Tuesday, January 28, 2014

Unintended Consequences revised 1-28-14

Health care costs are at an unsustainable level and rising. In a recent report sponsored by the Institute of Medicine and the National Research Council, Americans under the age of 50 at this time have the lowest life expectancy in the developed world, even though as a nation we spend the most on health care (New York Times (NYT) 1-10-13).  Americans over 75 have increased life expectancy. Something is seriously wrong.  Moreover global warming is causing havoc around the world. Can these two problems have something in common?

It is my hypothesis that climate change,  increase in invasive plant and animal species, decline and extinction of species, and worsening human health are all linked to the increase of cadmium (Cd )in air which affects every living system on our planet and is not adequately measured with air filters designed when lead/Cd precipitates were present in air.

There was an experiment with our planet earth from 1920 until 1980 and a little beyond.  Tetraethyl lead was used in gasoline.  This polluted the air with lead.  Blood lead levels increased in children. In the mid 70's a doctor became convinced that low level lead toxicity was the cause of problems in children. Toxicologists and epidemiologists found that there was a linear correlation between low blood lead levels and various health effects. No such correlations could be found with low blood Cd levels. Extensive research was done and lead became the number one pollutant of concern by the US Environmental Protection Agency. Everyone was informed that lead was very dangerous and regulations were put in place.  Testing of blood lead levels was mandated.  In 1980 lead was removed from gasoline in the United States and by 2000 virtually all countries had removed lead from gasoline.

When lead was removed from gasoline, blood lead levels in children dropped dramatically. It was still possible to find that a small elevation of blood level above the background associated with adverse effects. The drop in blood lead levels was not associated with improvements in mental or physical health as predicted by the research correlating blood lead with these problems.  This is evidence that lead was not the cause of the health effects correlated with blood lead levels.  A better explanation is that toxic effects of low levels of Cd caused the linear correlation of blood lead levels under 15 mcg/dL with health effects.

 In the 1950's, Americans under the age of 50 had the highest life expectancy in the world and the highest exposure to lead air pollution in the world. At the current time, they are at the bottom for the developed countries.  Now our exposure to lead is very low and Cd air pollution is rising.  By understanding sources of  Cd air pollution,  one can say levels in air are rising even though the levels as measured by the air filters are not increasing.  We are the country with the largest consumption of fuel.  Crude oil is not typically analyzed for Cd levels but one sample had  32 ng/gm Cd. Cd is capable of having effects at picomolar levels, a very low level of exposure. It is impossible to directly measure Cd below nanomolar levels.  There are many aspects of life, other environmental exposures, genetics, gender, and age, which increase or decrease a person’s individual response to Cd air pollution.

These variable factors that influence an individual’s response cannot explain the effects of removing lead from gasoline on global warming. From 1960 to 1980 when lead air pollution was at its highest, there was a period in which global warming stopped, temperature variability decreased and there were no droughts. After 1980 the temperature started climbing again, there was more variability and in 2012 the global temperature was the highest in the last 110 years and the US experienced a devastating drought ( Wall Street Journal 1-9-13).  The removal of tetraethyl lead from gasoline increased the bio-availability of Cd air pollution.

I became interested in Cd in 1986 when I found that high achieving children in a white upper middle class suburb had the lowest levels of hair lead and Cd while the lowest achieving children had double the mean values. The correlation was significant for hair lead but not for hair Cd because of the high variability in hair Cd levels. I thought at first that this study provided evidence for a very low threshold for a toxic effect of lead. The children were exposed to a trash burning power plant that had been in operation for two years at the time of the study. This was a source of Cd pollution not lead.

 I studied the effects of lead and cadmium both in human health and the environment. I spent 10 years reading every research paper I could find on effects of cadmium on algae, bacteria, viruses, plants, fungi, marine life, rats, fish, birds, and humans before internet searches made this easy. In addition to the hair analysis study I worked with a psychologist looking at effects of lead and cadmium on the performance of rats on a learning task. The rats exposed to lead had no deficits. With increasing dose (10ppm to 50ppm Cd in drinking water) the rats had increased variability in their performance. The low dose exposure rats had increased weight compared to control and the high dose had decreased weight. One of the Cd exposed rats died of heart disease. Hair levels of Cd were not significantly associated with exposure.  I measured the level of Cd in tree leaves and found the levels were comparable to areas in heavily Cd exposed environments. As a physician, working with over 11,000 patients over the last 25 years  I  have had an opportunity to see how exposures to active and passive smoke, life style, age, gender and genetic background can affect behavior and health. 

