ACCA Ban Petition, Petition HP 01-3@

NOTE: The following is posted on behalf of Laurette Janak. She would appreciate your feedback. You may contact her at laurettejanak@cs.com

Laurette Janak
7185 Liebler Rd.
Colden, NY. 14033
(716) 941-4622
laurettejanak@cs.com

Office of the Secretary
Consumer Product Safety Commission
Washington, DC 20207

February 28, 2003

Re: ACCA Ban Petition, Petition HP 01-3@

I am here today to serve as an advocate for a subset of children who exceed your 1 in 10,000 risk assessment for cancer. This particularly vulnerable group of children requires protection and I will not stop until they get the recognition they deserve. The group I am referring to is special needs children.

Roughly one out of every 500 children born has Trisomy 21, better known as Down syndrome. My daughter, Emily, was born with Down syndrome. Anyone who has spent time with Down syndrome children knows that they experience their world through their mouths well beyond the oral stage seen in typical children. Emily at age 8 still mouths many objects and uses her hands to
play with her protruding tongue.

We had frequently observed Emily putting her tongue directly on our wooden deck or chewing on the railing. Like many other parents, I was unaware that CCA wood contained toxic metals. We became painfully aware of this when we sanded our deck and Emily suffered neurological problems from an episode of acute arsenic poisoning.

I submitted a written letter to the school nurse forbidding Emily to play on the CCA playground. While my request was accommodated, they continued to take the rest of the special needs children to the playground despite my efforts to inform them of the increased risk our very "oral" children have.

What could a mother possibly know? Surely if there was any danger to our
special children, someone of "authority" would notify us.

I would like to share with you exactly what someone who is "just a mother"
has learned.

Your study looking at the long-term risk of cancer from CCA exposure during
childhood is a step in the right direction; however, with childhood cancers
on the rise one needs to consider the impact of environmental toxins such as
CCA on childhood cancer. A recent study is quoted as saying, "Acute
lymphoblastic leukemia (ALL) is the most common pediatric cancer. The origin
of this disease can be explained by a combination of genetic susceptibility
factors and environmental exposures. For the purpose of our study it can be
considered as a complex disease, caused by the "carcinogenic" effect of the
environment modified by a series of genes" (1)

Down syndrome children have a 15-20 fold increase occurrence of leukemia
when compared to non-trisomic children. While Emily's genetics may have set
the stage for cancer, I believe her chronic exposure to CCA lumber was the
trigger to her leukemia. What follows is my reasoning.

Down syndrome(DS) chemistry and CCA exposure; A leukemia connection

Fact number one: Due to their genetics DS individuals overproduce hydrogen
peroxide; arsenic exposure increases hydrogen peroxide. This causes DNA
damage and increased risk for leukemia.

…excessive hydrogen peroxide production in Down syndrome

The gene for Cu-Zn superoxide dismutase (SOD) is coded on chromosome 21
which is overexpressed in DS. Such overexpression results in increased
oxidative stress (an increase in ROS) and an overproduction of hydrogen
peroxide (H2O2) in DS individuals.(2-4)

…excessive hydrogen peroxide production with arsenic exposure

Exposure to arsenic increases SOD activity (5) and results in excessive
hydrogen peroxide production and oxidative stress (6)

Clearly, arsenic exposure exacerbates the genetic overexpression of SOD and
compounds the already burdened oxidative stress seen in Down syndrome. A
study which looked at hydrogen peroxide induced DNA damaged states,

"The mechanism of carcinogenesis in Down syndrome could be explained by our
findings: SODs enchance metal-mediated DNA damage induced by H2O2. …We
conclude that SODs may increase carcinogenic risks, e. g. of tumors in Down
syndrome."(7)

Oxidative damage is especially true in the presence of copper. Excessive
copper levels have been reported in DS (8,9). Erythrocytes, thrombocytes and
neutrophils of DS individuals were found to have significantly higher levels
of copper.(9)

It has not yet been determined if copper leaches from CCA wood in the same
way that arsenic does; however, animal studies show high copper levels can
interfere with arsenic excretion. Delayed excretion would increase risk for
arsenic toxicity.

