ARSENIC HEALTH EFFECTS RESEARCH PROGRAM

PROJECTS

PRESENTATIONS

APPENDICES

Berkeley

University of California

Bladder Cancer Mortality Associated With Arsenic In Drinking Water In Argentina
Hopenhayn-Rich C, Biggs ML, Fuchs A, Bergoglio R, Tello E, Nicolli H, Smith AH.
Epidemiology, 1996 Mar;7(2):117-24. Erratum in: Epidemiology 1997 May;8(3):334.

Bladder cancer mortality for the years 1986-1991 was investigated in Córdoba, Argentina in an ecological study comparing counties categorized as previously having high, medium and low water levels of arsenic. The average water arsenic level in the two high exposure counties for arsenic contaminated water sources was 178 ug/L. Clear trends in bladder cancer mortality were shown up to standardized mortality ratios (SMRs) of 2.14 for men (95% CI 1.78-2.53) and 1.82 for women (95% CI 1.19-2.64) in the two high exposure counties. The clear trends found in a population with a different ethnic composition and a high protein diet support the evidence from Taiwan that arsenic in drinking water is a cause of human bladder cancer. While it was made clear that exposure was not uniform within counties, it was noted the findings were roughly consistent with risks which might be predicted from the Taiwan studies.

 

Intraocular melanoma linked to occupations and chemical exposures
Holly EA, Aston DA, Ahn DK, Smith AH.
Epidemiology, 1996 Jan;7(1):55-61.

We conducted a case-control study in the western United States to determine the relation between occupations or chemical exposures and increased risk of uveal melanoma. Among men (221 patients, 447 controls), we found increased risks for occupational groups who had intense exposure to ultraviolet light [odds ratio (OR) = 3.0; 95% confidence interval (CI) = 1.2-7.8], welding exposure (OR = 2.2; 95% CI = 1.3-3.5), and asbestos exposure (OR = 2.4; 95% CI = 1.5-3.9 for most likely exposed). The highest odds ratio was for the small number of men (nine cases, three controls) who were chemists, chemical engineers, and chemical technicians (OR = 5.9; 95% CI = 1.6-22.7). Odds ratios also were elevated for exposures to antifreeze, formaldehyde, pesticides, and carbon tetrachloride, but these findings, based on recall of specific chemical exposures, are more subject to recall bias than the findings based on occupational groups.

 

Meta-analysis of studies of lung cancer among silicotics
Smith AH, Lopipero PA, Barroga VR.
Epidemiology, 1995 Nov;6(6):617-24.

Summary findings from the Nevada bladder cell micronucleus study, with preliminary results from the Chile study, were reported. It was concluded that results from both the North and South American studies provided evidence that arsenic is genotoxic to human bladder epithelium. Further details are given in Warner et al, 1994, Moore et al. 1997, and Moore et al. 1997

 

Increased Bladder Cell Micronuclei Found In Two Populations Environmentally Exposed To Arsenic In Drinking Water
Moore L, Smith AH, Hopenhayn-Rich C, Biggs ML, Warner ML, Kalman D, Smith MT.
Clin Chem, Dec 1995 41(12): 1915-7.

Summary findings from the Nevada bladder cell micronucleus study, with preliminary results from the Chile study, were reported. It was concluded that results from both the North and South American studies provided evidence that arsenic is genotoxic to human bladder epithelium. Further details are given in Warner et al, 1994, Moore et al. 1997, and Moore et al. 1997

 

 

Case-Control Study Of Bladder Cancer And Arsenic In Drinking Water
Bates MN, Smith AH, Cantor KP.
Am J Epidemiol, 1995 Mar 15;141(6):523-30.