By connecting the dots of many pieces of evidence I conclude that the best working hypothesis for understanding Cd is to see it as the biochemical link that explains evolutionary processes and cycles of global warming and cooling.  It is the link that provides a mechanism for how stress of any kind can to lead to both disease and death and recovery and resiliency.  It explains why the young would be particularly vulnerable to increased exposures and the old would be more resilient.  This metal is dispersed globally in air and I am proposing it has global effects on all biological systems.  A global hypothesis will have global implications.  The scientists who influence public policy have not been open to this global hypothesis and its global implications.  However, we are all breathing the earth's air. It behooves everyone to examine the evidence.

What is Cadmium?
Although Cd is grouped with the heavy metals, it has unique properties that need to be understood. If you do an internet search you can find many articles. The best single book about Cd was edited by Michael Webb in 1979 (The Chemistry, Biochemistry, and Biology of Cadmium). References through 1996 can be found in my published and unpublished papers on my web page. Internet searches can provide documentation of the effects of Cd on stress, signal transduction, gene expression, synergies, and association with cancer, bone disease, and low vit D.  Recently, it has been possible to see a linkage of low and high quartiles of blood or urine Cd and behavioral effects and linkage with cancers (breast, ovary, prostate, lung, pancreas, and kidney, at least). But by looking at linear effects of low dose blood or urine Cd levels one fails to find correlations with disease in humans.

What does Cd do?
Lead is handled by the body as calcium. Ninety to  95% of lead in non-occupationally exposed persons is stored in bone.  Cd decreases the mechanical strength of bone and increases bone resorption. Experimentally, it significantly lowers 25-OH vitamin D, especially in rats made vitamin D deficient. These effects on bone were not due to low vitamin D, however, but to the actual exposure to Cd. In humans smoking is a well recognized risk factor for osteoporosis.  Smoking is a very efficient Cd delivery system.   Although there are 2,000 chemicals in tobacco smoke there is no precise mechanism for any of the others to have this effect. So Cd, if it is not bound up by the special metal binding protein metallothionein, can release lead from bone, where it is stored, into the blood. In any given environment of lead exposure a small but significant elevation of blood lead can (and I predict from my hypothesis does) denote a toxic effect of Cd on bone. In other words, low level lead toxicity was not measuring toxicity from very low levels of lead exposure but was instead measuring the increases in bone resorption from free Cd releasing lead into the blood. When lead exposure fell there was no improvement in health.  The toxic effects found  with  low level blood lead levels under 15 mcg/dL, which are very well documented, are in actuality the effects of low dose free Cd and not low levels of lead exposure. 

Why Can't Cd Health Effects be directly Linked to Blood and Urine Levels?
Although 50% of Cd coming from air into the lung is taken up by the body, it quickly is taken up by the endothelial lining of blood vessels.  Evidence for this is that at autopsy, the level of Cd in cadaver blood in the heart and blood vessels can be 100 times higher than levels found in living humans. The dispersion of Cd into the endocrine system and the choroid plexus was noted in an animal study in which radioactive Cd was injected into the abdomen. This route by-passes the GI tract where one gets just 5% uptake and absorption into the liver, a major source of binding to metallothionein. The quick disappearance of Cd from blood into the endothelial lining of blood vessels makes direct measure blood Cd a poor measure of low level cadmium exposure from air. Moreover, the ability of metallothionein to bind it up breaks up a direct link between exposure and health effects.

Cd, but not lead or mercury, is able to substitute for zinc in critical controls of cell functioning. Cd, but not lead or mercury, gets into the lining of blood vessels and into the endocrine organs throughout the body and the choroid plexus. The choroid plexus, in addition to producing cerebral spinal fluid, is a filtration system, analogous to the kidney, which maintains the environment required by the brain to function optimally.  Therefore, though Cd does not directly get into the brain, it plays an important role in affecting mental health.

