome guy eventually got some testing done, including stool testing for GI pathogens.

Voila! H Pylori was found (and later killed):

Screen_Shot_2012-11-24_at_3.54.01_PM.png


I hope you can see how multiple pieces of evidence (dental x rays, hair samples, blood work) suggested and provided cumulative evidence for a problem, and ultimately led to the discovery of a key root cause? Cool isn't it?

Our guy is now on the following plan:
  • Digestive enzyme therapy and gut repair w. regular follow up testing.
  • Regular re-testing for recurrence of H Pylori. (Once reasonably sure that H Pylori is absolutely gone, he will also supplement with HCL.)
  • He will address the copper toxicity. (Copper accumulation leads to numerous problems in its own right.)
He knows that the process will take time, probably years. Repairing tissue and re-growing bone takes time, but he is also certain of a couple of big picture ideas about health and aging:

  1. What people call "aging" is often not aging at all. It is the resulting degeneration that comes from chronic exposure to things like food sensitivity, infections, and toxicity which gradually erode the health of the body.
  2. Being free of symptoms, whether it is because of symptom suppressing medications or because of one's body, for one reason or another, not producing noticeable symptoms (yet), is a dangerous proposition. (Who knows, if the H Pylori and digestive issues hadn't been discovered, our guy might suffer a "sudden" fracture a couple of decades in the future, or his teeth might begin to fall out of his mouth, or he might develop cancer because of a lack of proper nutrition.) [Editor's note: On the last point, read up on Bruce Ames' triage theory of aging.]

Bottom line: Disease prevention and functional investigation of one's body should ideally start long before one ever experiences symptoms.

Monday, October 1, 2012

Polyphenols and Xenohormesis (How resveratrol, ginseng etc work)

I often recommend botanical compounds called plant polyphenols as part of helping people optimize their bodies' ability to getting rid of toxins and/or dealing with oxidative- or other types of stress,

Examples of polyphenols are curcumin from turmeric, EGCG from green tea, resveratrol from grapes, and silymarin from milk thistle. There are also polyphenols belonging to the family of botanical compounds called "adaptogens". (The most famous adaptogenic plant is Panax Ginseng.) Coffee has polyphenols too.

I know from observational experience, looking at lab results, and the scientific literature that polyphenols of various types often work very well to achieve desired effects with minimal unwanted effects. (I would add, especially when used as part of defined "protocols" for specific purposes rather than random supplementation.)

So how do polyphenols work?

Aren't they just like weaker, more "natural" versions of designer pharmaceuticals (aka biochemical monkey-wrenches), and hence just as un-natural and potentially harmful?

Not so!

It has been discovered that polyphenols' main pathway of conferring their effects seems to be to send messages to our genes.

Polyphenols tell the body to start doing certain things; for instance to create more anti-oxidants, or to alter its response to environmental stress.

This is a different way of action than, for instance, providing essential nutrients for processes that the body is already striving to perform at a certain rate, or from substituting compounds that the body might make on its own.

Interestingly, our bodies seem primed to receive messages from these compounds (in fact specific receptors for some of them have been found), but why would our bodies want to listen to strange biochemical messages from plants?

One explanation, which I find biologically compelling, is xenohormesis, and it goes something like this:

Plants produce higher quantities of polyphenols when under environmental stress. This is why grapes growing under harsh conditions are used in the most sought after wines in the world (polyphenols provide "complexity" to the taste), and it is why Swedish strawberries taste better than any other strawberries in the world (or, maybe that's just my nostalgia…).

Now, when animals (including us), eat these polyphenol rich plants their bodies receive advance warning of forthcoming stressful conditions, and may then adapt accordingly on the genetic/biochemical level. Such advance warning is life-serving, so this is why our bodies evolved and retained the biochemical means to "listen".

Example:

When wine grapes are made to suffer nutritionally, they produce more of the polyphenol resveratrol in the response.

When an animal then eats these grapes, the extra resveratrol in them tells the animal's genes that famine might be coming.

In response, the animal's physiology re-orients towards famine conditions without actually experiencing a lack of food yet. The famine-reorientation sets off reactions that have been found to increase longevity. (You have probably heard about caloric restriction, or CR, as a way to prolong life.) In this way, resveratrol acts as a "CR-mimetic", ie., giving the benefits of starvation without the downside.

Cool, isn't it ?!

Now before you go out and buy resveratrol or other polyphenol compounds to take indefinitely, be aware that if you make your body up-regulate, say, certain longevity processes, it must at the same time down-regulate something else. (Are you prepared for the potential problems from messing with your physiology in this way?)

Actually, the body seems to have evolved clever ways to counteract sustained and therefore possibly disruptive signals from plants and their polyphenols.