In a study which looked at DNA damage from lead or mercury, it has been
conclusively demonstrated, "that there is a causal relationship between the
induction of H2O2 and the mutagenic potential of these metals." (10)

Arsenic acts the same as lead or mercury in its excessive production of
hydrogen peroxide and related DNA damage.

Fact number two: DS individuals have poor DNA repair mechanisms; arsenic
exposure inhibits DNA repair. If DNA damage is unable to be repaired this
may initiate leukemia.

…poor DNA repair in DS

It is well documented that DS cells have a profound DNA repair
deficiency. "The same features apply for cells, which contain an
overexpressed Cu/Zn-superoxide (SOD-1) gene." (11) Two types of DNA repair
deficiencies have been noted; a "DNA repair deficiency in strand break
repair and also a second DNA repair deficiency in incision activity." (12)

It has been proposed that, "This altered repair system is probably
responsible for the increased frequency of chromosome aberrations that can
be induced in these cells by x-rays and the increased tendency for leukemia
observed in Down syndrome as well." (13)

…arsenic exposure inhibits DNA repair

Once again arsenic exposure compounds the genetic problems seen in DS.
Arsenic exposure has been documented to cause DNA repair deficiency.(14-16)
A newly published study shows that arsenic "interferes with various DNA
repair systems in concentrations in the low micromolar range." (16) More
specifically poly(ADP-ribosyl)ation has been shown to be "inhibited at
concentrations as low as 10nM…Since poly(ADP-ribosyl)ation is an immediate
cellular response to DNA damage, playing a major role in DNA base excision
repair and the maintenance of genomic stability, its inhibition by arsenite
may add to the risk of cancer formation under low-exposure conditions." (16)
This is bad news for DS where it has been demonstrated that "DS lymphocytes
are more sensitive to the inhibition of poly(ADP)ribose synthetase than
normal lymphocytes."(17)

How bad is the compounding effect of DS genetics and arsenic exposure?

One sudy states, "…chromosome rearrangements may exist in proliferating
cells in DS individuals after exposure to clastogens and that this
abnormality predisposes them to develop leukemia."(18) Of course arsenic has
been shown to be a potent clastogen so it can be viewed as a trigger to
leukemia in a genetically vulnerable population such as DS.

Fact number three: DS individuals have low plasma glutathione; arsenic
exposure can deplete glutathione. Epidemiologic evidence suggests low
glutathione is a risk factor for leukemia.

…plasma glutathione (GSH) in Down syndrome

The Nutrition-Environment Interactions Research Core Group at the
University of California at Berkeley "has uncovered epidemiologic evidence
that lower intakes of certain amino acids are associated with increased risk
of childhood leukemia. This research suggests that deficiency of
gluthathione, a major plasma antioxidant, and its precursor, cysteine, may
increase the risk of this disease." (19)

A recent study found the plasma glutathione (GSH) levels to be significantly
reduced in children with DS.(20) Animal models of DS have shown decreased
GSH in cultured hippocalmpal neurons which contributes to cell loss and
neurodegenration in DS.(21) Some Down syndrome cells have been shown to have
an adaptive mechanism of upregulating glutathione peroxidase (GPx) in
response to the SOD overexpression.(22) GPx activity remains unaltered in DS
brains (22) and lymphocytes (23) thereby leaving these cells more prone to
oxidative injury from excessive H2O2. Thus you can expect to see increased
neurotoxicity in addition to DNA damage in DS individuals exposed to CCA.

…glutathione (GSH) in arsenic exposure

A recent study found some human cells could develop tolerance to chronic
arsenic exposure. The tolerant cells "had increased basal GSH levels
(4.9-fold) and increased GST activity (2.4-fold) and both GSH depletion and
inhibition of GST activity abolished arsenic tolerance…..Our results
indicate that this tolerance in human cells involves increases in GSH levels
and GST activity that allow for more efficient arsenic efflux…"(24)

The ability of arsenic to perturb cellular glutathione regulation is highly
tissue specific. For example in one study GST activity was shown to increase
in keratinocytes but not in fibroblasts or breast tumor cells. (25) Studies
need to be tissue specific and in the case of CCA exposure include
simultaneous exposure to copper and chromium.

