Sunday, December 4, 2016

Revising what is known about cadmium

Cadmium is element 48, in the middle of the natural elements of the periodic chart. Vertically, it lies between zinc and mercury but it is quite different from both in its chemical and biochemical properties.

Cadmium, but not zinc or mercury, captures a photon of light producing the largest band gap. This makes it very useful in night vision for the military and as a component of solar panels. It is essential in technology.

It is not thought to have ANY essential biological function. It is looked upon as a highly toxic substance, which it is.  As an air pollutant in tobacco smoke it doubles the cadmium content in the kidney and in the placenta.  It is present in a very fine particle size in tobacco smoke.

There are no filters in use designed to analyze the amount of cadmium exposure in air coming from such particles. The analysis of 2.5 micrometer particles has a drying step that can lead to losses of cadmium species. When lead chloride was in the air from combustion of leaded gasoline the lead cadmium particulates were measured.  With the elimination of lead the cadmium measurements show a fall in cadmium exposure from air.  When one looks at the known sources of cadmium air pollution coming from combustion and from the planetary biome,  there is no reduction.

Cadmium is a known stress agent in all organisms. Stress is actually a necessary function of all living entities. It is the pathway to resiliency and hardiness.  That is an essential feature.  Cadmium can combine with other metals , chemicals, heat, cold, UV, endotoxins from bacteria and fungi and all kinds of other stressors.  The combined effects can cause far greater harm than they could  alone. But cadmium can activate pathways that are protective against certain cancers and infections. It truly has bi-directional effects.

What is even more remarkable is that this ability to capture a photon of light and turn it into chemical energy, may have made cadmium indispensable in evolution. The energy that it can provide is equivalent to that of one ATP molecule. Just this year (K Brown 2016)  cadmium sulfide was used to furnish the energy for a reaction that normally requires ATP.   Before mitochondria evolved, cadmium sulfide could provide energy to make molecules.  The first molecule that is both a structure that stores information in its sequence of nucleic acids and acts as an enzyme is the ribozyme. Cadmium binds to the nucleic acids of this structure and increases  its  catalytic function dramatically (Sigel  2013).

Cadmium has a  strong affinity for the amino acid cysteine, especially in peptides and proteins. This amino acid has a dominant role in cell biology ( Z. Chen 2001, V Laverne 2012).  Cadmium is always in the cell. It is present in sperm and ova.  A cysteine rich  enzyme is needed for the sperm to penetrate the tough lining of the ovum.

Cadmium triggers the gene expression of proteins needed for rapid cell division. Because it also triggers the gene expression of proteins that result in cell death, the amount of free cadmium in the cell must be carefully controlled.  In rapidly growing cells it is able to enter the cell through multiple pathways.

The irony is that cadmium is not considered essential because there is no way to make a cell deficient in cadmium. It is so completely essential that life would not exist as we know it without cadmium.

During the great extinctions there were increased exposures to cadmium air pollution.  Since cadmium interferes with DNA repair and can increase gene copy number,  it can promote the modifications that can lead to new information systems.

An element with a linear effect could not promote evolution.  Life is not linear and evolution is not linear.   Adaptive responses to  changing stressful environments in the planetary biome  produced the big blue marble we call home.  Cadmium played an essential role and still does.

Now we are confronted with a world that is showing stress at every level from climate change to mental illness, heroin overdose, and in the USA the lowest life expectancy in persons under the age of 50 in the developed world.  The ability of cadmium to inhibit an enzyme that removes phosphates can mess up  the delicate balance  required for successful adaptation.

Our children are the canaries in the mine shafts warning us that we are exposed to something in the air that at the current dose and in conjunction with other pollutants is toxic to humans even though kudzu and Japanese knotweed are flourishing.

What needs to be done?   We need a change in research funding. We need the media to provide information regarding the health effects of this element, its sources, and the available dietary and life style interventions needed to reverse its adverse effects.  Scientists at  environmental protective agencies around the world need to devise biological traps for measuring fine fumes of cadmium air pollution. Cadmium levels in blood of dead wild life and at autopsy, of persons  from stillborns  on up, especially non smokers, would provide some needed information on current levels of cadmium being absorbed. Because it quickly disappears out of the blood into the lining of the blood vessels, using blood cadmium levels under-estimates exposures in the living.

Cadmium  may be present in exhaled breath secretions. It is possible to monitor FENO (fractional exhaled nitrogen oxide). Cadmium can exit plant leaves with NO. The interactions of cadmium with NO, which was the molecule of the year in 1992, will be the subject of my next blog.

Perhaps cadmium will become the element of the year in 2017.  There is no dearth of information about cadmium, it just doesn't fit conventional ideas about proof.  It is time to change these ideas.


Saturday, November 19, 2016

Interpreting blood lead and blood, hair and urine cadmium

Interpretation of  blood lead and blood and urine cadmium

In the previous two blogs I have shown that blood lead is not a simple measure of exposure. In an given setting of environmental exposure from air pollution, water pollution or ingestion, blood lead levels are influenced by vitamin deficiencies, magnesium, potassium, zinc, and iron deficiency.   These deficiencies influence the uptake of cadmium as well as lead.

