Metabolism and formation of DNA adducts

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Carin Smit's response to Dr. Plumb's article.
If only those who physically worked in the WTC site during and after the blasts showed a higher
cancer incidence (statistically significant) vs. people living in the proximity, (the latter didn’t
develop cancers in the wake of the jetliner crashes), I would like to suggest that this population
needs to be examined for nitrosamines or nitrosopyrrolidines. There appears to be a very high
correlation between inhaling smoke, and compounds related to burnt organic matter and the
immanent development of cancers. I have reviewed just the lab results of just over 200 patients
who have been tested for DNA Adducts, Lymphocyte sensitivity for toxic elements (chemicals
and metals) whom I’ve seen in my practice and have had opportunity to review in other
practices, and have found that high nitrosamine and nitrosopyrrolidine levels appear to be ;inked
to carcinogenic risks due to epigenetic impacts via DNA Adducts.
http://www.tcmda.com/Global/Aminrapporter/MIT%20nitrosamines%20report%20final.pdf
Environmental Guidelines and Regulations for Nitrosamines:
A Policy Summary
Prepared for CO2 Technology Centre Mongstad by:
Dr. Noelle E. Selin
Assistant Professor of Engineering Systems and Atmospheric Chemistry Engineering Systems
Division and Department of Earth, Atmospheric and Planetary Sciences
Massachusetts Institute of Technology
77 Massachusetts Avenue (E40-379)
Cambridge, MA 02139-4307 USA
+1-617-324-2592
selin@mit.edu
http://mit.edu/selin/
Page Two
FINAL REPORT
Here is an excerpt from the above report:
Figure 1. Structure of nitrosamines.
From Luan et al., 2005.
Page Three
Figure 2. Structure of N-nitrosodimethylamine (NDMA).
From California Environmental Protection Agency, 2006.
2. Health Risks of Nitrosamines
The health risk of most concern for environmental levels of nitrosamine is carcinogenicity.
Exposure to nitrosamine has been shown to form tumors in laboratory animals, and have been
linked in epidemiological studies to human cancers including pancreatic cancer (Risch, 2003)
and childhood brain tumors (Huncharek and Kupelnick, 2004).
Nitrosamines are classified by a number of international organizations and regulatory authorities
as to their carcinogenicity. Under the International Agency for Research on Cancer (IARC),
which is part of the World Health Organization (WHO), NDMA and NDEA are classified as
Group 2A substances (probably carcinogenic to humans). The European Union categorizes
NDMA and NDEA as category 1B (Presumed to have carcinogenic potential for humans; largely
based on animal evidence). In the US, the Environmental Protection Agency classifies both
NDMA and NDEA as a “probable human carcinogen (category B2)” under its 1986
carcinogen assessment guidelines.
5. Environmental Levels: A Survey
High concentrations of NDMA have been measured in ground water near rocket engine testing
facilities, as mentioned above (Mitch et al., 2003).
Clinical Practice – Comment:
I lost two patients in my practice this year, both with very high nitrosamine and
nitrosopyrrolidine levels. Both had been smokers and inhaled significant amounts of burnt
organic material across a lifetime. The one patient had metastatic liver cancer and the other
metastatic melanoma.
Here’s another excerpt from a significant Peer Review Journal:
Cardnogenesis Vol.5 no.ll pp.1381 -1393, 1984
Commentary
Relevance of nitrosamines to human cancer
Helmut Bartsch and Ruggero Montesano
Division of Environmental Carcinogenesis, International Agency for
Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cedex 08,
France
Page Four
Introduction
It is now about three decades since the hepatocarcinogenic effect of N-nitrosodimethylamine
(NDMA)* was demonstrated in rats (1) and the suggestion was made that N-nitrosamines can be
formed following nitrosation of various amines (2).
Direct proof that such nitrosation reactions can occur was provided by Ender et al. (3) who
identified NDMA in nitrite preserved fish-meal, and by Sander and Seif (4) who demonstrated
the formation in vivo of a nitrosamine in the acidic conditions of the human stomach. Since then,
because of the potent carcinogenicity, wide environmental occurrence and easy formation of
nitrosamines, considerable efforts have gone into determining their levels in the external and
internal human environment, and attempts have been made to assess exposure and to correlate it
with human cancer at specific sites. Fundamental research into molecular and cellular
mechanisms of carcinogenesis has also concentrated on N-nitroso compounds (NOC), to find out
why and how this class of carcinogens produces tumours in up to 40 animal species (5,6) and
displays remarkable species, organ and cell specificity (7—11) and a wide variety of genetic
effects (12,13).