For instance, what often happens is that unless a polyphenol compound is cycled on and off, there will be diminished effects over time. The body's receptors seem to become deaf to the signal. This also makes biological sense. Who benefits from someone yelling "Fire! Fire! Fire!" long after a fire must reasonably have been extinguished?

So don't think about polyphenol compounds as universal panaceas. You are not going to override the bad effects from eating at McDonald's by putting curry (curcumin) on the burger.

However do think about them as powerful tools with a low risk/reward ratio in the toolkit of health, performance, and longevity.

Friday, September 14, 2012

"Organic", is it worth it? Q/A Part III

[Also check out part I, and part II of this mini series.]

If toxicity depends on highly individualized factors, then what basic evidence should a person look for to indicate that it could be affecting him?

Aside from clear cut cases where removal of a suspect substance is immediately associated with better health, one's evaluation of the impact of toxicity isn't so much about getting conclusive evidence, but about stacking the cards favorably in terms of the totality of your lifestyle.

As with many things related to health, the cumulative effect over decades of affecting something seemingly marginal, is often astounding. This is why you can have two fifty-something siblings (or twins), where one is a health wreck, and the other perfectly healthy and fit. (The health wreck is typically the person who only thought in binary terms about health: "My doctor says I'm healthy, so I don't need to do anything", whereas the fit sibling is the one somewhat obsessed about health optimization.)

People ask me: "You look so young for your age, and you are so healthy, so why are you so picky with diet? Why do you take all these lab tests? Why do you eat fistfuls of supplements?". My answer is "Duh."

If farm workers who were exposed to pesticides got "alterations of the digestive, neurological, respiratory, circulatory, dermatological, renal, and reproductive system", and my goal is to be continue to be healthy and youthful for as long as possible, why shouldn't I want to minimize my own exposure to these substances if I can do so with minimal financial hardship or other negatives?

Anyway, I shall stop dodging your question. Here are some suggestions if you want some hard data to work with:

1) Check your genetics. Do a 23andMe. There are a couple of polymorphisms or SNPs such as APOE and MTHFR associated with poor detoxification capacity.

2) Run functional lab tests to assess your toxic load and excretion rates. Examples of such tests are hair minerals analysis, urinary organic acid tests, and tests for urinary lipid peroxides and urinary bile acids.

If your detoxification/excretion capacity is low, then you have a stronger case for working on reducing exposures and on improving detoxification/excretion.

Note that as a matter of sound therapeutic philosophy, removing overtly- or potentially harmful items (as determined by what our bodies could be reasonably exposed to be exposed to in evolutionary times) has the least inherent risk, whereas adding things like medications and supplements have higher risks because of their inverse U shape dose/benefit curves.

The first consideration in health is always to look at eliminating bad "stuff", before adding good "stuff" (over and beyond baseline nutrition).

Personally, since I have rather good genetics and decent hormonal- and gastrointestinal health, I don't actually obsess over buying pesticide free veggies, but rather take a middle of the road approach: I get some of my veggies form a CSA for part of the year, and I buy organic when a particular item is on the EWG's dirty dozen list. I supplement periodically with detoxification supporting supplements, and I do regular functional lab testing to monitor the status of important systems in my body.



"Organic", is it worth it? Q/A Part II

I got some intricate questions on my first post on this subject, requiring more intricate answers. :)

How does the quantity of ingested pesticides compare to the total quantity of toxins absorbed by a human being in realistic quantities?

First of all, toxicity as a phenomena is not an either/or issue. A given substance's toxicity is a function of dose and exposure time relative to the organism's capacity to handle that particular profile of exposure without compromising health. This means that quantifying the toxicity of a given substance in a generalizable way is often difficult. This is particularly so when we are considering substances that are not toxic enough to reliably kill in a small acute quantity, but that with some probability may cause harm with chronic exposures.

I think that the above problem of context and quantification is one of the fundamental reasons why there will never be complete consensus about the toxicity of substances that are not positioned at extremes of the toxicity spectrum (such as botulinum toxin and water).

Those who expose us to pesticides and other synthetic, or "evolutionary novel", substances (with or against our will), tend to declare these substances as universally safe. And they do so with reference to relatively high "LD50s" (median lethal doses), while downplaying the potential harm from chronic low grade exposure.

Those, however, who take the opposite view will point to subtle effects observed with lower dose exposures on factors such as cancer risk and various health markers. The doses that are used in such studies are typically quite high compared to typical "realistic" everyday exposure, as this approach may be the only way to achieve statistical significance in the presence of confounding variables. So, for example, to study the effects on toxicity in humans, investigators often chose to include people who, for instance, get occupational exposure to the substances on a frequent basis.