Again we find that a DS child would be much more affected by the damages of
arsenic than a non-genetically predisposed child.

Fact number four: DS individuals have altered folate and methylation
cycles; arsenic exposure perturbs these same cycles. Alterations in folate
have been implicated in leukemia.

…altered folate and methylation in Down syndrome

Another gene localized to chr 21 is cystathionine Beta-synthase (CBS).
CBS catalyzes the conversion of homocysteine to cystathionine. A consequence
of the CBS over expression is a reduction of homocysteine available for
remethylation to methionine. Thus in DS you find reduced plasma levels of
homocysteine, methionine, S-adenosylmethionine (SAM) and
S-adenosylhomocysteine (SAH).(20) Folate trapping and a functional folate
deficiency are established. This is reflected in the elevated MCV and
increased sensitivity to the antifolant drug methotrexate found in the DS
population. The folate trapping caused by CBS overexpression results in
thymidylate deficiency and the consequential misincorporation of uracil.
This in turn requires that the DNA repair mechanism be working optimally; a
condition that arsenic exposure even in low doses prevents.

…altered folate and methylation in arsenic exposure

The resynthesis of GSH under conditions of GSH depletion has been shown to
cause a decrease in methionine and impairment in DNA methylation.(26,27)
Plasma methionine levels in DS children were found to be 53% of that for
control children.(20) Therefore the GSH depleting properties of arsenic
amplifies the problem of CBS overexpression associated with DS.
Additionally, arsenic has been shown to down regulate DNA
methyltransferase1. (5)

GSH depleting agents cause a diversion of folate away from the
biosynthesis of purines and the pyrimidine thymidylate.(26)

"Thus alterations in gene expression could result from a high dose and/or
prolonged exposure to GSH-depleting agents, e.g. medications,
chemotherapeutic agents and environmental toxins."(27)

This leaves DS individuals who have a functional folate deficiency and
low
plasma GSH levels at increased risk of cancer upon exposure to agents such
as those found in CCA wood. This risk exceeds that of non-trisomic
individuals.

A multitude of current research has implicated disruptions in the folate
cycle with the onset of leukemia. (28-32)

Arsenic causes disruptions in these same pathways(33-37) thus leukemia
should now be considered among the cancers induced by environmental exposure
to CCA wood in genetically susceptible children.

Dietary Folate Deficeincy Enhances Induction of Micronuclei by Arsenic in
Mice (33)
Mouse peripheral blood MN assay of polychromatic erythrocytes (PCE) was used
to measure damage to the bone marrow. Mice were made folate deficient. The
folate deficient mice had small increased levels of micronuclei before they
were exposed to arsenic.
Upon exposure to arsenic, the folate-deficient animals exhibited higher
MN-PCE frequencies than the folate-sufficient animals. At the highest dose
of arsenic used, the MN-PCE levels in folate deficient animals was 2.4 fold
higher than that found in the folate sufficient animals.
"the difference in MN-PCE levels between folate-deficient and
folate-sufficient mice treated with arsenic was greater than the sum of the
effects of folate deficiency and arsenic considered separately."(33).
The type of chromosomal damage was almost completely due to chromosome
breakage.

"Because humans are more sensitive than mice to the genotoxic effects of
both arsenic and folate deficiency, the potential enhancing effect of folate
deficiency on arsenic genotoxicity in exposed human populations may be
greater than that observed in mice. Although further work is needed to
address the effects of moderate to marginal folate deficiency and chronic
arsenic exposure at lower doses, our results give support to the ideas that
dietary folate deficiency may be a predisposing factor in arsenic
genotoxicity and carcinogenesis in individuals consuming nutritionally
inadequate diets."(33)
DS or other genetic polymorphisms can be the equivalent of "consuming
nutritionally inadequate diets". An example of this is seen in the reported
increase neurotoxicity of arsenic in persons with methylenetrahydrofolate
reductase deficiency.(36)

Fact number five: An abberant response to a viral infection has been
proposed to contribute to leukemia risk. DS individuals have altered immune
systems; arsenic exposure compounds this problem.