Human exposure to NOC
The introduction of the chemi-luminescence detector (Thermal Energy Analyzer) by Fine et al.
(14) represented a breakthrough in nitrosamine analysis and made it possible to assess human
exposure to (mostly) volatile nitrosamines. Today, reliable methods for the analysis of a wide
range of nonvolatile NOC are still not available, although progress has been made (15-18).
The occurrence of NOC in several matrices and the resulting potential human exposure have
been tabulated (10,19,20 and Tables I-III). Such can be divided into endogenous exposure,
though formation of NOC in vivo from precursor amines and nitrosating agents (Table I), and
intake of preformed NOC from occupational and environmental sources (Tables II and III).
Because of recent developments in detection methods, in the following we give some emphasis
to endogenously formed NOC. This shall, however, not detract from the fact that human
exposure to performed NOC from a variety of sources is firmly established.
Occupational sources of exposure are:
1.
Leather tanneries
2.
Rubber and tyre industries
3.
Metal working industries
4.
Chemical industries
5.
Rocket fuel
6.
Dye manufacture
7.
Surfactant production
8.
Foundries
9.
Fish processing
Page Five
Metabolism and formation of DNA adducts
Nitrosamines produce various adverse biological effects, including induction of tumours
following metabolic conversion into reactive intermediates which react with various cellular
macromolecules; this process is considered as one critical determinant in the carcinogenicity of
nitrosamines. The various forms of microsomal enzymes responsible for this metabolic
activation and the nature of the metabolites formed have been described (58 — 60). Various
organs and cells from different species, including human beings, have been shown to be capable
of carrying out such metabolic transformation, as determined by the detection of various
metabolic products (e.g., carbon dioxide, aldehydes) and/or initial DNA alkylation (e.g., 7methylguanine).
One of the gene areas impacted on DNA by Nitrosamines or Nitrosopyrrolidines appears to be
on the DNA Lygase or DNA Repair gene. Another place where significant mischief is
seemingly done is: the SOD1 gene, which protects against super-oxides inside cells and therefore
against intra-cellular damage by chemical and metal compounds which are toxic….
Here is a typical example of a smoker’s Lymphocyte Sensitivity test: note the nitrosamine levels.
Page Six
The following patient lives in the flight path of jet-liners near an international airport in South
Africa, which poses the question what role jet-fuels play in nitrosamine and nitrosopyrrolidine
deposition and whether that might not have been the critical cause for the higher incidence of
cancer for those who worked at WTC site….? This patient is 34 years of age and was diagnosed
with stage III testicular cancer 2 years ago and has never once smoked in his life:
This same patient’s DNA Adducts are telling:
Page Seven
The following is the DNA Adduct test of the first of two deceased patients (a smoker who
stopped smoking 20 years ago):
His Lymphocyte sensitivity test shows the dramatic issues with both Nitrosamines
and nitrosopyrrolidines:
Page Eight
Please note the amount of Cell-Free DNA recorded for this patient – this test was
done 6 weeks before his death:
Here is the DNA Adducts test result of a male patient (ex smoker) with significant oxidative
stress and neurological and mood problems: again note the nitrosopyrrolidine levels – he
owns a carpeting company and industrial warehousing facility -
Page Nine
This is his Lymphocyte Sensitivity Test result:
Finally, the test results of a young woman with MS (ex smoker), also living in the flight path
of jet-liners and near the same international airport mentioned above, which makes me wonder
about chemical trails: The Nitrosamine adduct is located this time on the PPARG gene.
Page Ten
My closing comment when considering the article submitted by Dr. Plumb is just this:
We have been schooled to believe that toxic metals are problematic…. When I review
the test results I’ve enclosed, it appears that far more than toxic metals is exerting
epigenetic and carcinogenic effects on man. The WTC was a devastating event – trauma
abounded, but what indeed WAS in that lethal cocktail that filtered down that day
when the two jet-liners crashed into the Twin Towers of the WTC?
Limited Bibliography
Dai, Q. (1998), Di-Region Theory , New Discovery on Mechanism of Carcinogenesis,
Molecular Engineering, 8, 61-89.
California Department of Public Health, 2010c. NDMA and Other Nitrosamines.
Online: http://www.cdph.ca.gov/certlic/drinkingwater/Pages/NDMA.aspx
[accessed 7 January 2010]
ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological profile for Nnitrosodimethylamine. Prepared by the Syracuse Research Corporation for ATSDR in
collaboration with the U.S. Environmental Protection Agency. U.S. Public Health Service,
Washington, D.C. 119 pp.
Kind regards
Carin S. Smit
M/CMT
South Africa
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