Cd has well studied biological effects in all living entities. It can interfere with DNA repair. This contributes on the one hand to evolution. However, increased mutations are found in sperm of fathers with children with autism. It is feature of influenza virus and also HIV-1, the major cause of global AIDS.  Some of the most aggressive cancers are associated with increased mutations.

Cd has bidirectional effects on cell signaling pathways.  Therefore, one would not expect a linear correlation of effects with exposure. On the contrary, it increases variability and flattens the Bell curve of distribution. It increases extremes. If one is looking for proof by looking for significant p values, one would conclude that there is not sufficient evidence to implicate Cd. Instead one must look at the signaling pathways that have been so clearly delineated in recent years.  Cd has very important effects on the immune system. Forty-eight genes associated with immune regulation are affected by cadmium. 700 genes are affected by Cd.

Cadmium’s Role in Stress
Cd gets into the nucleus of the cell and turns off the housekeeping genes and turns on the stress response genes. It can increase intracellular calcium, deplete glutathione, a potent anti-oxidant that protects mitochondria,   and increase tumor-necrosis-factor alpha (TNF-alpha). These are cellular manifestations of stress. It can increase catecholamines and glucocorticoids, hormonal mediators of stress. 

Cd can be looked upon as a messenger of the stress response. The inflammatory effects are necessary to trigger repair from injury but if not handled properly by the host can lead to disease or death. To control the stress response Cd increases the production of a metal binding protein called metallothionein, so that the stress response can be turned off.

The timing of exposure is critical.  Cd is particularly toxic during pregnancy and early childhood.  A recent study showed that prenatal exposure to increased  motor vehicle fumes and exposure in the first year of life triples the risk for autism. They did not associate this finding with Cd in the particulates but the exposure was there. The particulates come from combustion of materials containing Cd.  Current filters don’t trap the fine Cd fumes.  Exposure later in life, on the contrary, can increase resiliency and hardiness.

In the setting of chronic stress, mental or physical, there is a chronic elevation of glucocorticoids which break down proteins, preventing the binding and detoxification of Cd. High glucocorticoids short term are protective against acute Cd toxicity. Chronic high glucocorticoids are associated with physical problems such as poor outcome in pneumonia and acute myocardial infarction and mental problems like anxiety, depression and psychosis.  In studies of urinary hormones, there is a national tendency for an increase in glucocorticoid hormones that breakdown proteins over anabolic hormones that build them up.

High glucocorticoids have profound effects on the central nervous system. Low and high dose exposures to Cd in animals given by intraperitoneal injection produce free radicals in the brain and the effects are long lasting. It is possible these effects involve its presence in the choroid plexus as well as effects of glucocorticoids and other stress induced changes.

Sources of Cadmium
Cd is a global, ubiquitous pollutant that has been present in earth's environment since the beginning and it certainly could be a contributor to evolution. Volcanoes and forest fires are sources. .Massive Siberian volcanic eruptions are implicated in the great extinction ending the Permian period.  Combustion of all kinds increases Cd in the air.  All metal industries release Cd fumes. Animal wastes and phosphate fertilizers contribute Cd to soil and water. Through plants it can be transferred to air. Indoors Cd is incorporated into house dust, molds, and danders: common allergens. Outdoors it increases in pollen. Lead exposure actually decreases the Cd content of pollens.  Cd increases the allergenicity of pollens.  For humans, tobacco smoke has always been a source of Cd air pollution.

There is a Cd cycle. In the ocean, Cd is a growth stimulant for plankton. They in turn are eaten by krill.  Birds eating krill deposit guano, a source of super phosphate fertilizer and especially high levels of Cd. All phosphate fertilizers contain Cd because it is present in phosphate rocks.  Tobacco is high in cadmium because the plant concentrates Cd in its leaves. The increasing level of nicotine in tobacco is likely a response to increased cadmium exposure.  The increased toxicity of tobacco smoke recently described is most likely due to the absence of lead that formed a particulate with cadmium, decreasing its absorption.

Cadmium Effects on Global Living Systems
Protozoa feed on bacteria. Cd inhibition of their ability to ingest bacteria can lead to bacterial overgrowth. Bacteria can become resistant to Cd, in doing so they can acquire genes in plasmids that increase their virulence. They can also acquire the multiple drug resistant pump which is also the pump used to exclude Cd from the bacteria. Super-bugs are a major problem. No one is currently looking at the Cd content of these bacteria or how Cd exposure affects their acquisition of drug resistance. This is something that needs to be done. 