…immune function in Down syndrome

There are many published studies citing the immune deficiencies of
Down syndrome individuals. Immune supporting nutrients are also found to be
altered in DS.
"Serum zinc and selenium levels were significantly lowered in DS subjects,
whereas copper levels were elevated. Consequently a marked increase (40%) of
the copper/zinc ratio in DS persons was observed"(38)

…immune function in arsenic exposure
Toxicity of arsenic is partially mitigated by zinc and selenium so here
again this environmental toxin is particularly toxic in DS. Zinc deficiency
causes a shift from cell-mediated immunity (Th1) to a humoral immunity
(Th2).(39,40) Such a shift leaves individuals more sensitive to viral
infection. Heavy metal exposure and low GSH levels have also been shown to
cause a shift to Th2 thereby increasing susceptibility to viral infections.
GSH depletion allows for better replication of viruses while at the same
time causing them to mutate to a more virulent form. (41-43). This is a key
point; it is against the backdrop of chronic metal exposure that one can
have complications with relatively benign viral exposures.
"Research shows that arsenic is a general gene inducer. Genes induced are
involved in proliferation, recombination, amplification and the activation
of viruses."(44)

If an aberrant response to a viral infection is a contributor to leukemia
risk, then it is obvious that arsenic can cause such an aberrant response.

Fact number six: the preleukemic condition prior to development of Acute
Lymphocytic Leukemia (ALL) is consistent with that produced by arsenic
exposure.

…bone marrow dysfunction preceding ALL

A transient aplastic anemia recovering spontaneously within a few days or
weeks is reported to be a preleukemic condition to ALL. The "remission lasts
from a few weeks to several months and is followed by overt ALL."(45)

For my daughter, macrocytic anemia (elevated MCV above that which is seen in
DS) was picked up on a standard blood test 10 months prior to her diagnosis
with ALL. Lab tests were run to determine the underlying cause. No cause
could be found. Her liver enzymes were slightly elevated. Hepatitis
screening came back negative. I was told there was no need for concern and
no further testing was done to investigate the cause. Looking back now, I
know that an elevated MCV with a normal RDW is a preleukemic condition (46)
and I should have pushed for an investigation to determine the cause.

…hematological effects of arsenic exposure

"The heavy metals most commonly associated with hematologic toxicity are
arsenic and its derivative arsine, copper…" (47) Here we see 2 of the 3 CCA
metals listed as those which are most commonly associated with hematological
manifestations.

Both aplastic anemia (47) and macrocytosis (48) (like the unexplained
macrocytosis seen in my daughter prior to her leukemia) are found in arsenic
exposure. As stated above these are both preleukemic conditions. A case
history of acute myelogenous leukemia after arsenic induced aplastic anemia
is reported in the medical literature. (49)

An animal model of arsenic induce leukemia states, "The arsenic-induced
leukemias observed showed the whole spectrum of forms known in human
pathology." (50)

A recent leukemia study found an elevated risk for leukemia with exposure to
arsenic in drinking water. (51) It is once again important to bear in mind
that copper and chromium were not included in that study.

Fact number seven: there are miscellaneous other bits of evidence to
support a CCA leukemia connection.

…epidemiological studies

"From the epidemiological studies, there is suggestive evidence that
hexavalent Cr causes increased risk of bone, prostate, lymphomas, Hodgkins,
leukemia, stomach, genital, renal, and bladder cancer, reflecting the
ability of hexavalent chromate to penetrate all tissues in the body." (52)
While the main focus has been on arsenic exposure from CCA wood, little has
been done to determine the bioavailability of the toxic chromium.