Each side of this debate can easily be accused by the other side of cherry picking data; to not account for various contextual factor; to use either too low or too high doses in experiments; to be biased for financial or ideological reasons, etc.

So (to get back to your question!) an attempt to make an inventory of all our exposures (through ingestion, inhalation and skin contact) and assign a universally applicable toxicity level to each of them is a difficult task to say the least, and probably not meaningful as individual variability in terms of both specific exposures and "total body burden" is so high.

Another problem related to both exposure and individual propensities is the compounding effect of all types of environmental stress including toxicity. The presence above a certain threshold level in an individual of a given toxin could make that individual more vulnerable to any, or all, classes of toxins than would otherwise be the case. For example, if a person is exposed to mercury from leaking fillings his antioxidant reserves may be depleted and not be sufficient to neutralize the load of other potentially toxic exposures.

So, should you worry more about the pesticides in your food than, for instance, the air pollutants that you inhale?

Generally speaking, I think that you must come to some reasonably accurate estimates of your specific exposures and your vulnerabilities, and act accordingly.

Identify and take care of the obvious problems first.

If you, for instance, smoke a daily pack of cigarettes, jog frequently in a high traffic zone, live in a mold infested home, drink contaminated well water, eat junk foods on a daily basis, or expose yourself to any other established health risk, you should probably change those habits before you even think about pesticides in your vegetables, or low grade air pollution for that matter.

In other words, prioritize getting rid of the big and sustained exposures, and then survey your entire "perimeter" for potential lower risk threats and eliminate them as far as possible and desirable. (Context beyond pure health considerations, such as time, money, etc, obviously plays in strongly here.)

Remember that if the totality of what you are doing for your health (including diet, exercise, sleep, stress reduction, supplementation) is enough, you should be free of all persistent symptoms of any kind; or, if you are not there yet, you should see a gradual improvement of any persistent symptoms that you do experience. You should see good or improving results on functional lab tests. You should feel good, or gradually feel better. You should get stronger in the gym, or at least not move backwards.


What is the basic evidence that pesticides ingested in realistic quantities are harmful for a normal person?

Aside from the fact that there is no typical person relative to low potency toxins, and that harm is a very broad concept, the first types of evidence to consider are studies on health markers in animals exposed to pesticides, and studies on populations with occupational exposure.

You will probably find that you can look at such studies and come to very different assessments depending on your perception of risk and of harm, but that there are a lot of indicative findings.

I think that from a biological perspective it makes sense to believe that the toxic burden from manmade chemicals that have been added to the the background burden of natural toxins over just, say, a hundred years, is likely to be a challenge to the human body. This is because our genes have not had sufficient time to develop adaptations to the new level of environmental toxicity and/or to specific types of new toxins.

It it also reasonable to believe that we are even more vulnerable to toxins now (vs. pre-agricultural eras) because of a higher load of chronic stress which degrade the body's overall resistance to challenges, including chemical challenges. Incidentally, a crude measure of detoxification capacity is the presence of bile acids and lipid peroxides in the urine, and these markers tend to improve with reducing psychological-, dietary- and other types of chronic stress.

(I'm not saying that early eras were free of stress - quite the contrary, but that chronic stress was less common, and I think that the basic evidence in support of this idea lies in the fact that the human body is very vulnerable to chronic stress.)

So, the core issue is not that our bodies are inherently unable to deal with a variety of toxins. The issue is how to not exceed its capacity to do so.

Further regarding capacity, one needs to also take into account that even if one's body can detox and eliminate a certain quantity of toxins, such "processing" occurs at the expense of other processes in the body such as repair and regeneration. The body can only do so much given the resources that it has at its disposal.

The same Bruce Ames as mentioned above has proposed a compelling "triage theory of aging", essentially pointing out that modest shortages of micronutrients (vitamins and minerals) are likely one important factor behind the rise in chronic illness and premature aging. (The idea is that when the body is low on micronutrients, it will prioritize their use for processes needed for survival in the moment above repair processes that keep us functionally young).

If we integrate Ames' theory with the biochemical observation that micronutrients are used up in detoxification processes in the body, we arrive at the conclusion that the greater our toxic exposure (regardless of source), the greater our need for micronutrients for keeping ourselves youthful and healthy.

A problem however with adding micronutrients (or other compounds) as one's sole strategy to deal with toxicity is that micronutrients also become harmful above certain thresholds that are dependent on factors in each individual (each person essentially has an "RDA" at any given time for all nutrients), so reducing one's total toxic load seems to be the prudent choice over (only) trying to throw supplements at the problem. (I'm all for supplementation under reasonably controlled and monitored circumstances.)

