Daniel M. Byrd

Arsenic in drinking water and bladder cancer mortality in the United States: an analysis based on 133 u.s.counties and 30 years of observation.

This study analyzes the relationship between arsenic exposure through drinking water and bladder cancer mortality. The county-specific white male bladder cancer mortality data (1950–1979) and county-specific groundwater arsenic concentration data were obtained for 133 U.S. counties known to be exclusively dependent on groundwater for their public drinking water supply. No arsenic-related increase in bladder cancer mortality was found over the exposure range of 3 to 60 &mgr;g/L using stratified analysis and regression analyses (both unweighted and weighted by county population and using both mean and median arsenic concentrations). These results, which provide a direct estimate of arsenic-related cancer risk for U.S. residents, exclude the National Research Council’s 2001 risk estimate that was based on Southwest Taiwan data and required adjusting for differences between the body mass and water consumption rates of U.S. and Taiwanese residents.

Carcinogenic risks of inorganic arsenic in perspective.

Induction of cancer by inorganic arsenic occurs inconsistently between species and between routes of exposure, and it exhibits different dose-response relationships between different target organs. Inhaled or ingested arsenic causes cancer in humans but not in other species. Inhaled arsenic primarily induces lung cancer, whereas ingested arsenic induces cancer at multiple sites, including the skin and various other organs. Cancer potency appears to vary by route of exposure (ingestion or inhalation) and by organ site, and increases markedly at higher exposures in some instances. To understand what might explain these inconsistencies, we reviewed several hypotheses about the mechanism of cancer induction by arsenic. Arsenic disposition does not provide satisfactory explanations. Induction of cell proliferation by arsenic is a mechanism of carcinogenesis that is biologically plausible and compatible with differential effects for species or differential dose rates for organ sites. The presence of other carcinogens, or risk modifiers, at levels that correlate with arsenic in drinking water supplies, may be a factor in all three inconsistencies: interspecies specificity, organ sensitivity to route of administration, and organ sensitivity to dose rate.

Neonatal thyroid‐stimulating hormone level and perchlorate in drinking water

BACKGROUND The effect of perchlorate in drinking water on neonatal blood thyroid-stimulating hormone (thyrotropin; TSH) levels was examined for Las Vegas and Reno, Nevada. METHODS The neonatal blood TSH levels in Las Vegas (with up to 15 microg/L (ppb) perchlorate in drinking water) and in Reno (with no perchlorate detected in the drinking water) from December 1998 to October 1999 were analyzed and compared. The study samples were from newborns in their first month of life (excluding the first day of life) with birth weights of 2, 500-4,500 g. A multivariate analysis of logarithmically transformed TSH levels was used to compare the mean TSH levels between Las Vegas and Reno newborns, with age and sex being controlled as potential confounders. RESULTS This study of neonatal TSH levels in the first month of life found no effect from living in the areas with environmental perchlorate exposures of </=15 microg/L (P = 0.97). CONCLUSIONS This study, which was sensitive enough to detect the effects of age and gender on neonatal blood TSH levels, detected no effect from environmental exposures to perchlorate.

Chronic myelogenous leukemia and benzene exposure: A systematic review and meta-analysis of the case–control literature☆

Benzene exposure is well demonstrated as a cause of acute myelogenous leukemia, but not of chronic myelogenous leukemia. Previous literature reviews based on case series and cohort studies have not shown an association. We have now conducted a literature search for case-control studies that examine the association between benzene exposure and chronic myelogenous leukemia. Six case-control studies have been found. These derive from occupational groups, cancer registries, and a clinical laboratory. Their exposure ascertainments are all based on job histories, job-exposure matricies, or industrial hygiene data. The odds ratios (ORs) for individual studies range from 0.73 to 1.2. The pooled OR is 1.003 with 95% confidence interval (CI) of 0.94-1.07 (p=0.98) for both a fixed effects model and a random effects model. The case-control literature indicates that chronic myelogenous leukemia does not appear to be related to benzene exposure.

An Epidemiologic Study of Arsenic-Related Skin Disorders and Skin Cancer and the Consumption of Arsenic-Contaminated Well Waters in Huhhot, Inner Mongolia, China

ABSTRACT Well-use histories were obtained and dermatological examinations were conducted for 3,179 of the 3,228 (98.5%) residents of 3 villages in Inner Mongolia with well water arsenic levels as high as 2,000 ppb (ug/L). Eight persons were found to have skin cancer, 172 had hyperkeratoses, 121 had dyspigmentation, 94 had both hyperkeratoses and dyspigmentation, and, strikingly, none had Blackfoot disease. All 8 subjects with skin cancer also had both hyperkeratoses and dyspigmentation. Arsenic levels were measured for 184 wells and individual well-use histories were obtained. Arsenic exposure histories were summarized as both highest arsenic concentration (highest exposure level for at least 1-year duration) and cumulative arsenic exposure (ppb-years). Sixty-nine percent of the participants had highest arsenic concentrations below 100 ppb; 71% had cumulative arsenic exposures below 2,000 ppb-years. Exposure-response analyses included frequency-weighted, simple linear regression, and most-likely estimate (hockey-stick) models. Skin cancer cases were only found for those with a highest arsenic concentration greater than 150 ppb, and those with exposure less than 150 ppb had a statistically significant deficit. A frequency-weighted model showed a threshold at 150 ppb, and a hockey-stick model showed a threshold at 122 ppb. Considerations of duration, age, latency, and misclassification did not appear to markedly affect the analysis. The non-malignant skin findings showed thresholds of 40–50 ppb in the hockey-stick models. Application of these analytic models to the data from other epidemiological studies of arsenic ingestion and malignant and non-malignant skin disorders can be used to examine patterns of arsenic carcinogenicity.