In another study some of the factors found to have elevated and/or
significant ORs include: Down syndrome, MMR vaccination [OR = 3.7 for pre-B
ALL], measles, metal exposure [OR = 2.0 for pre-B ALL] , exposure to
insecticides [OR = 2.0 for pre-B ALL], exposure to dust (most commonly
recorded as wood dust) [OR = 8.0 for pre-B ALL] ect…(53)

What would be the OR and probability for my daughter with Down syndrome
exposed to the heavy metals arsenic and chromium from wood dust* known to
be derived from CCA treated wood?

*The study that found such a large OR for exposure to dust (most frequently
recorded as wood dust) does not go far enough in stating if the wood dust
was from chemically treated wood such as CCA).(53)

Aneuploidy, a condition which is found in cancer cells, has been
demonstrated in mouse bone marrow cells after exposure to arsenic. (54)

The cancers most commonly quoted as being associated with arsenic exposure
are lung, bladder, liver, kidney and skin. That list is by no means
exhaustive. This is clearly demonstrated by a study looking at disease in
areas with high levels of arsenic in drinking water. Increase mortality from
the following cancers were included: larynx, colon, stomach cancers, rectal
cancer, and lymphoma. (55) New associations will be made as science
progresses.

Lastly, the paper I think is the most important to understand and should be
read by anyone considering an arsenic leukemia connection is number 29 on my
reference sheet. That paper combined with a good understanding of Down
syndrome genetics and the effects of arsenic exposure clearly point a finger
at CCA exposure and leukemia in Down syndrome children.

Closing

So what does a person who is "just a mother" know about CCA exposure? I know
that we have not done enough to protect our environment and our most valued
gift; our children!
Thank you for taking the time to consider my ideas. I am most appreciative
of your willingness to take a stand on this serious health issue and to be
on the side of the consumer.
Laurette Janak

References
1 : Sinnett D, Krajinovic M, Labuda D.
Genetic susceptibility to childhood acute lymphoblastic leukemia.
Leuk Lymphoma. 2000 Aug;38(5-6):447-62. Review.

2 : Carratelli M, Porcaro L, Ruscica M, De Simone E, Bertelli AA, Corsi
Reactive oxygen metabolites and prooxidant status in children with Down's
syndrome.
Int J Clin Pharmacol Res. 2001;21(2):79-84.

3 : Sanij E, Hatzistavrou T, Hertzog P, Kola I, Wolvetang EJ.
Ets-2 is induced by oxidative stress and sensitizes cells to
H(2)O(2)-induced apoptosis: implications for Down's syndrome.
Biochem Biophys Res Commun. 2001 Oct 5;287(4):1003-8

4 : Midorikawa K, Kawanishi S.
Superoxide dismutases enhance H2O2-induced DNA damage and alter its site
specificity.
FEBS Lett. 2001 Apr 27;495(3):187-90

5 : H amadeh HK, Trouba KJ, Amin Rp, Afshari CA, Germolec G
Coordination of Altered DNA Repair and Damage Pathways in Arsenite-Exposed
Keratinocytes
Toxicological Sciences 69, 306-316 (2002)

6 : Kessel M, Liu SX, Xu A, Santella R, Hei TK.
Arsenic induces oxidative DNA damage in mammalian cells.
Mol Cell Biochem. 2002 May-Jun;234-235(1-2):301-8.

7 : Midorikawa K, Kawanishi S
Superoxide dismutases enchance H2O2-induced DNA damage and alter its site
specificity.
FEBS Lett 2001 Apr 27;495(3) : 187-90

8: Kadrabova J, Madaric A, Sustrova M, Ginter E.
Changed serum trace element profile in Down's syndrome.
Biol Trace Elem Res. 1996 Sep;54(3):201-6.

