Unintended Consequences
By Sandra M. Pinkham, M.D. 4-23-13
Introduction
Health care costs are at an unsustainable level and rising.
In a recent report sponsored by the Institute
of Medicine
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.
Conclusions
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.