Cd can also increase the infectivity and virulence of viruses. The scourge of AIDS developed since 1980. There have been no studies of the effect of Cd on infectivity or virulence of HIV.  They should be done. Cd has been shown to activate Herpes from a dormant state.  Shingles is very common. Physicians and patients are completely unaware of the connection.

The gastrointestinal microflora has a profound effect on human and animal health. Dairy, wheat, and sugar increase the expansion of intestinal gram negative E.coli. This results in weight gain, inflammation and insulin resistance. Vegetables promote a different bacterial composition that doesn't have these effects. It is possible that these bacteria sequester Cd in food, water, and bile secretions so that Cd is released from the host into the stool.  No one is doing these studies at this time. Gram negative bacteria contain lipopolysaccharides (LPS). LPS are synergistic with Cd.  Binge drinkers can drink enough alcohol to kill these bacteria, releasing LPS and Cd, causing liver injury.

Beetles are thriving. They are well adapted to Cd because they bind Cd into their chitin. Fungi are well-adapted to detoxify Cd with Cd binding proteins, as well. Cockroaches are flourishing and aggravate asthma and so do dust mites. Bedbugs have become a major problem.  According to Wikepedia, infestations were decreasing in the developed world from 1930 to 1980 when lead pollution could have inhibited them and they have been rapidly expanding since1980.  Tick borne diseases are a serious problem. Head lice are getting more difficult to treat.  

Just as all other organisms are affected by Cd air pollution, humans are as well. Since 1980 there have been very dramatic changes in health. Although these changes have biochemical links to Cd, scientists have not had definitive proof. The lack of recognition of Cd's role in human disease is due to the poor correlation of direct measures of blood, urine, and hair Cd levels and health effects, while correlations are found for lead and mercury.  Moreover, the conclusion that Cd was not an important source of Cd exposure was made when lead was present in gasoline. In heavy industrial exposure or contaminated water its toxicity was well-recognized. Tobacco smoke was also known to be an important source of Cd exposure and adverse health effects. Because of the large number of pollutants in tobacco smoke, it was not considered possible to attribute effects of tobacco smoke to Cd.

Cadmium Synergy
Of all the toxic metals, Cd has been shown to enhance the toxicity of metals like arsenic, nickel, and chromium. The combined exposure of lead, arsenic and Cd cancels out toxicity.  Cd and arsenic together without lead have a synergistic toxic effect.  Cd alters the metabolism of organic chemicals. The two together can be toxic at doses that would not cause toxicity if there was exposure to either one alone. Many of the endocrine disruptors have this synergistic effect with Cd, which is also classified as an endocrine disruptor.  It is also synergistic with nicotine.

With the current ability to look at gene effects and signal transduction effects in experimental systems, it has been possible to show that toxic effects of tobacco smoke are mediated by Cd.  The US EPA is struggling to find what dose of the various chemicals in the environment may be toxic. They attribute blood levels to exposure, ignoring the effect of Cd on increasing blood levels of the chemicals.  Because they don't see correlations with Cd in blood or urine, they ignore the synergistic effect with Cd. 

Cadmium and Metallothionein
The effect of metallothionein on Cd , mercury and arsenic is critical for understanding the synergy with these metals.  These metals and copper are bound by metallothionein, the principal metal binding protein in animals. Zinc induces the basal isoform and Cd is the strongest inducer of the inducible isoform. There is an entire book devoted to the intricate interactions of hormones, radiation, and toxic insults that affect metallothionein.

A major pollutant of concern that is present in processed food, bis-phenol A, inhibits the ability of liver cells to make metallothionein.  This would increase free Cd exposure and increase liver toxicity. The USA has the highest consumption of processed food on the planet. Metallothionein is very responsive to stress. Hormones, oxidative stress, radiation, all kinds of stresses affect the production of metallothionein. It binds, zinc, copper, arsenic, mercury and Cd.  But the promotor of the gene for one of the metallothioneins is much more responsive to Cd than to zinc.  This is consistent with Cd's role as mediator of the stress response.  It helps turn off the stress response. In chronic stress with chronic elevation of glucocorticoids metallothionein is broken down.

