Metabolism of inorganic arsenic and biomarkers of exposure
Author: Concha, Gabriela
Date: 2001-04-20
Location: Samuelssonsalen, Scheelelaboratoriet, Tomtebodavägen 6, Karolinska Institutet
Time: 9.15
Department: Institutet för miljömedicin (IMM) / Institute of Enviromental Medicine
Abstract
Humans as well as most mammals metabolize inorganic arsenic (Inorg As), a
recognized human carcinogen, by methylation. The end-metabolites
methylarsonic acid (MMA) and dimethylarsinic acid (DMA) are less toxic
and more readily excreted in the urine than Inorg As. Generally, people
exposed to arsenic have 10-30% Inorg As, 10- 20% MMA and 60-80% DMA in
urine, with considerable interindividual variation. Little is known about
factors influencing the metabolism in humans. The aim of the present
study was to investigate such factors e.g. age, ethnicity, and pregnancy
in people chronically exposed to arsenic via drinking water in two
villages in northern Argentina. Also, transfer of arsenic to the fetus
and human milk was studied.
For assessment of arsenic exposure, total arsenic concentrations in
drinking water, food, breast milk and blood (B- As) were determined using
hydride generation atomic absorption spectrophotometry (HGAAS), after dry
ashing. Concentrations of arsenic metabolites in urine (U-Asmet, i.e.
Inorg As+MMA+DMA; direct HG-AAS) and B- As were used as biomarkers of
exposure to Inorg As. In order to assess methylation capacity, arsenic
metabolites in urine and plasma were speciated. using ionexchange
chromatography and HG-AAS. Fetal exposure was investigated by
determination of arsenic concentrations in cord blood, placenta, matemal
blood and urine.
The concentration of arsenic in drinking water in the villages was about
200 µg As/L, which is considerably higher than the drinking water
guideline of 10 µg As/L recommended by the WHO. The staple food soup and
maize porridge had the highest concentrations of arsenic (300-400 µg
As/kg). The high arsenic exposure caused clearly elevated B-As and U-Asmet,
in the investigated children (n=57, age 3-15 yrs) and women (n=39, age
18-66 yrs). The B-As (10 µg As/L) was 10 times higher and the U-Asmet
(300-440 µg AsAL) was 30 times higher than in the control area, where the
water contained <1 µg As/L.
There was a unique pattern of arsenic metabolites in the urine,
characterized by the low urinary excretion of MMA (about 3%), compared to
more than 10% (often 10-20%) in other population groups studied. The data
indicate the existence of genetic polymorphism in the methylation of
arsenic. Interestingly, the individuals with low % MMA were of native
Andean origin and they seemed to retain less arsenic than people with
more MMA in urine.
Studies of intra- and inter-individual variation in the metabolism of
Inorg As showed a remarkably stable methylation from day-to-day, but a
slight diurnal variation. A pronounced inter-individual variation in
methylation (%DMA 51-8 1 %) was observed. Thus, the genetic influence
seemed to be more important than the environmental.
Another important finding was that children had significantly lower % DMA
(50%) and higher urinary % inorganic arsenic (about 47%) compared to the
women, but similar low %MMA. Thus, the results indicate lower arsenic
methylating capacity in children, and that children retain more arsenic
than adults.
The concentration of arsenic in cord blood was almost as high as, and
significantly correlated to, that in matemal blood in late gestation (9
and 11 µg As/L, respectively; r = 0.79). Thus, arsenic was readily
transferred to the human fetus. Essentially all arsenic in maternal
plasma and urine, cord plasma and infant urine was in the form of DMA,
indicating an increase in the arsenic methylation in late gestation and
that the fetus was mostly exposed to DMA prior to birth. This is
important from a toxicological point of view, as experimental studies
have indicated that DMA is less toxic to the embryo and fetus than Inorg
As.
In spite of the high concentrations of arsenic in maternal blood and
urine, the concentrations of arsenic in breast milk were low, on average
3 µg As/L. Breast feeding led to a decrease in the arsenic concentrations
in the urine of the infants during the nursing period.
List of papers:
I. Vahter M, Concha G, Nermell B, Nilsson R, Dulout F, Natarajan AT (1995). "A unique metabolism of inorganic arsenic in native Andean women. " Eur J Pharmacol 293(4): 455-62
Pubmed
II. Concha G, Vogler G, Nermell B, Vahter M (2001). "Intra-individual variation in the metabolism of inorganic arsenic." (Manuscript)
III. Concha G, Nermell B, Vahter MV (1998). "Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina. " Environ Health Perspect 106(6): 355-9
Pubmed
IV. Concha G, Vogler G, Lezcano D, Nermell B, Vahter M (1998). "Exposure to inorganic arsenic metabolites during early human development. " Toxicol Sci 44(2): 185-90
Pubmed
V. Concha G, Vogler G, Nermell B, Vahter M (1998). "Low-level arsenic excretion in breast milk of native Andean women exposed to high levels of arsenic in the drinking water. " Int Arch Occup Environ Health 71(1): 42-6
Pubmed
I. Vahter M, Concha G, Nermell B, Nilsson R, Dulout F, Natarajan AT (1995). "A unique metabolism of inorganic arsenic in native Andean women. " Eur J Pharmacol 293(4): 455-62
Pubmed
II. Concha G, Vogler G, Nermell B, Vahter M (2001). "Intra-individual variation in the metabolism of inorganic arsenic." (Manuscript)
III. Concha G, Nermell B, Vahter MV (1998). "Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina. " Environ Health Perspect 106(6): 355-9
Pubmed
IV. Concha G, Vogler G, Lezcano D, Nermell B, Vahter M (1998). "Exposure to inorganic arsenic metabolites during early human development. " Toxicol Sci 44(2): 185-90
Pubmed
V. Concha G, Vogler G, Nermell B, Vahter M (1998). "Low-level arsenic excretion in breast milk of native Andean women exposed to high levels of arsenic in the drinking water. " Int Arch Occup Environ Health 71(1): 42-6
Pubmed
Issue date: 2001-03-30
Publication year: 2001
ISBN: 91-628-4759-7
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