Tuesday, April 23, 2013

Unintended Consequences 4-23-13

Unintended Consequences
By Sandra M. Pinkham, M.D. 4-23-13

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). Something is seriously wrong. 

I have an idea why this is so: cadmium (Cd) air pollution.  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.

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 blood lead levels and various health effects. No such correlations could be found with 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. In the 1950's, Americans under the age of 50 had the highest life expectancy in world. At the current time, they are at the bottom for the developed countries.  We are also the country with the largest consumption of fuel.  However, as I will outline below, there are many aspects of life, other environmental exposures, genetics, gender, and age that increase or decrease a person’s individual response to cadmium 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  when global warming stopped, the variability of temperature  decreased and their 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).  I would like to show you the evidence for linking the removal of tetraethyl lead from gasoline with increased 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. As I studied the effects of lead and cadmium both in human health and the environment, I concluded that low level lead toxicity was actually due to Cd releasing lead from bone, where it is stored, into the blood. The quick disappearance of Cd from blood into the endothelial lining of blood vessels contributed to the failure to find it consistently in hair in my study and the general failure to associate low level cadmium exposure from air to health effects.

What is Cadmium?
Cd can be found in the periodic chart between zinc and mercury.  The best single book about cadmium is The Chemistry, Biochemistry, and Biology of Cadmium edited by Micheal Webb, 1979. It forms a covalent bond with chloride so that Cd Cl2 is a molecule like water and highly bioavailable. It tends to enter young cells with fluid membranes.  It can enter via multiple channels.  It can take the place of zinc but in doing so changes the activity of the enzymes. Cd, but not lead or mercury, is able to substitute for zinc in critical controls of cell functioning. 

In plant and animal studies it causes a stress response.  Stress and inflammation play a role in virtually all human disease. It is my hypothesis that Cd is the biochemical mediator of the stress response in all organisms. It enters cells when they are young and rapidly growing. It is kept sequestered but in any kind of stress it can become free to trigger the stress response and work together with other chemicals and metals. It can do this at very low levels, below the detection limit.  In cells that are adapted it may have little or no effect because it is bound.

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. This was shown in an animal study using radioactive Cd injected into the peritoneal cavity. The choroid plexus, in addition to producing cerebral spinal fluid, is a filtration system analogous to the kidney that 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 father’s 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. These protective and disease producing effects are well described by D. Breyersmann.

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.  It has very important effects on the immune system. When Cd is given to an animal which does not have the binding protein metallothionein it increases the activity of 78 immune regulating genes and decreases the activity of 35.

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, increase tumor‑necrosis‑factor alpha (TNF‑alpha), and lower vitamin D. 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 it increases the production of a metal binding protein called metallothionein, so that the stress response can be turned off. Although Cd is particularly toxic during pregnancy and early childhood, a pre‑exposure to Cd can increase resiliency and hardiness later in life.

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 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 ( personal communication with Genova Labs).

High glucocorticoids and low vitamin D have profound effects on the central nervous system. Low and high dose exposure to Cd in animals given by intraperitoneal injection produces 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 direct effects of glucocorticoids and low vitamin  D.

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. The Cd content of the heavier elements of the sun is 6%.  Solar winds could be one source of air Cd since polar animals have high levels of Cd in their kidneys. Volcanoes and forest fires are sources as well. Combustion of all kinds increases Cd in the air. One analysis of crude oil indicated it contained 32 ng/gm Cd.  Combustion of any product made from crude oil is thus a source of  Cd pollution. 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 in hot and windy conditions. 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.  The acid soil in which tobacco plants are grown increase Cd uptake.  Tobacco leaves contain 1mcg/gm or more Cd. Smokers have double the levels of Cd in their kidneys. The increasing level of nicotine in tobacco is likely a response to increased Cd exposure.

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.  Pelagic birds have exceptionally high levels of Cd in their kidneys with no apparent toxicity. 

Cadmium Effects on Global Warming
All life forms are exposed to and have a capacity to deal with Cd. Archae are widespread ancient microorganisms that share with prokaryocyles the lack of a nucleus and share with eukaryocytes the genes for DNA repair and signal transduction pathways. They are known for their ability to survive extreme environments.  It is plausible to believe that they adapted to use Cd . These organisms use carbon, nitrogen or sulfur to generate energy instead of oxygen. The methanogens generate methane, natural gas. The ones that use nitrogen produce nitrites and ammonia.  The ones that use sulfur produce sulfuric acid.

Methane is a major contributor to greenhouse gas. Scientists estimate that archaea make up 16% of the earth's biomass.  An effect of Cd stimulating the growth of methanogens would promote global warming by increasing production of methane gas. Ruminants contain these organisms in their gastrointestinal tract. The methane they produce is a major contributor to greenhouse gas emissions in New Zealand. Tannins administered to these ruminants decrease their production of methane. A plausible explanation is that tannins, known to bind Cd, decrease Cd's ability to stimulate the growth of the methanogens.  It is equally plausible to suggest that when lead formed a particulate with Cd that there was less stimulation of global methanogens.