Cases and controls from the National Bladder Cancer Study were used in this project, which was conducted in collaboration with Dr.Ken Cantor of the National Cancer Institute. Information concerning arsenic levels in drinking water was added to this dataset for respondents from Utah.Water levels ranged from 0.5 to 160 ug/L, but only three towns were served with water containing over 20 ug/L of arsenic. There was no overall association of inorganic arsenic with the risk of bladder cancer at these levels of exposure. However, among cigarette smokers, time window analysis yielded some evidence for a dose-response relationship for exposure to arsenic in drinking water 10-39 years prior to diagnosis with bladder cancer. The possibility was raised that smoking potentiates the effect of arsenic in causing bladder cancer.However, the discrepancy between these findings at such low exposure levels, and predictions based on studies in Taiwan and England, also raised the possibility of bias in the data. It was concluded that further carefully conducted studies in exposed populations were needed.

 

Increased micronuclei in exfoliated bladder cells of persons who chronically ingest arsenic contaminated water in Nevada
Warner M, Moore L, Smith MT, Kalman D, Fanning E, Smith AH.
Cancer Epidemiol Biom & Prev, 3: 583-90, 1994.

This study involved 18 subjects in Nevada whose well water contained on average 1312 ug/L of arsenic, and 18 age and sex matched controls whose well water averaged 16 ug/L. Exposed subjects had a 1.8 fold increase in bladder cell micronuclei, but the differences were largely confined to males. The absence of findings for females was thought to be due to the fact that women exfoliate large numbers of cells into urine, while men exfoliate predominantly transitional cells, which are the cells involved in bladder cancer. No increase was found in buccal cell micronuclei among the arsenic exposed group.

 

 

Epidemiological study designs to address potential high bladder cancer risks from arsenic in drinking water
Smith AH, Hopenhayn-Rich C, Biggs ML, Moore L, Dale J, Warner M, Bates M, Engel R
In: Chappell WR, Abernathy CO, Cothern CR (eds):
Arsenic: Exposure and Health, Northwood: Science and Technology Letters: 109-17, 1994.

Bladder cancer risks are markedly elevated in areas of Taiwan with high arsenic levels in drinking water. Limited data from studies elsewhere provide some support for a causal association, but confirmatory studies are needed. In this paper we outline various study designs which could be used to provide further information, including ecological studies, cohort studies, case-control studies, and biomarker studies. Advantages and disadvantages of each study are given and illustrated with features of actual studies, including ones in progress or being planned by our group in California, Nevada, and northern Chile. Traditional epidemiological studies suffer from problems due to the rarity of bladder cancer, the long latency between exposure and disease manifestation, and realtively small numbers of people exposed at high levels. The main advantages of biomarker studies using exfoliated bladder cells are that small studies can be conducted rapidly, accurate exposure data can be obtained, and the effect of intervention by providing water low in arsenic can be assessed. However, the interpretation of biomarker studies is open to question. It is concluded that the potential risks of bladder cancer from ingested arsenic in drinking water warrant a concerted epidemiological approach using a variety of different study designs.

 

Assessment of cancer clusters using limited cohort data with spreadsheets: application to a leukemia cluster among rubber workers
Smith AH, Duggan HM, Wright C
Am J Ind Med, 1994 Jun;25(6):813-23.

This paper presents methods for initial investigation of occupational cancer clusters using limited data. Phase 1 of the methods developed uses basic data from the cluster of cases, but with cohort data limited to the size of the workforce at the plant. Phase 2 of the methods requires knowledge of the number of workers entering and leaving the workforce in each year. In the absence of data concerning age, the spreadsheet programs explore a variety of worker age distributions in synthetic cohort analyses. The methods were used to assess a cluster of six cases of leukemia with an average duration of work of 11 years in a tire manufacturing plant. It was concluded that the relative risk for the age range 30-50 was at least 7, providing further evidence for the association of leukemia with work in tire manufacture. The use of spreadsheet programs can provide a valuable first step assessment of apparent workplace cancer clusters.

 

Vascular effects of chronic arsenic exposure: a review
Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH.
Epidemiol Rev, 1994;16(2):184-209.