Organ Specificity of Rodent Tumor Induction: A Test of Statistical and Graphical Methods by Examination of Tumor Induction from Ingestion of Selected Substances

With few exceptions current federal risk assessment policy regards the induction of tumors at one site as equivalent to the induction of tumors at any other site for purposes of risk assessment.1 Sufficient bioassay data exist to test this policy with the closely related rodent species, mouse and rat.

Multiplicity Reactivation of 5-Iodouracil-Substituted, Nonviable Bacteriophage T4td8

Nonviable, 5-iodouracil (IUra)-substituted bacteriophage T4td8 can be multiplicity reactivated. The data indicate that two nonviable, IUra-substituted T4td8 phage can complement each other intracellularly to produce viable progeny. Phage particles in lysates of T4td8-infected Escherichia coli BT−, prepared in the presence of varying mole fractions of IUra plus thymine, were examined by infecting with low and high dilutions of lysate. The yields of multiplicity reactivable particles were identical, regardless of the mole fractions of IUra present in the growth media. However, the yields of viable phage, measured at low multiplicities of infection, decreased with increasing mole fraction of IUra. The results are consistent with the hypothesis that the lethal effect of IUra is a consequence of its incorporation into DNA. Further, the IUra-induced lesion cannot involve genetic damage that shuts off expression at a single region of the genome.

Lethal and Mutagenic Effects of 5-Iodouracil on Bacteriophage T4td8rII

Evidence was obtained which indicates that the lethal effect of 5-iodouracil (IUra) on bacteriophage T4 is not due to a mutagenic process. T4td8rII (thymine requiring, rapid lysis) double mutants were constructed. Reversion of T4td8rII to r+ was measured. First, reversion by growth in the presence of the structural analogues chlorouracil (ClUra) and bromouracil (BrUra) did not correlate with their relative lethal effects (for mutagenesis: IUra ≤ ClUra ≤ BrUra; for lethality: ClUra < BrUra < IUra). Second, reversion frequencies of T4td8rII in infected cells increased linearly with time of growth in the presence of IUra, whereas the frequency of lethality was constant with time. Third, reversion frequencies increased markedly at low levels of IUra substitution, whereas lethal effects were apparent only with extensive IUra substitution. Fourth, the reversion frequency of the nonviable fraction of IUra-substituted T4td8rII (as examined by multiplicity reactivation) did not differ significantly from that of the viable IUra-substituted T4td8 fraction. If mutagenesis caused lethality, then the nonviable T4td8rII fraction should accumulate mutations and have a higher reversion frequency.

Endocrine Modulation and the Federal Government

Recent events have drawn attention to the hypothesis that some xenobiotics in the environment may elicit toxicities in humans by modulating endocrine pathways. From the perspective of regulatory toxicology, pursuit of this hypothesis w ill prove difficult, because current risk assessment m ethods do not readily apply to substances with very high potencies, reversibility, transgener-ational effects, and subtle biological outcomes. Such xenobiotics typically persist in the body and bioaccumulate in the food chain. Yet the exposures are important only during critical periods of vulnerability, and no sustained bio-markers of these important exposures currently exist. This article describes some recent efforts by federal agencies to pursue the hypothesis, including research planning and screening of potential endocrine modulating xenobiotics and risk assessment of dioxin conflicts with its policy for substances that cause thyroid follicular carcinomas.

Measurement Uncertainty in Epidemiological Studies of Two Cohorts Exhibiting Benzene-Induced Leukemia

This paper reviews several epidemiology papers by Vigliani and his coworkers about benzene-associated leukemia in the Milan and Pavia areas of Italy. Although the data have generally been thought not suitable for risk assessment, we find that the application of expert judgment and a previously developed combinatorial procedure successfully yields a description of the range of risk of benzene-associated leukemias in these studies. We also compare this risk distribution to that obtained with the same model and data from risk assessments of a study by Rinsky, Young and coworkers about benzene-exposed workers in Ohio. The leukemogenic risks of benzene differ between the two cohorts but are not inconsistent. Based on a probability distribution representing an aggregate of opinions, however, experts’ uncertainty about risk in the Italian cohort exceeds the assessors’ uncertainty about risk in the Ohio cohort.