9 : Anneren G, Johansson E, Lindh U.
Trace element profiles in individual blood cells from patients with Down's
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10:Ariza ME, Bijur GN, Williams MV.
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11: Schwaiger H, Weirich HG, Brunner P, Rass C, Hirshc-Kauffmann M, Groner Y, Schweiger M Raditation sensitivity of Down's syndrome fibroblasts might be due to overexpressed Cu/Zn-superoxide dismutase
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12: Sanford KK, Parshad R, Price FM, Tarone RE, Schapiro MB.
X-ray-induced chromatid damage in cells from Down syndrome and Alzheimer
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Cancer Genet Cytogenet. 1993 Oct 1;70(1):25-30.

13: Athanasiou K, Bartsocas CS
The implications of S-phase exchanges for the mechanism of radiosensitivity
in trisomy 21.
Am J Med Genet 1982 Jun; 12(2):141-6

14: H amadeh HK, Trouba KJ, Amin Rp, Afshari CA, Germolec G
Coordination of Altered DNA Repair and Damage Pathways in Arsenite-Exposed Keratinocytes
Toxicological Sciences 69, 306-316 (2002)

15: Andrew AS, Karagas MR, Hamilton JW
Decreased DNA repair gene expression among individuals exposed to arsenic in
United States drinking water.
Int J Cancer 2003 Apr1;104(3):263-8

16: Hartwig A, Pelzer A, Asmuss M, Burkle A.
Very low concentrations of arsenite suppress poly(ADP-ribosyl)ation in
mammalian cells.
Int J Cancer. 2003 Mar 10;104(1):1-6.

17: Maclaren RA, Au WW, Legator MS
The effect of 3-aminobenzamide on X-ray induction of chromosome aberrations
in Down syndrome lymphocytes.
Mutat Res 1989 Jan;222(1):1-7

18: Shafik HM, Au WW, Whorton EB Jr, Legator MS.
Distribution of X-ray-induced chromosome breakpoints in Down syndrome
lymphocytes.
Am J Med Genet Suppl. 1990;7:195-200.

19: www.niehs.nih.gov/centers/res-core/ucb-res6.htm

20: Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ.
Homocysteine metabolism in children with Down syndrome: in vitro modulation.
Am J Hum Genet. 2001 Jul;69(1):88-95.

21: Stabel-Burow J, Kleu A, Schuchmann S, Heinemann U.
Glutathione levels and nerve cell loss in hippocampal cultures from trisomy
16
mouse--a model of Down syndrome.
Brain Res. 1997 Aug 15;765(2):313-8.

22: de Haan JB, Wolvetang EJ, Cristiano F, Iannello R, Bladier C, Kelner
MJ,
Kola I.
Reactive oxygen species and their contribution to pathology in Down
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Adv Pharmacol. 1997;38:379-402.

23: Crosti N, Bajer J, Gentile M, Resta G, Serra A.
Catalase and glutathione peroxidase activity in cells with trisomy 21.
Clin Genet. 1989 Aug;36(2):107-16.

24: Brambila EM, Achanzar WE, Qu W, Webber MM, Waalkes MP
Chronic arsenic-exposed human prostate epithelial cells exhibit stable
arsenic tolerance: mechanistic implications of altered cellular glutathione
and glutathione S-transferase.
Toxicol Appl Pharmacol 2002 Sep 1;183(2):99-107

25: Schuliga M, Chouchane S, Snow ET
Upregulation of glutathione-related genes and enzyme activities in cultured
human cells by sublethal concentrations of inorganic arsenic.
Toxicol Sci 2002 Dec; 70(2):183-92

26: Lertratanangkoon K, Savaraj N, Scimeca JM, Thomas ML.
Glutathione depletion-induced thymidylate insufficiency for DNA repair
synthesis.
Biochem Biophys Res Commun. 1997 May 19;234(2):470-5.

27: Lertratanangkoon K, Wu CJ, Savaraj N, Thomas ML.
Alterations of DNA methylation by glutathione depletion.
Cancer Lett. 1997 Dec 9;120(2):149-56.

28: Morgan GJ, Smith MT.
Metabolic enzyme polymorphisms and susceptibility to acute leukemia in
adults.
Am J Pharmacogenomics. 2002;2(2):79-92.