Existing literature concerning vascular effects from chronic exposure to inorganic arsenic was reviewed in this publication containing 177 citations. It was concluded that there was good epidemiologic evidence indicating that chronic arsenic consumption at high levels is a cause of severe peripheral vascular disease with resulting gangrene and amputations of the limbs. We hypothesized that marginal zinc status might explain the differential occurrence of these conditions in populations ingesting large doses of arsenic. It was also concluded that it was plausible, though epidemiologic evidence is limited, that arsenic might cause increases in vascular mortality beyond that found in patients with severe peripheral vascular disease.

 

Arsenic in drinking water and mortality from vascular disease: an ecologic analysis in 30 U.S. counties
Engel RR, Smith AH.
Arch Environ Health 1994 Sep-Oct;49(5):418-27.

An investigation was made of the ecological relationship between arsenic concentrations in drinking water and mortality from circulatory disease in 30 U.S. counties from 1968 to 1984. Mean arsenic levels ranged from 5.4 to 91.5 ug/L. The standardized mortality ratios (SMRs) for diseases of arteries, arterioles, and capillaries for counties exceeding 20 ug/L were 1.9 (90% CI 1.7-2.1) for females and 1.6 (CI 1.5-1.8) for men. The SMRs for congenital anomalies of the heart and circulatory system were also elevated. Possible problems with the ecological study design and explanations for potentially spurious results were discussed. It was concluded that further investigation of vascular effects of arsenic exposure was warranted.

 

Alpha-fetoprotein: a biomarker for pregnancy outcome
Smith AH, Hopenhayn-Rich C, Warner M, Biggs ML, Moore L, Smith MT.
Epidemiology, 1993 Sep;4(5):471-6.

Biological markers of effect of toxic human exposures have the potential to allow exploration of dose-response relationships at levels of exposure lower than those which can be assessed by traditional epidemiological studies involving the ultimate disease end-point. In this paper we give reasons for proposing that exfoliated bladder cell micronuclei might be a good marker for carcinogenic effects of ingestion of inorganic arsenic. Based on studies in Taiwan, it was noted that the highest internal cancer relative risks involved bladder cancer. Bladder cells can be collected from urine, and originate from a target organ of particular importance for arsenic effects. We described several studies from our group, which used bladder cell micronuclei as biomarkers, noting the important potential contribution of intervention studies incorporating cessation of exposure.

 

Rationale for selecting exfoliated bladder cells micronuclei as potential biomarkers for arsenic genotoxicity
Smith AH, Hopenhayn-Rich C, Warner M, Biggs ML, Moore L, Smith MT.
J Toxicol Environ Health, 1993 Oct-Nov;40(2-3):223-34.

Biological markers of effect of toxic human exposures have the potential to allow exploration of dose-response relationships at levels of exposure lower than those which can be assessed by traditional epidemiological studies involving the ultimate disease end-point. In this paper we give reasons for proposing that exfoliated bladder cell micronuclei might be a good marker for carcinogenic effects of ingestion of inorganic arsenic. Based on studies in Taiwan, it was noted that the highest internal cancer relative risks involved bladder cancer. Bladder cells can be collected from urine, and originate from a target organ of particular importance for arsenic effects. We described several studies from our group, which used bladder cell micronuclei as biomarkers, noting the important potential contribution of intervention studies incorporating cessation of exposure.

 

Elevated blood pressure in treated hypertensives with low-level lead accumulation
Sharp DS, Osterloh J, Becker CE, Smith AH, Holman BL, Fisher JM.
Arch Environ Health, 1989 Jan-Feb 44(1): 18-22.