 In comparing 16 metals, cadmium was the most toxic and about 200 times more toxic than lead in an experiment where  metals were given to a rodent and the toxic effect was lowering body temperature and  negatively influencing mitochondrial function as evidenced by decreasing consumption of oxygen (Gordon 1990).  Cadmium is a ubiquitous pollutant. It is present in all cells.  In a setting of stress,  free cadmium  appears to be released from the lining of blood vessels and or the choroid plexus and triggers an acute stress reaction.  Cadmium influences bone metabolism resulting in activation of osteoclasts  (Sughis 2011).   This is an effect blocked by zinc  (Baljit S 1995).  Resorption of bone  releases lead which is stored in bone into  blood, elevating blood lead levels from a toxic effect of cadmium.

Children who live in poverty  with  dietary deficiencies, emotional stress, and often co-exposure to cadmium in environmental tobacco smoke or  other chemicals  which are synergistic with cadmium,  will have blood lead levels that are higher than children without these factors.  Blood lead elevations are a useful marker of children in need of intervention.  The lead programs set up to help these children need to focus on the dietary deficiencies and cadmium exposures.  The lack of correlation with blood cadmium is not evidence that cadmium is not involved. It disappears readily into the blood vessel lining so that blood cadmium levels do not necessarily correlate with exposure or toxic effect.

In the 1994-2004 NHANES study, children aged 6 to 15  in the highest quartile of  urine cadmium had a three fold risk of placement in special education placement (Ciesielski et al 2012).   Urine cadmium, however, is not a simple measure of exposure, either.  This study is consistent with my finding that children exposed to cadmium and in the highest quartile of hair cadmium had the lowest achievement. Although there was no linear correlation with hair cadmium and achievement, there was a correlation with hair lead even though there was no increased lead exposure in the affected children.

 In a Japanese study, the urine cadmium of women with breast cancer who  knew they had breast cancer was much higher than the urine cadmium of women who were screened for breast cancer and did not know they had the disease (Nagata C 2013).   In an American study (McElroy et al 2005)  women in the  highest quartile for cadmium had  twice the risk  of breast cancer.  In the most recent  American study ( Adams et al 2016)  there was no correlation between  quartiles of urinary cadmium and breast cancer.   

Urine cadmium in men in NHANES III, however, was associated with all cause mortality, cancer mortality, and specifically prostate cancer mortality ( (Cheung M 2014).  Urine cadmium in women was higher but not associated with any specific disease.  Urine cadmium in the same NHANES III  was correlated with impaired glucose tolerance and  diabetes.   

 Just as with lead, deficiencies of vitamins  and minerals and processed food  that contains bisphenol A can increase the uptake and toxicity of cadmium.  Children and adults  with higher urine cadmium need the same assessment and treatment as those with small elevations of blood lead . 

Toxicity to cadmium can occur in the absence of any exposure to lead.  Toxicity to lead  except in acute ingestions resulting in blood lead levels over 40 mcg/dL  occurs with co-exposure to cadmium but correlations with blood, hair, and urine cadmium levels are inconsistent. Neither blood, urine, or hair cadmium is a marker of  acute or chronic exposure. It is variable and strongly influenced by stress which transiently releases it from blood vessels.

The magnitude of this reservoir is evident from a study by Koizumi in 1994 in Japan. Blood cadmium levels at autopsy were a hundred times higher than while living.  This increase was seen only for  cadmium and not other metals.   Blood cadmium levels would undoubtedly be higher in current smokers and past smokers.  Blood cadmium of non smokers at autopsy would provide useful information regarding environmental exposure to   cadmium, especially cadmium air pollution. 

Thursday, November 17, 2016

How does cadmium elevate blood lead levels

How can a toxic effect of cadmium cause a small elevation of blood or hair lead above the average for that environment?

To understand the behavior of metals it is necessary to look at their biochemical behavior.   Statistical correlations can be misleading. It has been known for a long time that zinc and iron deficiencies were associated with toxic effects of lead.  These deficiencies are known to increase the absorption and toxicity of cadmium.   The inhibition of the enzyme ALAD which is considered particularly characteristic of toxicity to lead occurs with cadmium.   Zinc protects this enzyme from inhibition. Cadmium is an anti-metabolite of zinc. Zinc protects cells from cadmium toxicity. So lead toxicity is not just a simple matter of exposure to a toxic metal and a toxic effect that one can measure with blood lead levels or inhibition of ALAD. 
 An excellent article is available regarding the use of dietary strategies for the treatment of lead and cadmium toxicity.
Nutrients. 2015 Jan 14;7(1):552-71. doi: 10.3390/nu7010552.
Dietary strategies for the treatment of cadmium and lead toxicity.

