Introduction
Health care costs are at an unsustainable level and rising.
In a recent report sponsored by the Institute
of Medicine
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.
Conclusions
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.
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