The relationship between blood pressure (BP) and blood lead concentration (PbB) was examined in 51 bus drivers who were treated for hypertension. These drivers were a subset of a representative sample (N = 342) of the driver population (N = approximately 2,000), and were not selected for hypertension or lead exposure. Blood lead concentrations ranged from 2-24 micrograms/dl (median: 6.9 micrograms/ld). There were 33 subjects treated primarily with diuretics, and 18 subjects were treated with beta blockers. Adjusted regression coefficients relating systolic BP with PbB were -6.4 +/- 11.4 and 4.5 +/- 12.9 mmHg/In(micrograms/dl) in each group, respectively, but were not statistically significant. The adjusted coefficients for diastolic BP were 1.12 +/- 3.89 and 14.3 +/- 5.69 mmHg/In(micrograms/dl) (p = 0.036), respectively. The latter relationship represents an average increment of 12 mmHg in diastolic BP over the range of observed PbBs (2.0 to 11.4 micrograms/dl) in subjects treated with beta blockers. Thus, beta blocker therapy may be less effective in reducing diastolic pressure in individuals with higher PbBs and suggests an action of lead at PbBs below current standards.

Once the concentration in sediment was calculated, fish-to-sediment ratios for the various dioxin and furan isomers from published field and laboratory studies were utilized to project fish concentrations.

The described method was incorporated into a risk assessment for a resource recovery facility. The analysis found that if an indvidual received 5 percent of an average daily freshwater fish intake from the potentially contaminated lake, this exposure pathway would comprise 40 percent of the toal daily dioxin equivlalent intake from all pathways of exposure. It is apparent that ingestion of contaminated fish may be an important exposure pathway and that potential contamination of fish should be closely evaluated in the risk assessment of dioxins and furans emitted from waste incineration plants.

 

A method for estimation of fish contamination from dioxins and furans emitted by resource recovery facilities
Goeden HM, Smith AH.
In:
Bonin JJ, Stevenson DE (eds): Advances in Risk Analysis, vol 7, New York: Plenum Press, 1989

A new method for calculating fish contamination resulting from dioxin and furan emissions have been developed. The method is based on the fact that the major determinant of fish dioxin and furan concentration is sediment. Estimates of the sediment concentration were made under the following assumptions: (1) bottom burial of sediment is the only significant removal pathway; (2) suspended sediment concentration is in equilibrium with the top layer of the bottom sediment; and (3) at steady state the newly deposited particulate will have the same concentration of dioxins and furans as a lake sediment. Under these assumptions it is only necessary to calculate the concentration of dioxins and furans in the particulate matter entering the lake or pond through air deposition and runoff. Deposition on the lake surface and indirectly from runoff of the surrounding contaminated watershed area.

Once the concentration in sediment was calculated, fish-to-sediment ratios for the various dioxin and furan isomers from published field and laboratory studies were utilized to project fish concentrations.

The described method was incorporated into a risk assessment for a resource recovery facility. The analysis found that if an indvidual received 5 percent of an average daily freshwater fish intake from the potentially contaminated lake, this exposure pathway would comprise 40 percent of the toal daily dioxin equivlalent intake from all pathways of exposure. It is apparent that ingestion of contaminated fish may be an important exposure pathway and that potential contamination of fish should be closely evaluated in the risk assessment of dioxins and furans emitted from waste incineration plants.

 

Estimation of human exposure from fish contaminated with dioxins and furans emitted by a resource-recovery facility
Goeden HM, Smith AH.
Risk Anal, 1989 Sep 9(3):377-83.

Ingestion of contaminated fish can be an important human exposure pathway for dioxins and furans emitted from waste incineration plants. A new method for calculating fish contamination resulting from dioxin and furan emissions has been developed to overcome some of the problems of those currently used. The method is based on evidence that the major determinant of fish dioxin and furan uptake is sediment concentrations. Only two steps are necessary to calculate fish tissue levels. Step 1: Calculation of the concentration of dioxins and furans in particulate matter entering the lake or pond, and hence, the resulting sediment concentration. Step 2: Calculation of fish concentrations utilizing fish-to-sediment ratios for the various dioxin and furan isomers.

 

 

 

2470 Telegraph Avenue, Suite 301, Berkeley, CA  94704  Tel: (510) 990-8354    Email: asrg@berkeley.edu