When Cd and mercury are released from metallothionein by any of number of factors, mercury, which is less bio-available, will hang around in the blood and be excreted in the urine while Cd will disappear from the view of toxicologists by uptake into the lining of blood vessels and the choroid plexus.  The dose response that toxicologists find for blood mercury has lead to its placement above Cd as a metal of concern, ignoring the synergy that is generally present when blood mercury is elevated.  In a recent study maternal blood mercury was a marker for a toxic effect in the baby but actual increased mercury exposure by the mother's eating more fish led to a decrease in toxicity.  Rather than monitoring exposure, the maternal blood mercury was monitoring release of mercury from metallothionein.  Routinely, mothers are told to limit consumption of fish because of concern about mercury exposure when actually eating fish is healthful for them and their babies.

Health Changes since Lead Removal from gasoline
In the thirty years since lead was removed from gasoline the world has seen many adverse health effects. In addition to the global emergence of HIV, autism has increased 3 fold.  In 2012 children in the highest quartile for blood or urine Cd,  had a three-fold  increased risk of placement in special education. This is confirmation of the small study I did in 1986.  Clearly, Cd is having a negative effect on the brain health of children.

If one looks at mass shootings, the majority have occurred since 1980.  Violence is a major problem that is of great concern to all of us. Violence has been found by Dr. Daniel Amen to be associated with poor blood flow to the left amygdala and the left prefrontal cortex. We cannot prevent gun violence by back-ground checks of gun buyers. We need to educate gun owners of the need to keep their brains healthy by avoiding alcohol, getting a good night sleep, eating a healthy diet and learning to skillfully manage stress.  The Dept of Defense needs this information to assess recruits and to monitor soldiers in combat and returning from tours to prevent suicides and homicides. Violence is one of the factors lowering the life expectancy of those under the age of 50.

Cadmium and low 25-OH vit D3
There has been a dramatic increase in the finding of low levels of 25-OH vit D3 in all kinds of chronic diseases that are major contributors to the dramatic increase in health care expenditures. These diseases are autism, Alzheimer's disease, obesity, diabetes, cancer, auto-immune disease, severe allergies, gluten sensitivity, epilepsy, kidney disease, insomnia, anxiety, depression, ADHD, alcoholism, drug addiction, psychosis, traumatic brain injury, degenerative joint disease, chronic fatigue, etc. The list goes on and on. All these diseases are in some way associated not only with low vitamin D but also stress and inflammation. They are clearly not caused by lead exposure although they may be associated with mild blood lead elevations. Instead the removal of lead from gasoline appears to have had the unintended consequence of increasing the availability of Cd.  Cd can lower vit D and cause stress and inflammation. It can cause all these problems in association with many other factors.

Implications for Improving Health and Lowering Health Care Costs
To paraphrase Tolstoy in Anna Karenina, healthy individuals are all alike. Their genetic make-up, life style, social support, and stress management techniques protect them from Cd induced chronic stress, inflammation, and reduction of vitamin D. Unhealthy individuals are unhealthy in a myriad of ways. Low vitamin D and markers of chronic stress and inflammation point to a role for Cd in their disease.

To lower health care costs, a wellness check should focus on whether vitamin D levels are in the mid range between 50 and 70 ng/mL without large doses of supplemental vitamin D. Signs and symptoms of physical or mental stress should be assessed. Deviations from the mean in blood parameters, insomnia, chronic fatigue, muscle weakness, chronic pain, high or low BP, high or low adipocity, high or low body temperature could all be used by health care providers to identify the population at risk for adverse health effects. A ten minute wellness check focused on updating immunizations and treating high BP and high cholesterol with medications instead of life style changes is not going to reduce health care costs. 

Double blind controlled trials have been considered to be the best way of coming up with effective treatments for individual diseases when the cause of disease was not understood at a biochemical level. At this time much more is known about the cause of disease. There are many modifying factors in individuals. These trials are not enabling physicians to discover the most cost-effective ways of promoting health or treating chronic disease in specific patients. Using a single subject design, one can observe abnormalities at baseline, institute a therapeutic plan in cooperation with the patient and follow the outcome to determine efficacy. By looking at gene expression in circulating tumor cells in patients with pancreatic cancer, physicians were able to predict the best treatment and determine when changes needed to be made.