29: Skibola CF, Smith MT, Hubbard A, Shane B, Roberts AC, Law GR, Rollinson
S, Roman E, Cartwright RA, Morgan GJ.
Polymorphisms in the thymidylate synthase and serine
hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia.
Blood. 2002 May 15;99(10):3786-91.

30: Crott JW, Mashiyama ST, Ames BN, Fenech MF.
Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic
acid deficiency-induced uracil incorporation into primary human lymphocyte
DNA in vitro.
Carcinogenesis. 2001 Jul;22(7):1019-25.

31: Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF.
Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of
molecularly defined subtypes of childhood acute leukemia.
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4004-9.

32: Krajinovic M, Labuda D, Sinnett D.
Childhood acute lymphoblastic leukemia: genetic determinants of
susceptibility and disease outcome.
Rev Environ Health. 2001 Jul-Sep;16(4):263-79.

33: McDorman EW, Collins BW, Allen JW.
Dietary folate deficiency enhances induction of micronuclei by arsenic in
mice.
Environ Mol Mutagen. 2002;40(1):71-7.

34: Van Tongern JHM, Kunst A, Majoor CLM, Schinnings PHM
Folic-acid deficiency in chronic arsenic poisoning
Lancet April 10,1965 (784-786)

35: Ruan Y, Peterson MH, Wauson EM, Waes JG, Finnell RH, Vorce RL.
Folic acid protects SWV/Fnn embryo fibroblasts against arsenic toxicity.
Toxicol Lett. 2000 Nov 20;117(3):129-37.

36: Brouwer OF, Onkenhout W, Edelbroek PM, de Kom JF, de Wolff FA, Peters
AC.
Increased neurotoxicity of arsenic in methylenetetrahydrofolate reductase
deficiency.
Clin Neurol Neurosurg. 1992;94(4):307-10.

37: Crandall LZ, Vorce RL
Differential effects of arsenic on folate binding protein 2 (FOLBP2) null
and wild type fibroblasts
Toxicology Letters volume 136,Issue 1, 15 November 2002 Pages 43-54

38: Kadrabova J, Madaric A, Sustrova M, Ginter E.
Changed serum trace element profile in Down's syndrome.
Biol Trace Elem Res. 1996 Sep;54(3):201-6.

39: Solomons NW.
Mild human zinc deficiency produces an imbalance between cell-mediated and
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Nutr Rev. 1998 Jan;56(1 Pt 1):27-8. Review.

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41: Beck MA
Selenium and host defense towards viruses.
Proc Nutr Soc 1999 Aug;58(3):707-11

42: Beck MA, Esworthy RS, Ho YS, Chu FF
Glutathione peroxidase protects mice from viral-induced myocarditis.
FASEB J 1998 Sep;12(12):1143-9

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Antiviral Res 1995 Jun;27(3):237-53

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Arch Toxicol 1991;65(7):525-31

45: Wegelius R
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Leuk Res. 1992;16(1):71-6

46: Walters MC, Abelson HT
Interpretation of the complete blood count.
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47: Ringenberg QS, Doll DC, Patterson WP, Perry MC, Yarbro JW
Hematologic effects of heavy metal poisoning.
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48: Heaven R, Duncan M, Vukelja SJ
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Acta Haematol 1994;92(3):142-3

49: kjeldsberg CR, Ward HP
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50: Osswald H, Goerttler KL
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51: Infante-Rivard C, Olson E, Jacques L, Ayotte P
Drinking water contaminants and childhood leukemia.
Epidemiology. 2001 Jan;12(1):13-9.

52: Costa M
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Crit Rev Toxicol. 1997 Sep;27(5):431-42

53: Buckley JD, Buckley CM, Ruccione K, Sather HN, Waskerwitz MJ, Woods WG,
Robison LL.
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54: Kashiwada E, Kuroda K, Endo G
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Mutation Research 413 (1998) 33-38

55: Tsai SM, Wang TN, Ko YC
Mortality for certain diseases in areas with high levels of arse