DNA adduct formation by 12 chemicals with populations potentially suitable for molecular epidemiological studies.

DNA adduct formation, route of absorption, metabolism and chemistry of 12 hazardous chemicals are reviewed. Methods for adduct detection are also reviewed and approaches to sensitivity and specificity are identified. The selection of these 12 chemicals from the Environmental Protection Agency list of genotoxic chemicals was based on the availability of information and on the availability of populations potentially suitable for molecular epidemiological study. The 12 chemicals include ethylene oxide, styrene, vinyl chloride, epichlorohydrin, propylene oxide, 4,4'-methylenebis-2-chloroaniline, benzidine, benzidine dyes (Direct Blue 6, Direct Black 38 and Direct Brown 95), acrylonitrile and benzyl chloride. While some of these chemicals (styrene and benzyl chloride, possibly Direct Blue 6) give rise to unique DNA adducts, others do not. Potentially confounding factors include mixed exposures in the work place, as well the formation of common DNA adducts. Additional research needs are identified.

Chlorination, water hardness and serum cholesterol in forty-six Wisconsin communities.

The Wisconsin Heart Health Research Program measured serum lipids and other clinical parameters among residents of 46 neighbouring small communities in central Wisconsin. The purpose of the study was to determine whether distribution of serum lipids, blood pressure or thyroid hormones differed according to the chlorination of water supply, or to its calcium and magnesium content (hardness). This report examines serum lipid levels in relation to the drinking water characteristics chlorination and hardness. Variables measured on individuals included age, education level, alcohol intake, cigarette smoking, dietary fat and dietary calcium. An analysis of covariance was used to estimate effects of chlorination and hardness on each of the serum lipids, with individual variables included as covariates. Among females, serum cholesterol (SC) levels are significantly higher in chlorinated communities than in non-chlorinated communities. Community SC levels are also higher for males in chlorinated communities, on the average, but differences are smaller and not statistically significant. Low density lipoprotein (LDL) cholesterol levels follow a similar pattern to that for total SC levels, higher in chlorinated communities for females, but not different for males. On the other hand, high density lipoprotein (HDL) cholesterol community means are nearly identical in the chlorinated and non-chlorinated communities for each sex.

Thyroid cancer risk in the population around the Nevada Test Site.

Potential thyroid cancer risk in Utah populations due to weapons testing fallout has been examined in two ways. Thyroid cancer incidence rates for Utah for the years 1973-77 were compared to those of the reporting areas of the Surveillance, Epidemiology and End Results Registry. In addition, numbers of lifetime thyroid cancer cases and distribution of probability of causation values for those cases have been estimated for a population of about 23,000 who were in the fallout area of three major shots at the Nevada Test Site during the 1950s. A computer program designed to estimate numbers of expected and excess cases occurring in the remaining lifetime after exposure was used to make the estimates. The estimates of internal dose distribution within various age at exposure groups were made using dose estimates developed by the Off-Site Radiation Exposure Review Project. The potential human risk from 131I at low doses is far from certain. The upper bound risk must be considered to be near that for low doses of acutely delivered external radiation to the thyroid. A practical upper limit for risk from low-dose 131I was taken to be one per million per rad-yr for males and four per million per rad-yr for females (although absolute upper limits would need to be higher). The upper bound estimate of excess cases in the lifetime of the population is about 13, compared to an estimate of about 58 cases expected to occur in the population on the basis of ordinary incidence. If excess risk is assumed to increase linearly with dose, and not to change with age, 12 of 13 excess cases fall into the group aged 18 and below at the time the dose occurred, and 11 of 13 excess cases fall into the group exposed to 10 rad or more.

Permissible concentrations of chemicals in air and water derived from RTECS entries: a "rash" chemical scoring system.

Many chemicals are of concern to human health, but only a few have epidemiologically derived risk estimates. About 45,000 chemicals are listed in RTECS, most of which have had some testing in subhuman models. RTECS entries range from cellular effects through organoleptic damage to lethality, with many pathological endpoints listed, including mutagenic changes, irritation, teratogenesis, cancer, mortality, etc. However, it is difficult to extend any biological test results to human risk assessments. If the results are extended, the degree of validity is highly uncertain. This paper describes a logical basis for using the entire complex spectrum of test results to evaluate the overall toxicological potency of a chemical to be assayed (i.e., an interviewing chemical) and describes how to derive tentative, permissible concentrations in air and water for any particular chemical for which no regulatory guidance exists. This approach has been tested for 16 reference chemicals discussed in NIOSH Criteria Documents, EPA-CAG reports, etc. The evaluations are uncomplicated, but occasionally it is difficult to match RTECS entries for two different chemicals. Difficult comparisons may require some familiarity with experimental design and the toxicological literature. One important product of this novel approach is that a distribution or array of potency values is obtained for any chemical evaluated. This distribution reflects many uncertainties stemming from low statistical power, experimental design, pharmacological processes, interspecies variability, dose rate, biological effect monitored, route of treatment, etc. The array of relative values for a particular chemical reflects many different biological and physical conditions. The distribution of the array helps to index a composite toxicological profile for many different biological effects resulting from numerous treatment protocols. To minimize the effect of extreme sensitivity of certain (perhaps novel) biological test models, possible errors in the RTECS data-base, and possible human pharmacological insensitivity to a particular chemical and/or a particular route of administration, we consider the interquartile range (i.e., the central 50%) of the array of relative potency values between two chemicals being compared as a practical measure of uncertainty. Thus, the range in response derived from variability in relative potency should be useful in addressing the range of response in man as estimated from extrapolations of test data.

Laryngeal cancer and occupational exposure to sulfuric acid.

Workers on an ethanol unit which used sulfuric acid in strong concentrations at a large refinery and chemical plant in Baton Rouge, Louisiana were reported, in 1979, at excess risk for upper respiratory cancer. The carcinogen implicated by indirect evidence was diethyl sulfate. However, with the continued use of sulfuric acid in the same plant, and with additional cases not attributable to the ethanol process, the hypothesis of an association between sulfuric acid exposure and upper respiratory cancer was tested. Each of 50 confirmed cases of upper respiratory cancer diagnosed between 1944 and 1980, was matched to at least three controls on sex, race, age, date of initial employment, and duration of employment. Thirty-four of the 50 cases were laryngeal cancers. Data were obtained from existing plant records. Retrospective estimates of exposure were made without regard to case or control status. Findings from conditional logistic regression techniques were supported by other statistical methods. Among workers classified as potentially highly exposed, four-fold relative risks for all upper respiratory cancer sites combined were exceeded by the relative risk for laryngeal cancer specifically. Exposure-response and consistency across various comparisons after controlling statistically for tobacco-use, alcoholism and other previously implicated risk factors, suggest increased cancer risk with higher exposure.

The measurement and interpretation of proportionate mortality.

The standardized proportionate mortality ratio (SPMR) is shown to be a summary measure which is a weighted average of age-specific proportionate mortality ratios which uses an internally derived set of standard weights. As with any summary measure, the SPMR is only meaningful when the stratum-specific values can be judged to represent a common value. When stratum-specific values are not homogeneous, the use of the stratum-specific values themselves is more appropriate than the use of a summary measure. A test for homogeneity of the age-specific proportionate mortality ratios is presented. The test also provides an estimate of the common value and its variance, when that single parameter can be presumed to exist. A procedure of external standardization is presented which uses weights derived from the standard population.