The current emphasis on coding for specific diseases is driven by the conviction that diagnosis of disease determines the appropriate treatment based on evidence from double blind controlled trials. Instead, physicians need to really listen to their patients and work with them to find ways to work with the body’s natural healing ability to promote mental and physical health. This is not the direction being fostered by Heath Care Reform.

Ophthalmologists are able to directly observe blood vessels. They have found changes observable in the eye predict chronic disease. Robert Ritch, a Canadian Ophthalmologist describes 22 natural compounds that are protective to the eye. They have virtually all been found helpful in experimental studies of Cd toxicity. As non-patent-able natural products, they are much lower in cost that pharmaceuticals, usually.

Physicians need to be aware of these helpful tools that could safely be used in a single subject research design.  Any time a patient is given a drug. It is an experiment.  Just because the drug has been tested in a very large double blind controlled study does not mean that a patient given that drug will have an optimal outcome.  The unintended consequence of using statins is muscle pain in patients that have low muscle carnitine at baseline. Those with low co-enzyme Q10 also suffer from statin side effects.  Neither carnitine nor co q 10 are measured before giving patients statins.  Excessive lowering of blood cholesterol has the unintended consequence of increasing depression, Alzheimer’s disease and cataracts.   Fish oils lower the inflammatory cytokine interleukin-6 which statins also lower but without these side effects.

If individuals  were given a tax credit of $2,000 per person to use for nutritional supplements, vacations, massage, hypnosis, acupuncture, yoga, gluten free foods, whatever they felt was necessary for their health. It would help to motivate them to see that their behavior has a major impact on their health.  Universal health Insurance does not lower health care costs. But changing individual decisions about diet, exercise, smoking, alcohol, recreational drugs, nutritional supplements, and stress management can improve health and lower health care costs together with a high deductible universal health insurance. 

There is a new clinical trial using a pharmaceutical drug for Alzheimer's disease. The double blind trial will be expensive and if efficacy is found, insurance companies will be obligated to cover a very expensive drug for a common disease. In a recent study, vitamin D3 and curcumin, a tumor necrosis factor inhibitor, enabled macrophages to ingest amyloid, the toxic product that builds up in Alzheimer's disease. Giving sufficient vitamin D3 to maintain levels at 50-70 ng/mL and sufficient curcumin to inhibit TNF-alpha to patients at risk for Alzheimers would be a much less expensive approach. The doses would need to be individualized. Recognizing that Alzheimer's is a Cd induced disease would trigger additional interventions, such as the supplements reviewed by Dr. Ritch.   Already noted to be helpful are the following: a healthy diet, avoiding processed, inflammatory food, keeping blood sugar stable with multiple smaller meals, exercise, social engagement, and novelty.

The unintended consequence of the removal of lead from gasoline has been an increase in global warming and a drop in vitamin D levels in virtually all chronic diseases.  These changes parallel an increase in the bio-availability of Cd and an absolute increase in Cd pollution driven by population growth, industrial activity, and intensive agriculture with phosphate fertilizers.  Clearly, low level blood lead elevations are a marker of a toxic effect of Cd on bone rather than exposure to environmental sources of lead. Mild elevations in blood mercury can be a marker for breakdown of metallothionein and not always environmental mercury exposure. Elevations of blood arsenic should raise suspicion that free Cd may be elevated as well. Such suspicions can be reinforced by finding low 25-OH vitamin D3 levels or other indications of stress. 

No single line of evidence is conclusive. With the weight of evidence along so many lines of inquiry there is enough evidence to conclude that Cd needs to become the number one pollutant of concern.  It is an essential component of the stress response. Both too much and too little can be a problem.  Currently, there is too much.  All disciplines need to become knowledgeable about its far-reaching effects in order for our policy makers to come up with successful strategies to  improve health, lower health care costs, and prevent devastating global warming.  A global air pollutant doesn't work alone. It is magnifying the toxic effect of other metals, chemicals, viruses, bacteria, archae, fungi, protozoa, and parasites around the world.