Now, aside from these more theoretical types of arguments, it is frequently reported by health practitioners that helping patients discover and eliminate various toxins (which may be current exposures, or toxins accumulated in the body) improves symptoms and health outcomes. Perhaps these patients represent a subclass of particularly vulnerable people, but, how do you know for sure that you are not one of them now, or will become one of them later?

[Also read part III in this series!]

"Organic", is it worth it? Q/A Part I

Q: Are organically grown fruits and veggies really healthier to eat? I mean, there's new research recently touted in the mainstream media indicating that their nutrient content isn't better than that in conventionally grown produce.  

Yes, I think that organic produce is generally healthier and safer to eat than conventionally produced products. This is basically because they tend to have less pesticides in them. (More about the nuances of this later in this post.)

This said, note that the label "organic" is sometimes applied to questionable products, and more so after the USDA got involved in handing it out.

Some excellent and conscientious food producers can't afford to (or don't want to) buy the label "organic" from the USDA-maffia, whereas some shady operators who don't give a sh*t about the health of their customers are able to get the label.

So the label "organic" doesn't mean that you can happily suspend your thinking about if a particular product is really good for you.

Q: So, labels aside, what kinds of produce should I choose for health purposes?

There are two major health considerations with all foods:

1) How much potentially harmful "stuff" is in it?
2) How much nutritious "stuff" is in it?

Regarding the first consideration, it has been found (HT: SuppVersity) in a comprehensive study that organic produce (that is veggies and fruits grown without synthetic pesticides) generally has orders of magnitudes lower pesticide content than conventional products. (Duh!)

Why does that matter?

There is a large body of research that indicates that pesticide chemicals, ingested in realistic quantities, may impair health in numerous ways.

Yes, it is also true (as the brilliant Bruce Ames showed) that plants themselves produce toxins that may be just as harmful as toxins that are man made.

HOWEVER: One's total body burden of absorbed toxins in relation to one's body's detoxification/elimination ability (a function of genetics, health status, and stress levels) is what ultimately counts.

Most of us live in environments which, by default, expose our bodies to a higher toxic load than they are "designed" to cope with optimally (especially if we want to live for a long time past our reproductive age).

If we want to stay healthy our task is therefore to keep the total body burden of toxins as low as (practically) possible, while, on the other hand, optimizing our bodies' ability to deal with the toxins that we can't (or don't want to) avoid. (The latter involves, for instance, making sure that our digestive-, hormonal-, detox- and immune systems work correctly. A wide subject.)

What about the second consideration (nutritional content)? How can I get the most nutrition out of my fruits and vegetables? 

To begin with, major factors that matter for the nutritional value of these foods are:

1) The nutritional quality of the soil in which the produce was grown. This factor is a function of what nutrients are already in the soil (how "depleted" the soil is), and of the type of fertilizer used during the growing process.

Regarding fertilizer, taking a biological viewpoint, I don't think that enough is known about nutrition to design a "multi-vitamin/mineral" for soils that produces as nutritious results as using, for instance, manure, or dead animals or plants for fertilizer.

2) The strain or variety that is grown, and its propensity to absorb and retain nutrients from the soil, as well as its ability to synthesize nutrients that we benefit from.

A focus on crop yields in the development of new strains (e.g., GMO) compromise these nutritional aspects.

3) The level of processing and transport that the produce undergoes before it reaches your plate. (The longer the supply chain, the less will be left of volatile nutrients.)

[Let me know if I missed or misinterpreted some aspect - I'm not an expert on agriculture!]

Regarding these nutritional considerations, I think that the label "organic" matters less than when considering toxic load.

Rather, the most important factor is probably large scale production vs. small scale local production - not necessarily "organic" vs. conventional.

Small farms typically (but not always) access less depleted soils to begin with, and if they also use good crop rotation practices and natural fertilizer (e.g., manure, and crop waste materials) their products should be more nutritious.

In addition, small farms, often try to compete by growing tastier products. This means using varieties which may grow slower than those used in large scale production and which both absorb and produce more nutrients. (Think about the difference in taste between the tomatoes that you get in Tuscany, Italy vs. supermarket tomatoes.)

Bottom line: (Here taking the luxury of considering health as virtually the only consideration.)

BEST: Locally produced fruits and vegetables from small farms that use "organic" practices and with a focus on taste, but not necessarily labeled organic. Ideally, visit the farm that you will be buying from. Make sure that it is not situated next to a major source of pollution. (I don't think I'd like to buy veggies home grown on a roof top next to a known polluter).

NEXT BEST: Items that are labeled "organic", but that are not necessarily local and/or small scale. 

NEXT NEXT BEST: Conventional produce products that are not on EWG's dirty dozen list. ( http://www.ewg.org/foodnews/summary/ )

[Also see part II, and part III of this mini series.]

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