A dose-response and susceptibility investigation of skin keratoses
and hyperpigmentation caused by arsenic in drinking water
Allan H. Smith1, Reina Haque1, D.N. Guha
Mazumder2, Binay K. De2, Nilima Ghosh2,
Soma Mitra2, David Kalman3
1. University of California, Berkeley
2. Institute of Post Graduate Medical Education and Research,
3. University of Washington, Seattle
Background, project goals and objectives
Keratoses and hyperpigmentation are hallmark dermal signs of arsenic
toxicity. Keratoses are hard raised lesions that appear on the palms and
soles. Hyperpigmentation is marked by raindrop shaped diffuse dark spots
on the trunk and limbs. The first detailed assessment of the dose-response
relationship of arsenic induced keratoses and hyperpigmentation is underway
by our group, and a key objective is to determine if susceptibility varies
by arsenic methylation capability and nutritional factors, such as methionine
and cysteine. Arsenic methylation will be assessed by urinary assays. Nutritional
status will be determined by blood measurements of key macronutrients and
micronutrients as well as by analysis of a dietary questionnaire.
A case-control study has commenced which takes advantage of the largest
population-based survey conducted in an arsenic-affected area of West Bengal,
India. The landmark cross-sectional survey, conducted between 1995 and
1996, included over 7000 participants, 400 of whom were found to have arsenic-induced
skin lesions. Approximately 280 of the 400 individuals with skin lesions
were exposed to drinking water containing less than 500 *g/l of inorganic
arsenic. These 280 individuals comprise the case group for our present
investigation. The control group consists of lesion-free individuals randomly
selected from the cross-sectional survey database, and matched on age and
sex. Data obtained from personal interviews and chemical analyses of drinking
water samples will be used to assess arsenic exposure. The interviews consist
of questions about lifetime residential history, water sources at work,
and fluid consumption. The clinical exam involves various dermatologic,
neurologic, respiratory, and hepatic endpoints. A dietary questionnaire
supplemented with results of blood assays will be used to ascertain the
participants' nutritional status. Urinary assays will be used to determine
arsenic methylation efficiency.
The interviews and sample collection commenced June 1998. Our field
team reached its target rate of 5 interviews per week. To date, a little
over a 100 participants have been seen. Approximately 50 urine and blood
samples have been transported to the U.S. for analyses. Significance of
findings By building upon an existing study, the present investigation
was specifically designed to identify the shape of the dose-response curve
for arsenic and skin lesions, and to determine where a threshold might
lie. The study will also identify potential susceptibility factors, and
thereby reduce the uncertainty in generalizing risk to other populations.
Because keratoses and hyperpigmentation are the most common and earliest
occurring endpoints of chronic ingestion, and because evidence suggests
that these skin lesions are biomarkers of subsequent cancer risks, this
study will significantly contribute to a fuller understanding of the long
term health effects of consuming water containing low levels of arsenic.
Interviewing and sample collection will continue in India while data
entry, and analyses of urine and blood samples will continue in the U.S.
Approximately 400 individuals will be recruited by December 1999 (200 cases
and 200 controls).
Corresponding author: Allan H. Smith, M.D., Ph.D., University of
California, Berkeley, School of Public Health, 140 Warren Hall, Berkeley,
CA 94720-7360, USA.