In this article the effects of vitamins, minerals, herbs, and probiotics on toxic effects of lead and cadmium are discussed. In most cases it is clear that a reduction of blood lead with these strategies also reversed toxic effects of cadmium. 

 One could consider that both lead and cadmium are toxic but that elevation of blood lead is the indicator of toxicity, not blood cadmium.  Certainly the toxicity is directly associated with deficiencies of vitamins and minerals. However, one could also consider that lead exposure directly influences the uptake of cadmium.

 Cadmium is very interactive with all nutrient and toxic metals and also with toxic chemicals. Lead is treated more like calcium in the body and is stored in bone. Cadmium is stored in the lining of blood vessels and in the choroid plexus surrounding the brain. It is in the kidney, liver, ovary, testes, thyroid, and adrenals. With acute stress, like handling an animal, cadmium is released into the body.  Consequently, cadmium effects can occur without directly adding cadmium to an experimental animal.   

Cadmium causes a stress response in all cells. Lead does so only through increasing the absorption of cadmium.  For instance, lead in water increases metallothionein production in the liver.  Metallothionein is part of the acute stress response that cadmium produces.  Cadmium activates the promotor of metallothionein  whether cadmium has been added in the experiment or not. When lead is directly added to liver cells there is no increase in metallothionein production. Lead in drinking water increases the uptake of cadmium which promotes the stress response resulting in increased metallothionein production. It is not just that lead and cadmium are both toxic.  Toxic effects attributed to lead are caused by cadmium.

It is this effect of lead ingestion increasing the absorption of cadmium that is directly related to the small but significant elevations in blood lead levels and health effects.  Cadmium increases resorption of bone where lead is stored increasing blood lead levels.  So the level of lead in blood is not a measure just of exposure,but exposure plus a toxic effect of cadmium on bone. Blood cadmium is not a helpful measurement because cadmium is taken up rapidly into the blood vessels and the various organs.  The levels are highly variable through the day responding to various stresses.  Blood hair, and urine cadmium levels are not just measures of exposure but also of stressed induced releases.  

 Based on this information alone, it is clear that cadmium is important. It should be measured accurately in air. New approaches are needed to detect these volatile ultrafine fumes of cadmium.  The US EPA needs to fund research on effective ways to measure cadmium.   Children with elevated blood lead levels should be evaluated for toxic effects of cadmium.  Their urine cotinine should be measured to determine exposure to environmental tobacco smoke.  Children in tee highest quartile of urine cadmium have a three fold risk for placement in special education. These children need the dietary strategies suggested by Q Zhai et al.  They need stress reduction and excellent care both at home and at school. They are not permanently damaged.  It is neglect and indifference that leads to permanent damage in most instances.

Time for a change

Sandra M. Pinkham, M.D<   Time for  A Change
. 11-17-2016
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 Since lead was taken out of gasoline in 1980, the public has been told that lead is the most serious toxic agent. Flint Michigan parents were told that their children were being permanently damaged by exposure to lead in water.  The public has been old that removing lead from gasoline which lowered blood lead levels dramatically has made the air cleaner. What is wrong with this message?   
In the last 30 years I have made an extensive search of the world literature on lead and cadmium and other toxic substances known to have an adverse effect on health. This was triggered by a finding in a hair analysis study that I did on children in 1986. The children in my study with the highest levels of lead and cadmium in their hair had the lowest scores on achievement. This was statistically significant for lead but not cadmium.  All the children were exposed to cadmium from a large waste incineration plant in operation for 2 years, a very significant source of cadmium pollution and other chemicals that act in synergy with cadmium. Only 2 of the 60 were exposed to passive smoke, another very significant source of cadmium air pollution exposure in humans.  The children with the higher levels of lead and cadmium were experiencing stress from having learning problems. The hair lead levels were associated with very low levels of blood lead. The children had minimal exposure to lead. Although the cadmium levels were elevated in the children with learning problems, the high variability in hair cadmium compared to hair lead resulted in an insignificant statistical correlation.
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From my literature search, I discovered that it is the  statistical correlation of small elevations of blood leads at any level along the line from a blood lead of 20 ug/dL to zero that is the main proof that lead is so toxic. In studies where lead is given for long periods of time to show adverse effects in experimental animals, there was no attempt to see what happens to other metals, especially cadmium in most studies. In the few where that was studied researchers showed that ingestion of lead in water increased cadmium uptake into the brain.  Just the fact that when blood lead levels averaged 15 the toxic children had blood lead levels of 20 and when the average was 5 the toxic children had 10 and now when the average blood lead level is less than one a blood lead level of 5 is considered toxic should make one suspicious that lead exposure may not be the cause of the linear correlation. .  Clearly all the children in the 1960’s and 70s were not being poisoned by lead.

 An alternate explanation which makes more sense is that blood lead is not just an indicator of exposure. Small increases over a background level is actually an indicator of a toxic effect that is increasing the presence of lead ions in blood. My next blog will explain the biochemical basis for this effect.