Plants affected by Cd can decrease photosynthesis, the process which takes up atmospheric CO2 and changes it into food and oxygen in the chloroplast. Cd can increase photo‑respiration which generates energy by consuming oxygen and producing CO2, increasing atmospheric CO2. So plants affected by Cd also contribute to global warming. Similarly, when lead formed a particulate with Cd, it is plausible to suggest that there was less Cd stimulation of photo‑respiration increasing global CO2.

Attention has been given to the direct production of CO2 by combustion of fuels. What has been overlooked has been the release of Cd in combustion. By further increasing methane and CO2 in living systems around the globe, Cd emissions can be predicted to accelerate global warming.

This very significant effect on global warming is currently not being evaluated by any scientist concerned with studying this problem.  The excuse is that there is not sufficient proof that Cd is playing a role. The reason Cd pollution has not been addressed is that the filters used around the world to measure Cd emissions were designed when tetraethyl leaded gasoline was in use. Lead/Cd particulates are caught in these filters.  With the removal of lead from gasoline, the filters do not measure Cd pollution accurately.

There are problems with direct measurements of Cd.  Specimens collected in the environment are typically dried at high temperatures which can drive off volatile Cd compounds. It is possible to take advantage of the effect of Cd changing the copy number of genes for Cd binding proteins.  In algae , for example, one could determine this copy number to assess increasing levels of free, bio-available Cd.

With the understanding of the role of Cd in global warming, it will be possible to devise better solutions for this pressing global problem. Could one solution be the resumption of tetraethyl lead in gasoline at some level in some environments?  Could targeted lead air pollution block Cd emissions from coal burning power plants by forming particulates that could be trapped better in filters?

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 a testable hypothesis that could lead to improved treatment.

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 could 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. Vitamin D decreases the risk of getting influenza. Not only is the public not educated on the ways to stay healthy by increasing their vitamin D but they are getting the message that the only approach to decreasing the flu is to wash hands and get a flu shot.

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 in mice fed gluten containing feed.  This flora is found in pregnant women in the last trimester and in individuals with metabolic syndrome. E.Coli contain lipopolysaccharide a chemical that increases an inflammatory substance called Tumor-necrosis-factor-alpha.  Vegetables promote a different bacterial composition that doesn't have these effects. It is possible that 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.

Plants can adapt to Cd and thrive. The aggressive invasive plants need to be studied for Cd resistance. This is not being done. Other plants are being stressed and suffer from disease and death. Currently, forests are under stress from climate change, flooding, drought, and infestation by beetles and fungi. Beetles bind Cd into their chitin. They easily adapt to Cd. Fungi are well‑adapted to detoxify Cd with Cd binding proteins, as well.  The nitrogen fixing archae in forests can be inhibited by too much Cd, which deprives the trees of needed nitrites. 

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. However, in a study of embryonic stem cells, exposure to cigarette smoke and to cadmium alone caused shortening of teleomeres.

Cadmium Synergy

Of all the toxic metals, Cd has been shown to enhance the toxicity of metals like arsenic, nickel, and chromium. It 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 and they ignore the synergistic effect with Cd.  

Cadmium and Metallothionein
Another factor that makes Cd exposure and toxicity complicated is the interaction of Cd with the metal binding protein, 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. 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  metallothioneins is much more responsive to Cd than to zinc, which is consistent with Cd's role as  mediator of the stress response.  When Cd and mercury are released from metallothionein by any of a 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.

Health Changes since Lead Removal form 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 were found to have 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 can not 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.

There has been a dramatic increase in the finding of low levels of 25‑OH vitamin D 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. Instead the removal of lead appears to have had the unintended consequence of increasing the availability of Cd to cause toxicity 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 low 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 for free 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. 

To moderate the rising cost of health care, to improve the health and life expectancy of young people and at the same time address multiple environmental problems it is imperative that regulatory agencies recognize that the unintended consequence of the removal of lead from gasoline has been the increased availability of Cd. Cd must 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. It is magnifying the toxic effect of other metals, chemicals, viruses, bacteria, archae, fungi, protozoa, and parasites around the world. 

Air pollution makes our planet a global village. As members of this village,  everyone needs to be concerned that there is a stress agent in the air we breathe that is hurting our children  and our  planet.

I am writing this account so that you, the reader, will understand that if you don't take action to urge our institutions to deal with this problem we will continue to fail to lower health care cost and fail to curb global warming. Severe droughts are devastating to agriculture as are beetle and fungal infestations. Fracking needs to be studied from the point of view that since methane is produced by methanogens, there is a possibility that Cd pollution could occur when it is retrieved. 

There is really no problem that is not being made worse by Cd air pollution even though some individuals are able to adapt and thrive. By causing stress all aspects of our planet are affected. It is imperative that the global blind spot regarding Cd air pollution is replaced by a broad based initiative to address this problem and all its ramifications.