Dr. Richard Sauerheber
(B.A. Biology, Ph.D. Chemistry, University of CA, San Diego)
Palomar College, San Marcos, CA

December 23, 2012

Comments on Toxicologic Mechanisms of Arsenic, Lead and Fluoride

Arsenic is a certain human carcinogen, and lead is a probable (EPA), or a reasonably anticipated to be (NTP), human carcinogen. Indeed, lead and arsenic both inhibit enzymes that synthesize and repair DNA. Arsenic and lead both incorporate into all organ systems to produce toxic effects, and both accumulate in bone and teeth. Each exhibits many distinct toxicologic features, and the sizes of these ions are much different, but both arsenic and lead as metal ions irreversibly bind sulfhydryl groups on proteins, including both structural and enzymatic proteins. Sulfhydryl groups that are affected can vary in importance depending on location and the importance of the enzyme. The EPA MCL for each metal ion has been set at 10 ppb, but this is 0.21 microMolar for arsenic and 0.05 microMolar for lead.

The two forms of inorganic arsenic, reduced (trivalent As (III)) and oxidized (pentavalent As(V)), can be absorbed, and accumulate in tissues and body fluids. Arsenite, As(III), binds with higher affinity to sulfhydryl groups. Numerous studies have shown that arsenic is cytotoxic at micromolar concentrations. Micromolar arsenic can induce chromosomal damage and inhibit DNA repair. Cells lacking telomerase are paradoxically prone to genomic instability and carcinogenesis. Studies conducted at Johns Hopkins describe arsenic as a potent inhibitor of human telomerase expression at 0.7 micromolar (50 ppb) [http://www.jci.org/articles/view/14064]. Arsenite inhibits succinate dehydrogenase at micromolar concentrations:

[http://www.ncbi.nlm.nih.gov/pubmed/9806419]. Arsenic inhibits pyruvate dehydrogenase at 0.25 micromolar (18 ppb).

Lead severely inhibits creatine kinase and pyryuvate kinase

[http://www.ncbi.nlm.nih.gov/pubmed/19925858]. Lead causes neurobehavioral abnormality in children with blood levels below 50 ppb

[http://www.atsdr.cdc.gov/csem/lead/docs/lead.pdf] . Lead lines occur in bone on Xray exams in 3 year old children with 100 ppb blood lead levels. Enzymes responsible for the synthesis of blood cell hemoglobin are directly and immediately substantially inhibited by lead at only 50 ppb.

Under the Lead Copper Rule (LCR), EPA requires testing of public water systems, and if more than 10% of the samples at residences contain lead levels over 15 ppb, actions must be taken to lower these levels [http://www.atsdr.cdc.gov/toxprofiles/tp13.pdf].

Unfortunately, the combined effects of arsenic and lead dual exposure have not been evaluated. No MCL has been developed for either substance when the other is also known to be present. The effects of lead at 10 ppb together with arsenic at 10 ppb, typical of water supplies and the EPA MCL’s for lead and arsenic separately, during lifelong exposure are unknown. Many municipal water supplies in the U.S. now contain over 10  ppb total of lead plus arsenic.

Industrial fluoride ingestion from 1 ppm treated water supplies in conjunction with fluoridated toothpaste use averages 0.21 ppm in blood and most soft tissues (National Research Council, 2006, p. 70). Fluoride accumulates in bone to thousands of mg/kg over lifelong drinking.  Fluoride is also alters protein structure and is a general enzyme inhibitor, but by a mechanism entirely distinct from that for arsenic and lead. Fluoride disrupts hydrogen bonds that normally exist between water molecules, between water and biological molecules, and within individual macromolecules. Fluoride inhibits glutamine synthase, a DNA repair enzyme, at only 0.2 ppm, but unlike enzyme inhibition due to metal ions, fluoride enzyme inhibition is reversed after reduction of the fluoride concentration in the media. This is because hydrogen bonds are not actual bonds but rather are associations, regions where molecules become attracted temporarily. Hydrogen bonding is merely a dipolar interaction between polar groups where opposite charges attract and is strong enough when between hydrogen and nitrogen, oxygen or fluoride, to then be referred to as hydrogen bonding.  Hydrogen bonding determines many unique characteristics of water as the exclusive solvent forming the bulk matrix of all living organisms. The EPA MCL for fluoride is currently set at 2 ppm in drinking water without consideration of the amount of fluoride ingested from toothpaste use or from foods. Based on fluoride exposure studies reviewed  by the NRC, if fluoride were not present in drinking water, then blood levels of fluoride would average approximately 0.1 ppm in the U.S. Indeed, this is a typical fluoride blood level for those residing in non-fluoridated regions (NRC).